Treatment of tumors in subjects having FGL-1 positive samples

Abstract

The disclosure provides a method of treating a tumor in a human subject in need thereof with an immunotherapy when a sample of the subject's tumor, plasma, or serum is FGL-1 positive. The disclosure also provides methods of selecting a tumor in a human subject for an immunotherapy and selecting a human subject afflicted with a malignant tumor for an immunotherapy when a sample of the subject's tumor, plasma, or serum is FGL-1 positive. Corresponding methods with a population of human subjects are also provided. The immunotherapy includes a LAG-3 antagonist (e.g., an anti-LAG-3 antibody) alone or in combination with a PD-1 pathway inhibitor (e.g., an anti-PD-1 antibody).

Description

TREATMENT OF TUMORS IN SUBJECTS HAVING FGL-1 POSITIVE SAMPLES CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This PCT application claims the priority benefit of U.S. Provisional Application No. 63 / 651,830, filed May 24, 2024, which is incorporated herein by reference in its entirety. REFERENCE TO SEQUENCE LISTING SUBMITTED ELECTRONICALLY

[0002] The content of the electronically submitted sequence listing (Name: 3338_340PC01_Seqlisting_ST26; Size: 101,707 bytes; and Date of Creation: May 23, 2025) is herein incorporated by reference in its entirety. FIELD OF THE INVENTION

[0003] The present disclosure provides a method of treating a tumor in a human subject in need thereof comprising administering to the subject an immunotherapy comprising a lymphocyte activation gene-3 (LAG-3) antagonist, a method of selecting a tumor in a human subject for an immunotherapy comprising a LAG-3 antagonist, a method of selecting a human subject afflicted with a tumor for an immunotherapy comprising a LAG- 3 antagonist, wherein a sample of the subject’s tumor, plasma, or serum is fibrinogen-like protein 1 (FGL-1) positive, and corresponding methods comprising a population of human subjects. BACKGROUND OF THE INVENTION

[0004] FGL-1 is a ligand for LAG-3. However, methods of treating tumors with immunotherapies comprising LAG-3 antagonists, such as combination therapy with anti- LAG-3 and anti-PD-1 antibodies, have not been established with respect to FGL-1 expression levels.

[0005] There is a need for improved methods for treating tumors in human subjects, including populations of human subjects, with immunotherapies comprising LAG-3antagonists as well as selecting tumors, human subjects, and populations of human subjects for treatment with immunotherapies comprising LAG-3 antagonists. SUMMARY OF THE INVENTION

[0006] The present disclosure is directed to a method of treating a tumor in a human subject in need thereof, the method comprising administering to the subject an immunotherapy comprising a lymphocyte activation gene-3 (LAG-3) antagonist, wherein a sample of the subject’s tumor is fibrinogen-like protein 1 (FGL-1) positive. In some aspects, the method further comprises determining the level of FGL-1 expression in the sample prior to administering the immunotherapy.

[0007] The present disclosure is directed to a method of treating tumors in a population of human subjects in need thereof, the method comprising administering to each subject in the population an immunotherapy comprising a LAG-3 antagonist, wherein a sample of each subject’s tumor in the population is FGL-1 positive. In some aspects, the method further comprises determining the level of FGL-1 expression in the sample prior to administering the immunotherapy.

[0008] The present disclosure is directed to a method of selecting a tumor in a human subject for an immunotherapy comprising a LAG-3 antagonist, comprising: (a) determining the level of FGL-1 expression in a sample of the subject’s tumor; and (b) administering the immunotherapy to the subject if the sample is FGL-1 positive.

[0009] The present disclosure is directed to a method of selecting tumors in a population of human subjects for an immunotherapy comprising a LAG-3 antagonist, comprising: (a) determining the level of FGL-1 expression in a sample of each subject’s tumor in the population; and (b) administering the immunotherapy to the subject if the sample is FGL- 1 positive.

[0010] The present disclosure is directed to a method of selecting a human subject afflicted with a tumor for an immunotherapy comprising a LAG-3 antagonist, comprising: (a) determining the level of FGL-1 expression in a sample of the subject’s tumor; and (b) administering the immunotherapy to the subject if the sample is FGL-1 positive.

[0011] The present disclosure is directed to a method of selecting a population of human subjects afflicted with tumors for an immunotherapy comprising a LAG-3 antagonist, comprising: (a) determining the level of FGL-1 expression in a sample of a tumor from ahuman subject, wherein the subject is a member of the population selected for the immunotherapy if the sample is FGL-1 positive; and (b) administering the immunotherapy to each subject in the population.

[0012] In some aspects, at least about 1% of tumor cells in the sample express FGL-1.

[0013] In some aspects, less than about 95%, less than about 90%, less than about 85%, less than about 80%, less than about 75%, less than about 70%, less than about 65%, less than about 60%, less than about 55%, less than about 50%, less than about 45%, less than about 40%, less than about 35%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, or less than about 5% of tumor cells in the sample express FGL-1.

[0014] In some aspects, about 1% to about 100%, about 1% to about 95%, about 1% to about 90%, about 1% to about 85%, about 1% to about 80%, about 1% to about 75%, about 1% to about 70%, about 1% to about 65%, about 1% to about 60%, about 1% to about 55%, about 1% to about 50%, about 1% to about 45%, about 1% to about 40%, about 1% to about 35%, about 1% to about 30%, about 1% to about 25%, about 1% to about 20%, about 1% to about 15%, about 1% to about 10%, or about 1% to about 5% of tumor cells in the sample express FGL-1.

[0015] In some aspects, FGL-1 expression has been determined from an immunohistochemistry assay.

[0016] In some aspects, the sample comprises a histoscore (H-score) of 1 to 300 according to the formula: (1 × percentage of tumor cells in the sample with weak FGL-1 expression) + (2 × percentage of tumor cells in the sample with moderate FGL-1 expression) + (3 × percentage of tumor cells in the sample with strong FGL-1 expression). In some aspects, the H-score is a manual calculation. In some aspects, the H-score is an automated calculation by image analysis software.

[0017] In some aspects, the sample is LAG-3 positive. In some aspects, the method further comprises determining the level of LAG-3 expression in the sample prior to administering the immunotherapy.

[0018] In some aspects, the sample is programmed death ligand-1 (PD-L1) negative. In some aspects, the method further comprises determining the level of PD-L1 expression in the sample prior to administering the immunotherapy.

[0019] The present disclosure is directed to a method of treating a tumor in a human subject in need thereof, the method comprising administering to the subject an immunotherapy comprising a lymphocyte activation gene-3 (LAG-3) antagonist, wherein a sample of the subject’s plasma or serum is FGL-1 positive. In some aspects, the method further comprises determining the level of FGL-1 expression in the sample prior to administering the immunotherapy.

[0020] The present disclosure is directed to a method of treating tumors in a population of human subjects in need thereof, the method comprising administering to each subject in the population an immunotherapy comprising a LAG-3 antagonist, wherein a sample of each subject’s plasma or serum in the population is FGL-1 positive. In some aspects, the method further comprises determining the level of FGL-1 expression in the sample prior to administering the immunotherapy.

[0021] The present disclosure is directed to a method of selecting a tumor in a human subject for an immunotherapy comprising a LAG-3 antagonist, comprising: (a) determining the level of FGL-1 expression in a sample of the subject’s plasma or serum; and (b) administering the immunotherapy to the subject if the sample is FGL-1 positive.

[0022] The present disclosure is directed to a method of selecting tumors in a population of human subjects for an immunotherapy comprising a LAG-3 antagonist, comprising: (a) determining the level of FGL-1 expression in a sample of each subject’s plasma or serum in the population; and (b) administering the immunotherapy to the subject if the sample is FGL-1 positive.

[0023] The present disclosure is directed to a method of selecting a human subject afflicted with a tumor for an immunotherapy comprising a LAG-3 antagonist, comprising: (a) determining the level of FGL-1 expression in a sample of the subject’s plasma or serum; and (b) administering the immunotherapy to the subject if the sample is FGL-1 positive.

[0024] The present disclosure is directed to a method of selecting a population of human subjects afflicted with tumors for an immunotherapy comprising a LAG-3 antagonist, comprising: (a) determining the level of FGL-1 expression in a sample of plasma or serum from a human subject, wherein the subject is a member of the population selected for the immunotherapy if the sample is FGL-1 positive; and (b) administering the immunotherapy to each subject in the population.

[0025] In some aspects, the tumor comprises a hepatocellular carcinoma, colorectal carcinoma, gastric cancer, small-cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), squamous NSCLC, non-squamous NSCLC, solid cancer with liver metastatic disease, cervical cancer, breast cancer, triple-negative breast cancer, pancreatic cancer, urothelial cancer, prostate cancer, hormone refractory prostate adenocarcinoma, hematological cancer, squamous cell carcinoma, glioma, gastrointestinal cancer, renal cancer, clear cell carcinoma, ovarian cancer, liver cancer, endometrial cancer, kidney cancer, renal cell carcinoma (RCC), thyroid cancer, neuroblastoma, glioblastoma, glioblastoma multiforme, stomach cancer, bladder cancer, hepatoma, colon cancer, head and neck cancer, gastroesophageal cancer, germ cell tumor, pediatric sarcoma, sinonasal natural killer T-cell lymphoma, melanoma, bone cancer, skin cancer, uterine cancer, cancer of the anal region, testicular cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, rectal cancer, solid tumor of childhood, cancer of the ureter, carcinoma of the renal pelvis, neoplasm of the central nervous system (CNS), primary CNS lymphoma, spinal axis tumor, brain cancer, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid cancer, environmentally-induced cancer, virus- related cancer or cancer of viral origin, or any combination thereof.

[0026] In some aspects, the tumor is recurrent or refractory.

[0027] In some aspects, the tumor is unresectable, advanced, and / or metastatic.

[0028] In some aspects, the tumor is a malignant tumor.

[0029] In some aspects, the tumor comprises a hepatocellular carcinoma, and the sample from the subject’s tumor comprises an H-score of less than about 250. In some aspects, the H-score is a manual calculation. In some aspects, the H-score is an automated calculation by image analysis software.

[0030] In some aspects, the tumor comprises a hepatocellular carcinoma, and the sample from the subject’s tumor comprises an H-score of less than about 140. In some aspects, the H-score is a manual calculation. In some aspects, the H-score is an automated calculation by image analysis software.

[0031] In some aspects, the tumor comprises a NSCLC, and the sample from the subject’s tumor comprises an H-score of less than or equal to about 10. In some aspects, the NSCLC comprises non-squamous NSCLC.

[0032] In some aspects, the tumor comprises a NSCLC and the sample from the subject’s tumor comprises an H-score of greater than about 45. In some aspects, the NSCLC comprises non-squamous NSCLC. In some aspects, the H-score is a manual calculation. In some aspects, the H-score is an automated calculation by image analysis software.

[0033] In some aspects, the immunotherapy further comprises a programmed death-1 (PD- 1) pathway inhibitor.

[0034] In some aspects, the LAG-3 antagonist comprises an anti-LAG-3 antibody. In some aspects, the anti-LAG-3 antibody comprises a full-length antibody. In some aspects, the anti-LAG-3 antibody comprises a monoclonal, human, humanized, chimeric, or multispecific antibody. In some aspects, the multispecific antibody comprises a dual- affinity re-targeting antibody, a dual variable domain immunoglobulin, or a bispecific antibody. In some aspects, the anti-LAG-3 antibody comprises a F(ab')2 fragment, a Fab' fragment, a Fab fragment, a Fv fragment, a scFv fragment, a dsFv fragment, a dAb fragment, or a single chain binding polypeptide. In some aspects, the anti-LAG-3 antibody comprises BMS-986016 (relatlimab), IMP731 (H5L7BW), MK4280 (28G-10, favezelimab), REGN3767 (fianlimab), GSK2831781, humanized BAP050, IMP-701 (LAG525, ieramilimab), aLAG3(0414), aLAG3(0416), Sym022, TSR-033, TSR-075, XmAb841 (XmAb22841), MGD013 (tebotelimab), BI754111, FS118, P 13B02-30, AVA- 017, 25F7, AGEN1746, RO7247669, INCAGN02385, IBI-110, EMB-02, IBI-323, LBL- 007, ABL501, or an antigen binding portion thereof. In some aspects, the anti-LAG-3 antibody comprises CDR1, CDR2 and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID NO:3, and CDR1, CDR2 and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID NO:4. In some aspects, the anti-LAG-3 antibody comprises: (a) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO:5; (b) a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO:6; (c) a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO:7; (d) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO:8; (e) a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO:9; and (f) a light chain variable regionCDR3 comprising the sequence set forth in SEQ ID NO:10. In some aspects, the anti-LAG- 3 antibody comprises heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs:3 and 4, respectively. In some aspects, the anti-LAG-3 antibody comprises heavy and light chains comprising the sequences set forth in SEQ ID NOs:1 and 2, respectively. In some aspects, the anti-LAG-3 antibody comprises heavy and light chains comprising the sequences set forth in SEQ ID NOs:21 and 2, respectively.

[0035] In some aspects, the LAG-3 antagonist comprises a soluble LAG-3 polypeptide. In some aspects, the soluble LAG-3 polypeptide is a fusion polypeptide. In some aspects, the soluble LAG-3 polypeptide comprises a ligand binding fragment of the LAG-3 extracellular domain. In some aspects, the ligand binding fragment of the LAG-3 extracellular domain comprises an amino acid sequence with at least about 90%, at least about 95%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO:22. In some aspects, soluble LAG-3 polypeptide further comprises a half-life extending moiety. In some aspects, the half-life extending moiety comprises an immunoglobulin constant region or a portion thereof, an immunoglobulin-binding polypeptide, an immunoglobulin G (IgG), albumin-binding polypeptide (ABP), a PASylation moiety, a HESylation moiety, XTEN, a PEGylation moiety, an Fc region, or any combination thereof. In some aspects, the soluble LAG-3 polypeptide comprises IMP321 (eftilagimod alpha).

[0036] In some aspects, the LAG-3 antagonist is formulated for parenteral administration.

[0037] In some aspects, the LAG-3 antagonist is formulated for intravenous, intraperitoneal, intramuscular, intrathecal, or subcutaneous administration.

[0038] In some aspects, the LAG-3 antagonist is administered at a flat dose.

[0039] In some aspects, the LAG-3 antagonist is administered at a dose of from at least about 0.25 mg to about 2000 mg, about 0.25 mg to about 1600 mg, about 0.25 mg to about 1200 mg, about 0.25 mg to about 800 mg, about 0.25 mg to about 400 mg, about 0.25 mg to about 100 mg, about 0.25 mg to about 50 mg, about 0.25 mg to about 40 mg, about 0.25 mg to about 30 mg, about 0.25 mg to about 20 mg, about 20 mg to about 2000 mg, about 20 mg to about 1600 mg, about 20 mg to about 1200 mg, about 20 mg to about 800 mg, about 20 mg to about 400 mg, about 20 mg to about 100 mg, about 100 mg to about 2000 mg, about 100 mg to about 1800 mg, about 100 mg to about 1600 mg, about 100 mg to about 1400 mg, about 100 mg to about 1200 mg, about 100 mg to about 1000 mg, about100 mg to about 800 mg, about 100 mg to about 600 mg, about 100 mg to about 400 mg, about 400 mg to about 2000 mg, about 400 mg to about 1800 mg, about 400 mg to about 1600 mg, about 400 mg to about 1400 mg, about 400 mg to about 1200 mg, or about 400 mg to about 1000 mg.

[0040] In some aspects, the LAG-3 antagonist is administered at a dose of about 0.25 mg, about 0.5 mg, about 0.75 mg, about 1 mg, about 1.25 mg, about 1.5 mg, about 1.75 mg, about 2 mg, about 2.25 mg, about 2.5 mg, about 2.75 mg, about 3 mg, about 3.25 mg, about 3.5 mg, about 3.75 mg, about 4 mg, about 4.25 mg, about 4.5 mg, about 4.75 mg, about 5 mg, about 5.25 mg, about 5.5 mg, about 5.75 mg, about 6 mg, about 6.25 mg, about 6.5 mg, about 6.75 mg, about 7 mg, about 7.25 mg, about 7.5 mg, about 7.75 mg, about 8 mg, about 8.25 mg, about 8.5 mg, about 8.75 mg, about 9 mg, about 9.25 mg, about 9.5 mg, about 9.75 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, about 800 mg, about 810 mg, about 820 mg, about 830 mg, about 840 mg, about 850 mg, about 860 mg, about 870 mg, about 880 mg, about 890 mg, about 900 mg, about 910 mg, about 920 mg, about 930 mg, about 940 mg, about 950 mg, about 960 mg, about 970 mg, about 980 mg, about 990 mg, about 1000 mg, about 1040 mg, about 1080 mg, about 1100 mg, about 1140 mg, about 1180 mg, about 1200 mg, about 1240 mg, about 1280 mg, about 1300 mg, about 1340 mg, about 1380 mg, about 1400 mg, about 1440 mg, about 1480 mg, about 1500 mg, about 1540 mg, about 1580 mg, about 1600 mg, about 1640 mg, about 1680 mg, about 1700 mg, about 1740 mg, about 1780 mg, about1800 mg, about 1840 mg, about 1880 mg, about 1900 mg, about 1940 mg, about 1980 mg, or about 2000 mg.

[0041] In some aspects, the LAG-3 antagonist is administered at a weight-based dose.

[0042] In some aspects, the LAG-3 antagonist is administered at a dose of from about 0.003 mg / kg to about 25 mg / kg, about 0.003 mg / kg to about 20 mg / kg, about 0.003 mg / kg to about 15 mg / kg, about 0.003 mg / kg to about 10 mg / kg, about 0.003 mg / kg to about 5 mg / kg, about 0.003 mg / kg to about 1 mg / kg, about 0.003 mg / kg to about 0.9 mg / kg, about 0.003 mg / kg to about 0.8 mg / kg, about 0.003 mg / kg to about 0.7 mg / kg, about 0.003 mg / kg to about 0.6 mg / kg, about 0.003 mg / kg to about 0.5 mg / kg, about 0.003 mg / kg to about 0.4 mg / kg, about 0.003 mg / kg to about 0.3 mg / kg, about 0.003 mg / kg to about 0.2 mg / kg, about 0.003 mg / kg to about 0.1 mg / kg, about 0.1 mg / kg to about 25 mg / kg, about 0.1 mg / kg to about 20 mg / kg, about 0.1 mg / kg to about 15 mg / kg, about 0.1 mg / kg to about 10 mg / kg, about 0.1 mg / kg to about 5 mg / kg, about 0.1 mg / kg to about 1 mg / kg, about 1 mg / kg to about 25 mg / kg, about 1 mg / kg to about 20 mg / kg, about 1 mg / kg to about 15 mg / kg, about 1 mg / kg to about 10 mg / kg, about 1 mg / kg to about 5 mg / kg, about 5 mg / kg to about 25 mg / kg, about 5 mg / kg to about 20 mg / kg, about 5 mg / kg to about 15 mg / kg, about 5 mg / kg to about 10 mg / kg, about 10 mg / kg to about 25 mg / kg, about 10 mg / kg to about 20 mg / kg, about 10 mg / kg to about 15 mg / kg, about 15 mg / kg to about 25 mg / kg, about 15 mg / kg to about 20 mg / kg, or about 20 mg / kg to about 25 mg / kg.

[0043] In some aspects, the LAG-3 antagonist is administered at a dose of about 0.003 mg / kg, about 0.004 mg / kg, about 0.005 mg / kg, about 0.006 mg / kg, about 0.007 mg / kg, about 0.008 mg / kg, about 0.009 mg / kg, about 0.01 mg / kg, about 0.02 mg / kg, about 0.03 mg / kg, about 0.04 mg / kg, about 0.05 mg / kg, about 0.06 mg / kg, about 0.07 mg / kg, about 0.08 mg / kg, about 0.09 mg / kg, about 0.1 mg / kg, about 0.2 mg / kg, about 0.3 mg / kg, about 0.4 mg / kg, about 0.5 mg / kg, about 0.6 mg / kg, about 0.7 mg / kg, about 0.8 mg / kg, about 0.9 mg / kg, about 1.0 mg / kg, about 2.0 mg / kg, about 3.0 mg / kg, about 4.0 mg / kg, about 5.0 mg / kg, about 6.0 mg / kg, about 7.0 mg / kg, about 8.0 mg / kg, about 9.0 mg / kg, about 10.0 mg / kg, about 11.0 mg / kg, about 12.0 mg / kg, about 13.0 mg / kg, about 14.0 mg / kg, about 15.0 mg / kg, about 16.0 mg / kg, about 17.0 mg / kg, about 18.0 mg / kg, about 19.0 mg / kg, about 20.0 mg / kg, about 21.0 mg / kg, about 22.0 mg / kg, about 23.0 mg / kg, about 24.0 mg / kg, or about 25.0 mg / kg.

[0044] In some aspects, any of the above doses is administered once about every one week, once about every two weeks, once about every three weeks, once about every four weeks, once about every five weeks, once about every six weeks, once about every seven weeks, once about every eight weeks, once about every nine weeks, once about every ten weeks, once about every eleven weeks, or once about every twelve weeks.

[0045] In some aspects, the PD-1 pathway inhibitor comprises an anti-PD-1 antibody and / or an anti-PD-L1 antibody.

[0046] In some aspects, the PD-1 pathway inhibitor comprises an anti-PD-1 antibody. In some aspects, the anti-PD-1 antibody comprises a full-length antibody. In some aspects, the anti-PD-1 antibody comprises a monoclonal, human, humanized, chimeric, or multispecific antibody. In some aspects, the multispecific antibody comprises a dual- affinity re-targeting antibody, a dual variable domain immunoglobulin, or a bispecific antibody. In some aspects, the anti-PD-1 antibody comprises a F(ab')2 fragment, a Fab' fragment, a Fab fragment, a Fv fragment, a scFv fragment, a dsFv fragment, a dAb fragment, or a single chain binding polypeptide. In some aspects, the anti-PD-1 antibody comprises nivolumab, pembrolizumab, PDR001 (spartalizumab), MEDI-0680, TSR-042, cemiplimab, JS001, PF-06801591, BGB-A317, BI 754091, INCSHR1210, GLS-010, AM- 001, STI-1110, AGEN2034, MGA012, BCD-100, IBI308, SSI-361, or an antigen binding portion thereof. In some aspects, the anti-PD-1 antibody comprises CDR1, CDR2 and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID NO:13, and CDR1, CDR2 and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID NO:14. In some aspects, the anti-PD-1 antibody comprises: (a) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO:15; (b) a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO:16; (c) a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO:17; (d) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO:18; (e) a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO:19; and (f) a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO:20. In some aspects, the anti-PD-1 antibody comprises heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs:13 and 14, respectively. In some aspects, the anti-PD-1 antibody comprises heavy and light chains comprising the sequences as set forth in SEQ ID NOs:11 and 12, respectively.

[0047] In some aspects, the PD-1 pathway inhibitor comprises a soluble PD-L2 polypeptide. In some aspects, the soluble PD-L2 polypeptide is a fusion polypeptide. In some aspects, the soluble PD-L2 polypeptide comprises a ligand binding fragment of the PD-L2 extracellular domain. In some aspects, the soluble PD-L2 polypeptide further comprises a half-life extending moiety. In some aspects, the half-life extending moiety comprises an immunoglobulin constant region or a portion thereof, an immunoglobulin- binding polypeptide, an immunoglobulin G (IgG), albumin-binding polypeptide (ABP), a PASylation moiety, a HESylation moiety, XTEN, a PEGylation moiety, an Fc region, or any combination thereof. In some aspects, the soluble PD-L2 polypeptide comprises AMP- 224.

[0048] In some aspects, the PD-1 pathway inhibitor comprises an anti-PD-L1 antibody. In some aspects, the anti-PD-L1 antibody comprises a full-length antibody. In some aspects, the anti-PD-L1 antibody comprises a monoclonal, human, humanized, chimeric, or multispecific antibody. In some aspects, the multispecific antibody comprises a dual- affinity re-targeting antibody, a dual variable domain immunoglobulin, or a bispecific antibody. In some aspects, the anti-PD-L1 antibody comprises a F(ab')2 fragment, a Fab' fragment, a Fab fragment, a Fv fragment, a scFv fragment, a dsFv fragment, a dAb fragment, or a single chain binding polypeptide. In some aspects, the anti-PD-L1 antibody comprises BMS-936559, atezolizumab, durvalumab, avelumab, STI-1014, CX-072, KN035, LY3300054, BGB-A333, ICO 36, FAZ053, CK-301, or an antigen binding portion thereof. In some aspects, the PD-1 pathway inhibitor comprises BMS-986189.

[0049] In some aspects, the PD-1 pathway inhibitor is formulated for parenteral administration.

[0050] In some aspects, the PD-1 pathway inhibitor is formulated for intravenous, intraperitoneal, intramuscular, intrathecal, or subcutaneous administration.

[0051] In some aspects, the PD-1 pathway inhibitor is administered at a flat dose.

[0052] In some aspects, the PD-1 pathway inhibitor is administered at a dose of from at least about 0.25 mg to about 2000 mg, about 0.25 mg to about 1600 mg, about 0.25 mg to about 1200 mg, about 0.25 mg to about 800 mg, about 0.25 mg to about 400 mg, about 0.25 mg to about 100 mg, about 0.25 mg to about 50 mg, about 0.25 mg to about 40 mg, about 0.25 mg to about 30 mg, about 0.25 mg to about 20 mg, about 20 mg to about 2000 mg, about 20 mg to about 1600 mg, about 20 mg to about 1200 mg, about 20 mg to about 800mg, about 20 mg to about 400 mg, about 20 mg to about 100 mg, about 100 mg to about 2000 mg, about 100 mg to about 1800 mg, about 100 mg to about 1600 mg, about 100 mg to about 1400 mg, about 100 mg to about 1200 mg, about 100 mg to about 1000 mg, about 100 mg to about 800 mg, about 100 mg to about 600 mg, about 100 mg to about 400 mg, about 400 mg to about 2000 mg, about 400 mg to about 1800 mg, about 400 mg to about 1600 mg, about 400 mg to about 1400 mg, about 400 mg to about 1200 mg, or about 400 mg to about 1000 mg.

[0053] In some aspects, the PD-1 pathway inhibitor is administered at a dose of about 0.25 mg, about 0.5 mg, about 0.75 mg, about 1 mg, about 1.25 mg, about 1.5 mg, about 1.75 mg, about 2 mg, about 2.25 mg, about 2.5 mg, about 2.75 mg, about 3 mg, about 3.25 mg, about 3.5 mg, about 3.75 mg, about 4 mg, about 4.25 mg, about 4.5 mg, about 4.75 mg, about 5 mg, about 5.25 mg, about 5.5 mg, about 5.75 mg, about 6 mg, about 6.25 mg, about 6.5 mg, about 6.75 mg, about 7 mg, about 7.25 mg, about 7.5 mg, about 7.75 mg, about 8 mg, about 8.25 mg, about 8.5 mg, about 8.75 mg, about 9 mg, about 9.25 mg, about 9.5 mg, about 9.75 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, about 800 mg, about 810 mg, about 820 mg, about 830 mg, about 840 mg, about 850 mg, about 860 mg, about 870 mg, about 880 mg, about 890 mg, about 900 mg, about 910 mg, about 920 mg, about 930 mg, about 940 mg, about 950 mg, about 960 mg, about 970 mg, about 980 mg, about 990 mg, about 1000 mg, about 1040 mg, about 1080 mg, about 1100 mg, about 1140 mg, about 1180 mg, about 1200 mg, about 1240 mg,about 1280 mg, about 1300 mg, about 1340 mg, about 1380 mg, about 1400 mg, about 1440 mg, about 1480 mg, about 1500 mg, about 1540 mg, about 1580 mg, about 1600 mg, about 1640 mg, about 1680 mg, about 1700 mg, about 1740 mg, about 1780 mg, about 1800 mg, about 1840 mg, about 1880 mg, about 1900 mg, about 1940 mg, about 1980 mg, or about 2000 mg.

[0054] In some aspects, the PD-1 pathway inhibitor is administered at a weight-based dose.

[0055] In some aspects, the PD-1 pathway inhibitor is administered at a dose of from about 0.003 mg / kg to about 25 mg / kg, about 0.003 mg / kg to about 20 mg / kg, about 0.003 mg / kg to about 15 mg / kg, about 0.003 mg / kg to about 10 mg / kg, about 0.003 mg / kg to about 5 mg / kg, about 0.003 mg / kg to about 1 mg / kg, about 0.003 mg / kg to about 0.9 mg / kg, about 0.003 mg / kg to about 0.8 mg / kg, about 0.003 mg / kg to about 0.7 mg / kg, about 0.003 mg / kg to about 0.6 mg / kg, about 0.003 mg / kg to about 0.5 mg / kg, about 0.003 mg / kg to about 0.4 mg / kg, about 0.003 mg / kg to about 0.3 mg / kg, about 0.003 mg / kg to about 0.2 mg / kg, about 0.003 mg / kg to about 0.1 mg / kg, about 0.1 mg / kg to about 25 mg / kg, about 0.1 mg / kg to about 20 mg / kg, about 0.1 mg / kg to about 15 mg / kg, about 0.1 mg / kg to about 10 mg / kg, about 0.1 mg / kg to about 5 mg / kg, about 0.1 mg / kg to about 1 mg / kg, about 1 mg / kg to about 25 mg / kg, about 1 mg / kg to about 20 mg / kg, about 1 mg / kg to about 15 mg / kg, about 1 mg / kg to about 10 mg / kg, about 1 mg / kg to about 5 mg / kg, about 5 mg / kg to about 25 mg / kg, about 5 mg / kg to about 20 mg / kg, about 5 mg / kg to about 15 mg / kg, about 5 mg / kg to about 10 mg / kg, about 10 mg / kg to about 25 mg / kg, about 10 mg / kg to about 20 mg / kg, about 10 mg / kg to about 15 mg / kg, about 15 mg / kg to about 25 mg / kg, about 15 mg / kg to about 20 mg / kg, or about 20 mg / kg to about 25 mg / kg.

[0056] In some aspects, the PD-1 pathway inhibitor is administered at a dose of about 0.003 mg / kg, about 0.004 mg / kg, about 0.005 mg / kg, about 0.006 mg / kg, about 0.007 mg / kg, about 0.008 mg / kg, about 0.009 mg / kg, about 0.01 mg / kg, about 0.02 mg / kg, about 0.03 mg / kg, about 0.04 mg / kg, about 0.05 mg / kg, about 0.06 mg / kg, about 0.07 mg / kg, about 0.08 mg / kg, about 0.09 mg / kg, about 0.1 mg / kg, about 0.2 mg / kg, about 0.3 mg / kg, about 0.4 mg / kg, about 0.5 mg / kg, about 0.6 mg / kg, about 0.7 mg / kg, about 0.8 mg / kg, about 0.9 mg / kg, about 1.0 mg / kg, about 2.0 mg / kg, about 3.0 mg / kg, about 4.0 mg / kg, about 5.0 mg / kg, about 6.0 mg / kg, about 7.0 mg / kg, about 8.0 mg / kg, about 9.0 mg / kg, about 10.0 mg / kg, about 11.0 mg / kg, about 12.0 mg / kg, about 13.0 mg / kg, about 14.0 mg / kg, about 15.0 mg / kg, about 16.0 mg / kg, about 17.0 mg / kg, about 18.0 mg / kg, about 19.0 mg / kg,about 20.0 mg / kg, about 21.0 mg / kg, about 22.0 mg / kg, about 23.0 mg / kg, about 24.0 mg / kg, or about 25.0 mg / kg.

[0057] In some aspects, the dose is administered once about every one week, once about every two weeks, once about every three weeks, once about every four weeks, once about every five weeks, once about every six weeks, once about every seven weeks, once about every eight weeks, once about every nine weeks, once about every ten weeks, once about every eleven weeks, or once about every twelve weeks.

[0058] In some aspects, in the PD-1 pathway inhibitor is administered before the LAG-3 antagonist.

[0059] In some aspects, the LAG-3 antagonist is administered before the PD-1 pathway inhibitor.

[0060] In some aspects, the LAG-3 antagonist and the PD-1 pathway inhibitor are administered concurrently.

[0061] In some aspects, the LAG-3 antagonist and the PD-1 pathway inhibitor are formulated separately.

[0062] In some aspects, the LAG-3 antagonist and the PD-1 pathway inhibitor are formulated together.

[0063] In some aspects, the method is a first line therapy.

[0064] In some aspects, the method is a second line therapy.

[0065] In some aspects, the method is a third line therapy.

[0066] In some aspects, the subject has progressed on or is intolerant of a prior therapy.

[0067] In some aspects, the subject is naïve to prior systemic therapy.

[0068] In some aspects, the subject is naïve to prior immuno-oncology therapy, the subject is naïve to prior immuno-oncology for the tumor, or the tumor is naïve to prior immuno- oncology therapy.

[0069] In some aspects, the LAG-3 antagonist comprises relatlimab intravenously administered between about 160 mg to about 480 mg once about every four weeks and the PD-1 pathway inhibitor comprises nivolumab intravenously administered between 240 mg to about 480 mg once about every four weeks.

[0070] In some aspects, the LAG-3 antagonist comprises relatlimab intravenously administered at about 160 mg once about every four weeks and the PD-1 pathway inhibitorcomprises nivolumab intravenously administered at about 480 mg once about every four weeks.

[0071] In some aspects, the LAG-3 antagonist comprises relatlimab intravenously administered at about 360 mg once about every four weeks and the PD-1 pathway inhibitor comprises nivolumab intravenously administered at about 360 mg once about every four weeks.

[0072] In some aspects, the LAG-3 antagonist comprises relatlimab intravenously administered at about 480 mg once about every four weeks and the PD-1 pathway inhibitor comprises nivolumab intravenously administered at about 480 mg once about every four weeks.

[0073] In some aspects, the LAG-3 antagonist comprises relatlimab subcutaneously administered at about 320 mg once about every four weeks and the PD-1 pathway inhibitor comprises nivolumab subcutaneously administered at about 960 mg once about every four weeks.

[0074] In some aspects, the LAG-3 antagonist comprises relatlimab subcutaneously administered at about 960 mg once about every four weeks and the PD-1 pathway inhibitor comprises nivolumab subcutaneously administered at about 960 mg once about every four weeks.

[0075] The present disclosure is directed to a method of treating a tumor in a human subject in need thereof comprising intravenously administering to the subject relatlimab at about 480 mg once about every four weeks and nivolumab at about 480 mg once about every four weeks, wherein the subject’s tumor is identified as having a histoscore (H-score) of less than about 250 according to the formula: (1 × percentage of tumor cells in the sample with weak FGL-1 expression) + (2 × percentage of tumor cells in the sample with moderate FGL-1 expression) + (3 × percentage of tumor cells in the sample with strong FGL-1 expression). In some aspects, the tumor comprises a hepatocellular carcinoma. In some aspects, the H-score is less than about 140.

[0076] The present disclosure is directed to a method of treating a tumor in a human subject in need thereof comprising intravenously administering to the subject relatlimab at about 360 mg once about every four weeks and nivolumab at about 360 mg once about every four weeks, wherein the subject’s tumor is identified as having an H-score of less than or equal to about 10 according to the formula: (1 × percentage of tumor cells in the sample withweak FGL-1 expression) + (2 × percentage of tumor cells in the sample with moderate FGL-1 expression) + (3 × percentage of tumor cells in the sample with strong FGL-1 expression). In some aspects, the tumor comprises a non-small cell lung cancer. In some aspects, the non-small lung cancer comprises non-squamous non-small cell lung cancer.

[0077] The present disclosure is directed to a method of treating a tumor in a human subject in need thereof comprising intravenously administering to the subject relatlimab at about 360 mg once about every four weeks and nivolumab at about 360 mg once about every four weeks, wherein the subject’s tumor is identified as having an H-score of greater than about 45 according to the formula: (1 × percentage of tumor cells in the sample with weak FGL- 1 expression) + (2 × percentage of tumor cells in the sample with moderate FGL-1 expression) + (3 × percentage of tumor cells in the sample with strong FGL-1 expression). In some aspects, the tumor comprises a non-small cell lung cancer. In some aspects, the non-small lung cancer comprises non-squamous non-small cell lung cancer.

[0078] The present disclosure is directed to a method of treating a tumor in a human subject in need thereof comprising intravenously administering to the subject relatlimab at about 360 mg once about every four weeks and nivolumab at about 360 mg once about every four weeks, wherein a sample of the subject’s plasma or serum comprises less than about 360 ng / mL of soluble FGL-1. In some aspects, the tumor comprises a non-small cell lung cancer. In some aspects, the non-small lung cancer comprises non-squamous non-small cell lung cancer.

[0079] In some aspects, the method further comprises administering to the subject an additional therapeutic agent. In some aspects, the additional therapeutic agent comprises an anti-cancer agent. In some aspects, the anti-cancer agent comprises a tyrosine kinase inhibitor, an anti-angiogenesis agent, a checkpoint inhibitor, a checkpoint stimulator, a chemotherapeutic agent, an immunotherapeutic agent, a platinum agent, an alkylating agent, a taxane, a nucleoside analog, an antimetabolite, a topoisomerase inhibitor, an anthracycline, a vinca alkaloid, or any combination thereof. In some aspects, the checkpoint inhibitor comprises a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor, a T cell immunoglobulin and ITIM domain (TIGIT) inhibitor, a T cell immunoglobulin and mucin-domain containing-3 (TIM-3) inhibitor, a TIM-1 inhibitor, a TIM-4 inhibitor, a B7- H3 inhibitor, a B7-H4 inhibitor, a B and T cell lymphocyte attenuator (BTLA) inhibitor, a V-domain Ig suppressor of T cell activation (VISTA) inhibitor, an indoleamine 2,3-dioxygenase (IDO) inhibitor, a nicotinamide adenine dinucleotide phosphate oxidase isoform 2 (NOX2) inhibitor, a killer-cell immunoglobulin-like receptor (KIR) inhibitor, an adenosine A2a receptor (A2aR) inhibitor, a transforming growth factor beta (TGF-β) inhibitor, a phosphoinositide 3-kinase (PI3K) inhibitor, a CD47 inhibitor, a CD48 inhibitor, a CD73 inhibitor, a CD113 inhibitor, a sialic acid-binding immunoglobulin-like lectin-7 (SIGLEC-7) inhibitor, a SIGLEC-9 inhibitor, a SIGLEC-15 inhibitor, a glucocorticoid- induced TNFR-related protein (GITR) inhibitor, a galectin-1 inhibitor, a galectin-9 inhibitor, a carcinoembryonic antigen-related cell adhesion molecule-1 (CEACAM-1) inhibitor, a G protein-coupled receptor 56 (GPR56) inhibitor, a glycoprotein A repetitions predominant (GARP) inhibitor, a 2B4 inhibitor, a programmed death-1 homolog (PD1H) inhibitor, a leukocyte-associated immunoglobulin-like receptor 1 (LAIR1) inhibitor, or any combination thereof. In some aspects, the checkpoint inhibitor comprises a CTLA-4 inhibitor. In some aspects, the CTLA-4 inhibitor comprises an anti-CTLA-4 antibody. In some aspects, the anti-CTLA-4 antibody comprises a full-length antibody. In some aspects, the anti-CTLA-4 antibody comprises a monoclonal, human, humanized, chimeric, or multispecific antibody. In some aspects, the multispecific antibody comprises a dual- affinity re-targeting antibody, a dual variable domain immunoglobulin, or a bispecific antibody. In some aspects, the anti-CTLA-4 antibody comprises a F(ab')2fragment, a Fab' fragment, a Fab fragment, a Fv fragment, a scFv fragment, a dsFv fragment, a dAb fragment, or a single chain binding polypeptide. In some aspects, the anti-CTLA-4 antibody comprises ipilimumab, tremelimumab, MK-1308, AGEN-1884, or an antigen binding portion thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0080] FIG. 1 shows probability of survival curves based on progression free survival (PFS) per blinded independent central review (BICR) in a phase 2 clinical study of patients having hepatocellular carcinoma (HCC) treated with either 480 mg of nivolumab (N) in Arm A or 480 mg of nivolumab and 480 mg of relatlimab (N+R) in Arm B. Tumor samples from the patients had baseline manually calculated FGL-1 histoscores of less than 250. Months of treatment are indicated on the x-axis.

[0081] FIG. 2 shows probability of survival curves as described for FIG. 1, except that tumor samples from the patients had baseline manually calculated histoscores of greater than or equal to 250.

[0082] FIG.3 shows probability of survival curves as described for FIG.1, but based on overall survival of the patients having manually calculated FGL-1 histoscores of less than 250 prior to treatment.

[0083] FIG. 4 shows probability of survival curves as described for FIG. 3, except that tumor samples from the patients had manually calculated histoscores of greater than or equal to 250 prior to treatment.

[0084] FIGs. 5A-5D show fitted response rate curves and regression splines (FIGs. 5A- 5B) and PFS probability (FIGs. 5C-5D) curves for patients in the phase 2 clinical study described in FIG.1. FIGs.5A-5B show manually calculated (FIG.5A, FGL1_HSCORE) or digital algorithm calculated (FIG. 5B, FGL1_d.HScore) FGL-1 histoscores for tumor samples from the patients on the x-axis, with fitted response rates based on overall response rates per independent review committee (IRC). The probability curves in FIGs.5C-5D are based on PFS per IRC in patients with manually calculated histoscores of less than 250 (FIG.5C) or digitally calculated histoscores of less than 140 (FIG.5D), with months of treatment indicated on the x-axis. NIVO = nivolumab; RELA = relatlimab. DETAILED DESCRIPTION OF THE INVENTION

[0085] The present disclosure provides a method of treating a tumor in a human subject in need thereof, the method comprising administering to the subject an immunotherapy comprising a lymphocyte activation gene-3 (LAG-3) antagonist (e.g., an anti-LAG-3 antibody), wherein a sample of the subject’s tumor, plasma, or serum is fibrinogen-like protein 1 (FGL-1) positive. The present disclosure also provides a method of selecting a tumor in a human subject for an immunotherapy comprising a LAG-3 antagonist and a method of selecting a human subject afflicted with a tumor for an immunotherapy comprising a LAG-3 antagonist, wherein a sample of the subject’s tumor, plasma, or serum is FGL-1 positive. In some aspects, the immunotherapy further comprises a PD-1 pathway inhibitor (e.g., an anti-PD-1 antibody). The present disclosure also provides corresponding methods comprising a population of human subjects.I. Terms

[0086] In order that the present disclosure can be more readily understood, certain terms are first defined. As used in this application, except as otherwise expressly provided herein, each of the following terms shall have the meaning set forth below. Additional definitions are set forth throughout the application. It is to be noted that the term "a" or "an" entity refers to one or more of that entity; for example, "a nucleotide sequence," is understood to represent one or more nucleotide sequences. As such, the terms "a" (or "an"), "one or more," and "at least one" can be used interchangeably herein.

[0087] The term "and / or" where used herein is to be taken as specific disclosure of each of the two specified features or components with or without the other. Thus, the term "and / or" as used in a phrase such as "A and / or B" herein is intended to include "A and B," "A or B," "A" (alone), and "B" (alone). Likewise, the term "and / or" as used in a phrase such as "A, B, and / or C" is intended to encompass each of the following aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0088] It is understood that wherever aspects are described herein with the language "comprising," otherwise analogous aspects described in terms of "consisting of" and / or "consisting essentially of" are also provided.

[0089] The terms "about" or "comprising essentially of" refer to a value or composition that is within an acceptable error range for the particular value or composition as determined by one of ordinary skill in the art, which will depend in part on how the value or composition is measured or determined, i.e., the limitations of the measurement system. For example, "about" or "comprising essentially of" can mean within 1 or more than 1 standard deviation per the practice in the art. Alternatively, "about" or "comprising essentially of" can mean a range of up to 10% or 20% (i.e., ±10% or ±20%). In some aspects, "about" comprises a range of up to 10% (i.e., ±10%). In some aspects, "about" comprises a range of up to 20% (i.e., ±20%). For example, about 3 mg can include any number between 2.7 mg and 3.3 mg (for 10%) or between 2.4 mg and 3.6 mg (for 20%). Furthermore, particularly with respect to biological systems or processes, the terms can mean up to an order of magnitude or up to 5-fold of a value. When particular values or compositions are provided in the application and claims, unless otherwise stated, the meaning of "about" or "comprising essentially of" should be assumed to be within an acceptable error range for that particular value or composition.

[0090] As described herein, any concentration range, percentage range, ratio range or integer range is to be understood to include the value of any integer within the recited range and, when appropriate, fractions thereof (such as one-tenth and one-hundredth of an integer), unless otherwise indicated.

[0091] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure is related. For example, the Concise Dictionary of Biomedicine and Molecular Biology, Juo, Pei-Show, 2nd ed., 2002, CRC Press; The Dictionary of Cell and Molecular Biology, 5th ed., 2013, Academic Press; and the Oxford Dictionary Of Biochemistry And Molecular Biology, 2006, Oxford University Press, provide one of skill with a general dictionary of many of the terms used in this disclosure.

[0092] Units, prefixes, and symbols are denoted in their Système International de Unites (SI) accepted form. Numeric ranges are inclusive of the numbers defining the range.

[0093] The headings provided herein are not limitations of the various aspects of the disclosure, which can be had by reference to the specification as a whole. Accordingly, the terms defined immediately below are more fully defined by reference to the specification in its entirety.

[0094] An "antagonist" shall include, without limitation, any molecule capable of blocking, reducing, or otherwise limiting an interaction or activity of a target molecule (e.g., LAG- 3). In some aspects, the antagonist is an antibody. In some aspects, the antagonist comprises a small molecule. The terms "antagonist" and "inhibitor" are used interchangeably herein.

[0095] An "antibody" (Ab) shall include, without limitation, a glycoprotein immunoglobulin which binds specifically to an antigen and comprises at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds. Each H chain comprises a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region (abbreviated herein as CH). The heavy chain constant region comprises three constant domains, CH1, CH2and CH3. Each light chain comprises a light chain variable region (abbreviated herein as VL) and a light chain constant region (abbreviated herein as CL). The light chain constant region comprises one constant domain, CL. The VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FR). Each VH and VL comprises three CDRs and four FRs, arrangedfrom amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and light chains contain a binding domain that interacts with an antigen. The constant regions of the antibodies can mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (C1q) of the classical complement system. A heavy chain can have the C-terminal lysine or not. Unless specified otherwise herein, the amino acids in the variable regions are numbered using the Kabat numbering system and those in the constant regions are numbered using the EU system.

[0096] An immunoglobulin can derive from any of the commonly known isotypes, including but not limited to IgA, secretory IgA, IgG and IgM. IgG subclasses are also well known to those in the art and include but are not limited to human IgG1, IgG2, IgG3 and IgG4. "Isotype" refers to the antibody class or subclass (e.g., IgM or IgG1) that is encoded by the heavy chain constant region genes. The term "antibody" includes, by way of example, both naturally occurring and non-naturally occurring antibodies; monoclonal and polyclonal antibodies; chimeric and humanized antibodies; human or nonhuman antibodies; wholly synthetic antibodies; single chain antibodies; monospecific antibodies; bispecific antibodies; and multi-specific antibodies. A nonhuman antibody can be humanized by recombinant methods to reduce its immunogenicity in humans. Where not expressly stated, and unless the context indicates otherwise, the term "antibody" also includes an antigen-binding fragment or an antigen binding portion of any of the aforementioned immunoglobulins, and includes a monovalent and a divalent fragment or portion, that retains the ability to bind specifically to the antigen bound by the whole immunoglobulin. Examples of an "antigen binding portion" or "antigen-binding fragment" include: (1) a Fab fragment (fragment from papain cleavage) or a similar monovalent fragment consisting of the VL, VH, LC and CH1 domains; (2) a F(ab')2 fragment (fragment from pepsin cleavage) or a similar bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (3) a Fd fragment consisting of the VH and CH1 domains; (4) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody; (5) a single domain antibody (dAb) fragment (Ward et al., (1989) Nature 341:544-46), which consists of a VHdomain; (6) a bi-single domain antibody which consists of two VHdomains linked by a hinge (dual-affinity re-targeting antibodies (DARTs)); or (7) a dual variable domain immunoglobulin. Furthermore, although the twodomains of the Fv fragment, VLand VH, are coded for by separate genes, they can be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (known as single chain Fv (scFv); see, e.g., Bird et al. (1988) Science 242:423-426; and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883).

[0097] An "isolated antibody" refers to an antibody that is substantially free of other antibodies having different antigenic specificities (e.g., an isolated antibody that binds specifically to LAG-3 is substantially free of antibodies that do not bind specifically to LAG-3). An isolated antibody that binds specifically to LAG-3 can, however, have cross- reactivity to other antigens, such as LAG-3 molecules from different species. Moreover, an isolated antibody can be substantially free of other cellular material and / or chemicals.

[0098] The term "monoclonal antibody" ("mAb") refers to a non-naturally occurring preparation of antibody molecules of single molecular composition, i.e., antibody molecules whose primary sequences are essentially identical, and which exhibits a single binding specificity and affinity for a particular epitope. A mAb is an example of an isolated antibody. MAbs can be produced by hybridoma, recombinant, transgenic or other techniques known to those skilled in the art.

[0099] A "human" antibody (HuMAb) refers to an antibody having variable regions in which both the framework and CDR regions are derived from human germline immunoglobulin sequences. Furthermore, if the antibody contains a constant region, the constant region is also derived from human germline immunoglobulin sequences. The human antibodies of the invention can include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo). However, the term "human antibody," as used herein, is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences. The terms "human" antibodies and "fully human" antibodies and are used synonymously.

[0100] A "humanized antibody" refers to an antibody in which some, most or all of the amino acids outside the CDR domains of a non-human antibody are replaced with corresponding amino acids derived from human immunoglobulins. In some aspects of a humanized form of an antibody, some, most or all of the amino acids outside the CDRdomains have been replaced with amino acids from human immunoglobulins, whereas some, most or all amino acids within one or more CDR regions are unchanged. Small additions, deletions, insertions, substitutions or modifications of amino acids are permissible as long as they do not abrogate the ability of the antibody to bind to a particular antigen. A "humanized" antibody retains an antigenic specificity similar to that of the original antibody.

[0101] A "chimeric antibody" refers to an antibody in which the variable regions are derived from one species and the constant regions are derived from another species, such as an antibody in which the variable regions are derived from a mouse antibody and the constant regions are derived from a human antibody.

[0102] An "anti-antigen" antibody refers to an antibody that binds specifically to the antigen. For example, an anti-LAG-3 antibody binds specifically to LAG-3.

[0103] "LAG-3" refers to Lymphocyte Activation Gene-3. The term "LAG-3" includes variants, isoforms, homologs, orthologs and paralogs. For example, antibodies specific for a human LAG-3 protein can, in certain cases, cross-react with a LAG-3 protein from a species other than human. In some aspects, the antibodies specific for a human LAG-3 protein can be completely specific for the human LAG-3 protein and not exhibit species or other types of cross-reactivity, or can cross-react with LAG-3 from certain other species, but not all other species (e.g., cross-react with monkey LAG-3 but not mouse LAG-3). The term "human LAG-3" refers to human sequence LAG-3, such as the complete amino acid sequence of human LAG-3 having GenBank Accession No. NP_002277. The term "mouse LAG-3" refers to mouse sequence LAG-3, such as the complete amino acid sequence of mouse LAG-3 having GenBank Accession No. NP_032505. LAG-3 is also known in the art as, for example, CD223. The human LAG-3 sequence can differ from human LAG-3 of GenBank Accession No. NP_002277 by having, e.g., conserved mutations or mutations in non-conserved regions, and the LAG-3 has substantially the same biological function as the human LAG-3 of GenBank Accession No. NP_002277. For example, a biological function of human LAG-3 is having an epitope in the extracellular domain of LAG-3 that is specifically bound by an antibody of the instant disclosure or a biological function of human LAG-3 is binding to MHC Class II molecules.

[0104] A particular human LAG-3 sequence will generally be at least about 90% identical in amino acid sequence to human LAG-3 of GenBank Accession No. NP_002277 andcontains amino acid residues that identify the amino acid sequence as being human when compared to LAG-3 amino acid sequences of other species (e.g., murine). In certain cases, a human LAG-3 can be at least about 95%, or even at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical in amino acid sequence to LAG-3 of GenBank Accession No. NP_002277. In some aspects, a human LAG-3 sequence will display no more than 10 amino acid differences from the LAG-3 sequence of GenBank Accession No. NP_002277. In some aspects, the human LAG-3 can display no more than 5, or even no more than 4, 3, 2, or 1 amino acid difference from the LAG-3 sequence of GenBank Accession No. NP_002277.

[0105] "Programmed Death-1 (PD-1)" refers to an immunoinhibitory receptor belonging to the CD28 family. PD-1 is expressed predominantly on previously activated T cells in vivo, and binds to two ligands, PD-L1 and PD-L2. The term "PD-1" as used herein includes human PD-1 (hPD-1), variants, isoforms, and species homologs of hPD-1, and analogs having at least one common epitope with hPD-1. The complete hPD-1 sequence can be found under GenBank Accession No. U64863. "PD-1" and "PD-1 receptor" are used interchangeably herein.

[0106] "Cytotoxic T-Lymphocyte Antigen-4 (CTLA-4)" refers to an immunoinhibitory receptor belonging to the CD28 family. CTLA-4 is expressed exclusively on T cells in vivo, and binds to two ligands, CD80 and CD86 (also called B7-1 and B7-2, respectively). The term "CTLA-4" as used herein includes human CTLA-4 (hCTLA-4), variants, isoforms, and species homologs of hCTLA-4, and analogs having at least one common epitope with hCTLA-4. The complete hCTLA-4 sequence can be found under GenBank Accession No. AAB59385.

[0107] "Programmed Death Ligand-1 (PD-L1)" is one of two cell surface glycoprotein ligands for PD-1 (the other being PD-L2) that downregulate T cell activation and cytokine secretion upon binding to PD-1. The term "PD-L1" as used herein includes human PD-L1 (hPD-L1), variants, isoforms, and species homologs of hPD-L1, and analogs having at least one common epitope with hPD-L1. The complete hPD-L1 sequence can be found under GenBank Accession No. Q9NZQ7.

[0108] "Programmed Death Ligand-2 (PD-L2)" as used herein includes human PD-L2 (hPD-L2), variants, isoforms, and species homologs of hPD-L2, and analogs having at leastone common epitope with hPD-L2. The complete hPD-L2 sequence can be found under GenBank Accession No. Q9BQ51.

[0109] A "subject" as used herein includes any subject who is afflicted with a tumor (e.g., hepatocellular carcinoma). The terms "subject" and "patient" are used interchangeably herein.

[0110] "Administering" refers to the physical introduction of a therapeutic agent to a subject (e.g., a composition or formulation comprising the therapeutic agent), using any of the various methods and delivery systems known to those skilled in the art. Exemplary routes of administration include intravenous, intramuscular, subcutaneous, intraperitoneal, spinal or other parenteral routes of administration, for example by injection or infusion. The phrase "parenteral administration" as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion, as well as in vivo electroporation. In some aspects, the formulation is administered via a non-parenteral route, in some aspects, orally. Other non-parenteral routes include a topical, epidermal or mucosal route of administration, for example, intranasally, vaginally, rectally, sublingually or topically. Administering can also be performed, for example, once, a plurality of times, and / or over one or more extended periods.

[0111] As used herein, a "Child-Pugh" score or status is a measure of the severity of liver disease in a subject that employs five clinical measures of liver disease (i.e., (1) total bilirubin, (2) serum albumin, (3) ascites, (4) hepatic encephalopathy, and (5) either prothrombin time or international normalized ratio). Each measure of liver disease is scored from 1 to 3 points, with 3 points indicating the most severe disease, and total scores ranging from 5 to 15 points. A subject with a Child-Pugh score of 5-6 has a Child-Pugh A (or Class A) status, indicating normal or apparently normal liver function. A subject with a Child- Pugh score of 7-9 has a Child-Pugh B (or Class B) status, indicating mild to moderate liver damage. And, a subject with a Child-Pugh score of 10-15 has a Child-Pugh C (or Class C) status, indicating severe liver damage.

[0112] As used herein, "Eastern Cooperative Oncology Group Performance Status (ECOG PS)" is a numbering scale used to define the population of patients to be studied in a trial, so that it can be uniformly reproduced among physicians who enroll patients. The ECOG PS utilizes standard criteria for measuring how the disease impacts a patient's daily living abilities. Example definitions for ECOG PS include: "0" for a patient who is fully active and able to carry on all pre-disease performance without restriction; "1" for a patient who is restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature; "2" for a patient who is ambulatory and capable of all self-care, up and about more than 50% of waking hours, but unable to carry out any work activities; "3" for a patient who is capable of only limited self-care and is confined to a bed or chair more than 50% of waking hours; and "4" for a patient who is completely disabled, cannot carry on any self-care, and is totally confined to bed or chair.

[0113] As used herein, a "Barcelona Clinic Liver Cancer (BCLC)" staging system assesses the number of and size of tumors in a patient's liver, the patient's performance status (e.g., ECOG PS), and the patient's liver function (e.g., Child-Pugh score). Example descriptions of the stages include: "Stage 0" indicates a very early stage corresponding to ECOG PS 0 and Child-Pugh A; "Stages A and B" indicate early and intermediate stages, respectively, that correspond to ECOG PS 0 and either Child-Pugh A or B depending on liver function; "Stage C" indicates an advanced stage corresponding to PS 1 or 2 and either Child-Pugh A or B depending on liver function; and "Stage D" indicates severe liver damage corresponding to PS 3 or 4 and Child-Pugh C.

[0114] "Treatment" or "therapy" of a subject refers to any type of intervention or process performed on, or the administration of an active agent to, the subject with the objective of eliminating, reversing, alleviating, ameliorating, inhibiting, reducing, slowing down progression, development, severity or recurrence of a symptom, complication or condition, or biochemical indicia associated with a disease. Response Evaluation Criteria In Solid Tumors (RECIST) is a measure for treatment efficacy and are established rules that define when tumors respond, stabilize, or progress during treatment. RECIST 1.1 is the current guideline to solid tumor measurement and definitions for objective assessment of change in tumor size for use in adult and pediatric cancer clinical trials.

[0115] As used herein, "maintenance therapy" refers to a therapy that is intended to prevent the occurrence or recurrence of tumors.

[0116] As used herein, "a recovery period" is a duration beginning upon the completion of one therapy and ending upon the start of another therapy. In some aspects, the recovery period is a duration sufficient for a subject to recover from adverse events or serious adverse events associated with a therapy.

[0117] As used herein, "effective treatment" refers to treatment producing a beneficial effect, e.g., amelioration of at least one symptom of a disease or disorder. A beneficial effect can take the form of an improvement over baseline, i.e., an improvement over a measurement or observation made prior to initiation of therapy according to the method. A beneficial effect can also take the form of arresting, slowing, retarding, or stabilizing of a deleterious progression of a marker of solid tumor. Effective treatment can refer to alleviation of at least one symptom of a solid tumor. Such effective treatment can, e.g., reduce patient pain, reduce the size and / or number of lesions, can reduce or prevent metastasis of a tumor, and / or can slow tumor growth.

[0118] The term "effective amount" refers to an amount of an agent that provides the desired biological, therapeutic, and / or prophylactic result. That result can be reduction, amelioration, palliation, lessening, delaying, and / or alleviation of one or more of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. In reference to solid tumors, an effective amount comprises an amount sufficient to cause a tumor to shrink and / or to decrease the growth rate of the tumor (such as to suppress tumor growth) or to delay other unwanted cell proliferation. In some aspects, an effective amount is an amount sufficient to prevent or delay tumor recurrence. An effective amount can be administered in one or more administrations. The effective amount of a drug or composition can: (i) reduce the number of cancer cells; (ii) reduce tumor size; (iii) inhibit, retard, slow to some extent and can stop cancer cell infiltration into peripheral organs; (iv) inhibit (i.e., slow to some extent and can stop tumor metastasis); (v) inhibit tumor growth; (vi) prevent or delay occurrence and / or recurrence of tumor; and / or (vii) relieve to some extent one or more of the symptoms associated with the cancer. In one example, an "effective amount" is the amount of a LAG-3 antagonist (e.g., an anti-LAG-3 antibody) alone or the amount of a LAG-3 antagonist (e.g., an anti-LAG-3 antibody) and the amount an additional therapeutic agent (e.g., a PD-1 pathway inhibitor such as an anti-PD-1 antibody), in combination, clinically proven to affect a significant decrease in cancer or slowing of progression of cancer, such as an advanced solid tumor.

[0119] As used herein, the terms "fixed dose," "flat dose," and "flat-fixed dose" are used interchangeably and refer to a dose that is administered to a patient without regard for the weight or body surface area (BSA) of the patient. The fixed or flat dose is therefore not provided as a mg / kg dose, but rather as an absolute amount of the agent (e.g., an amount in μg or mg).

[0120] The use of the term "fixed dose combination" with regard to a composition of the invention means that two or more different inhibitors as described herein (e.g., a LAG-3 antagonist such as an anti-LAG-3 antibody and a PD-1 pathway inhibitor such as an anti- PD-1 antibody) in a single composition are present in the composition in particular (fixed) ratios with each other. In some aspects, the fixed dose is based on the weight (e.g., mg) of the inhibitors (e.g., a mg:mg ratio of the inhibitors). In some aspects, the fixed dose is based on the concentration (e.g., mg / ml) of the inhibitors (e.g., a mg / mL:mg / mL ratio of the inhibitors). In some aspects, the ratio is at least about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, about 1:10, about 1:15, about 1:20, about 1:30, about 1:40, about 1:50, about 1:60, about 1:70, about 1:80, about 1:90, about 1:100, about 1:120, about 1:140, about 1:160, about 1:180, about 1:200, about 200:1, about 180:1, about 160:1, about 140:1, about 120:1, about 100:1, about 90:1, about 80:1, about 70:1, about 60:1, about 50:1, about 40:1, about 30:1, about 20:1, about 15:1, about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, or about 2:1 mg first inhibitor (e.g., an anti-PD-1 antibody) to mg second inhibitor (e.g., an anti-LAG-3 antibody) or mg / mL first inhibitor (e.g., an anti-PD-1 antibody) to mg / mL second inhibitor (e.g., an anti-LAG-3 antibody). For example, a 3:1 ratio of a first inhibitor and a second inhibitor can mean that a vial can contain about 240 mg of the first inhibitor and about 80 mg of the second inhibitor, about 480 mg of the first inhibitor and about 160 mg of the second inhibitor, about 360 mg of the first inhibitor and about 120 mg of the second inhibitor, about 960 mg of the first inhibitor and about 320 mg of the second inhibitor, or about 12 mg / ml of the first inhibitor and about 4 mg / ml of the second inhibitor. For example, a 1:1 ratio of a first inhibitor and a second inhibitor can mean that a vial can contain about 480 mg of the first inhibitor and about 480 mg of the second inhibitor, about 360 mg of the first inhibitor and about 360 mg of the second inhibitor, about 960 mg of the first inhibitor and about 960 mg of the second inhibitor, or about 12 mg / ml of the first inhibitor and about 12 mg / ml of the second inhibitor.

[0121] The term "weight based dose" as referred to herein means that a dose that is administered to a patient is calculated based on the weight of the patient.

[0122] "Dosing interval," as used herein, means the amount of time that elapses between multiple doses of a formulation disclosed herein being administered to a subject. Dosing interval can thus be indicated as ranges.

[0123] The term "dosing frequency" as used herein refers to the frequency of administering doses of a formulation disclosed herein in a given time. Dosing frequency can be indicated as the number of doses per a given time, e.g., once a week or once in two weeks, etc.

[0124] The terms "about once a week," "once about every week," "once about every two weeks," or any other similar dosing interval terms as used herein means approximate number, and "about once a week" or "once about every week" can include every seven days ± two days, i.e., every five days to every nine days. The dosing frequency of "about once a week" or "once about every week" thus can be every five days, every six days, every seven days, every eight days, or every nine days. "Once about every three weeks" can include every 21 days ± 3 days, i.e., every 25 days to every 31 days. Similar approximations apply, for example, to once about every two weeks, once about every four weeks, once about every five weeks, once about every six weeks, once about every seven weeks, once about every eight weeks, once about every nine weeks, once about every ten weeks, once about every eleven weeks, and once about every twelve weeks. In some aspects, a dosing interval of once about every six weeks or once about every twelve weeks means that the first dose can be administered any day in the first week, and then the next dose can be administered any day in the sixth or twelfth week, respectively. In some aspects, a dosing interval of once about every six weeks or once about every twelve weeks means that the first dose is administered on a particular day of the first week (e.g., Monday) and then the next dose is administered on the same day of the sixth or twelfth weeks (i.e., Monday), respectively.

[0125] An "adverse event" (AE) as used herein is any unfavorable and generally unintended or undesirable sign (including an abnormal laboratory finding), symptom, or disease associated with the use of a medical treatment. For example, an adverse event can be associated with activation of the immune system or expansion of immune system cells (e.g., T cells) in response to a treatment. A medical treatment can have one or more associated AEs and each AE can have the same or different level of severity.

[0126] The term "tumor" as used herein refers to any mass of tissue that results from excessive cell growth or proliferation, either benign (non-cancerous) or malignant (cancerous), including pre-cancerous lesions.

[0127] The term "hematological" as used herein can be used interchangeably with "hematologic," and a hematological cancer can be interchangeably referred to as a hematological malignancy.

[0128] The term "biological sample" as used herein refers to biological material isolated from a subject. The term "biological sample" can be used interchangeably with the term "sample" as referred to herein, such as, for example, in the phrases "a sample of the subject’s tumor, plasma, or serum," "a sample of the subject's tumor," or "a sample of the subject's plasma or serum." The biological sample can contain any biological material suitable for analysis, for example, by sequencing nucleic acids in the tumor (or circulating tumor cells) and identifying a genomic alteration in the sequenced nucleic acids. The biological sample can be any suitable biological tissue or fluid such as, for example, tumor tissue, blood, blood plasma (also referred to herein as "plasma"), and serum. The biological sample can be a test tissue sample (e.g., a tissue sample comprising tumor cells and tumor- infiltrating inflammatory cells). In some aspects, the sample is a tumor tissue biopsy, e.g., a formalin-fixed, paraffin-embedded (FFPE) tumor tissue or a fresh-frozen tumor tissue or the like. In some aspects, the biological sample is a liquid biopsy that, in some aspects, comprises one or more of blood, serum, plasma, circulating tumor cells, exoRNA, ctDNA, and cfDNA.

[0129] By way of example, an "anti-cancer agent" promotes cancer regression in a subject. In some aspects, a therapeutically effective amount of the agent promotes cancer regression to the point of eliminating the cancer. "Promoting cancer regression" means that administering an effective amount of the anti-cancer agent, alone or in combination with another agent, results in a reduction in tumor growth or size, necrosis of the tumor, a decrease in severity of at least one disease symptom, an increase in frequency and duration of disease symptom-free periods, or a prevention of impairment or disability due to the disease affliction. In addition, the terms "effective" and "effectiveness" with regard to a treatment includes both pharmacological effectiveness and physiological safety. Pharmacological effectiveness refers to the ability of the agent to promote cancer regression in the patient. Physiological safety refers to the level of toxicity, or other adversephysiological effects at the cellular, organ and / or organism level (adverse effects) resulting from administration of the agent.

[0130] By way of example for the treatment of tumors, a therapeutically effective amount of an anti-cancer agent can inhibit cell growth or tumor growth by at least about 20%, at least about 40%, at least about 60%, or at least about 80% relative to untreated subjects. In some aspects, tumor regression can be observed and continue for a period of at least about 20 days, more preferably at least about 40 days, or at least about 60 days. Notwithstanding these measurements of therapeutic effectiveness, evaluation of immunotherapeutic drugs must also make allowance for immune-related response patterns.

[0131] As used herein, an "immuno-oncology" therapy or an "I-O" or "IO" therapy refers to a therapy that comprises utilizing an immune response to target and treat a tumor in a subject. As such, as used herein, an I-O therapy is a type of anti-cancer therapy. In some aspects, an I-O therapy comprises administering an antibody to a subject. In some aspects, an I-O therapy comprises administering to a subject an immune cell, e.g., a T cell, e.g., a modified T cell, e.g., a T cell modified to express a chimeric antigen receptor or a particular T cell receptor. In some aspects, the I-O therapy comprises administering a therapeutic vaccine to a subject. In some aspects, the I-O therapy comprises administering a cytokine or a chemokine to a subject. In some aspects, the I-O therapy comprises administering an interleukin to a subject. In some aspects, the I-O therapy comprises administering an interferon to a subject. In some aspects, the I-O therapy comprises administering a colony stimulating factor to a subject.

[0132] An "immune response" refers to the action of a cell of the immune system (for example, T lymphocytes, B lymphocytes, natural killer (NK) cells, macrophages, eosinophils, mast cells, dendritic cells and neutrophils) and soluble macromolecules produced by any of these cells or the liver (including antibodies, cytokines, and complement) that results in selective targeting, binding to, damage to, destruction of, and / or elimination from a vertebrate's body of invading pathogens, cells or tissues infected with pathogens, cancerous or other abnormal cells, or, in cases of autoimmunity or pathological inflammation, normal human cells or tissues.

[0133] A "tumor-infiltrating inflammatory cell" or "tumor-associated inflammatory cell" is any type of cell that typically participates in an inflammatory response in a subject andwhich infiltrates tumor tissue. Such cells include tumor-infiltrating lymphocytes (TILs), macrophages, monocytes, eosinophils, histiocytes and dendritic cells.

[0134] The term "FGL-1 positive" or "FGL-1 expression positive," relating to FGL-1 expression, refers to tumor tissue (e.g., a test tissue sample) that is scored as expressing FGL-1 based on the proportion (i.e., percentage) of tumor cells expressing FGL-1 (e.g., greater than or equal to 1% expression) or a Histoscore as described herein of 1 or more, or refers to the detection of FGL-1 in plasma or serum.

[0135] "FGL-1 negative" or "FGL-1 expression negative," refers to tumor tissue (e.g., a test tissue sample) that is not scored as expressing FGL-1 (e.g., less than 1% FGL-1 expression in tumor cells).

[0136] The term "LAG-3 positive" or "LAG-3 expression positive," relating to LAG-3 expression, refers to tumor tissue (e.g., a test tissue sample) that is scored as expressing LAG-3 based on the proportion (i.e., percentage) of immune cells (e.g., tumor-infiltrating lymphocytes such as CD8+ T cells) expressing LAG-3 (e.g., greater than or equal to 1% expression) or the proportion (i.e., percentage) of nucleated cells expressing LAG-3 (i.e., the immune cells that express LAG-3 as a proportion of total nucleated cells, e.g., greater than or equal to 1% expression).

[0137] "LAG-3 negative" or "LAG-3 expression negative," refers to tumor tissue (e.g., a test tissue sample) that is not scored as expressing LAG-3 (e.g., less than 1% LAG-3 expression in immune cells and / or nucleated cells).

[0138] The term "PD-1 positive" or "PD-1 expression positive," relating to cell surface PD- L1 expression, refers to tumor tissue (e.g., a test tissue sample) that is scored as expressing PD-L1 based on the tumor proportion score (TPS), which is the proportion (i.e., percentage) of tumor cells expressing PD-L1 (e.g., greater than or equal to 1% expression), or based on the combined positive score (CPS), which is the number of tumor and immune cells (e.g., tumor cells, lymphocytes, and macrophages) in the tumor tissue that express PD-L1 as a percentage of the total number of viable tumor cells (i.e., the number of tumor and immune cells expressing PD-L1 divided by the total number of viable tumor cells and multiplied by 100 (e.g., greater than or equal to 1%)), or based on the proportion (i.e., percentage) of nucleated cells expressing PD-L1 (i.e., the tumor cells that express PD-L1 as a proportion of total nucleated cells, e.g., greater than or equal to 1% expression).

[0139] "PD-1 negative" or "PD-1 expression negative," refers to tumor tissue (e.g., a test tissue sample) that is not scored as expressing PD-1 (e.g., less than 1% PD-1 expression).

[0140] The term "PD-L1 positive" or "PD-L1 expression positive," relating to cell surface PD-L1 expression, refers to tumor tissue (e.g., a test tissue sample) that is scored as expressing PD-L1 based on the proportion (i.e., percentage) of tumor cells expressing PD- L1 (e.g., greater than or equal to 1% expression) or the proportion (i.e., percentage) of nucleated cells expressing PD-L1 (i.e., the tumor cells that express PD-L1 as a proportion of total nucleated cells, e.g., greater than or equal to 1% expression).

[0141] The term "PD-L1 negative" or "PD-L1 expression negative" refers to tumor tissue (e.g., a test tissue sample) that is not scored as expressing PD-L1 (e.g., less than 1% expression).

[0142] Various aspects of the invention are described in further detail in the following subsections. II. Methods of the Disclosure

[0143] Provided herein is a method of treating a tumor in a human subject in need thereof, the method comprising administering to the subject an immunotherapy comprising a lymphocyte activation gene-3 (LAG-3) antagonist, wherein a sample of the subject’s tumor is fibrinogen-like protein 1 (FGL-1) positive. In some aspects, the method further comprises determining the level of FGL-1 expression in the sample prior to administering the immunotherapy.

[0144] Provided herein is a method of treating tumors in a population of human subjects in need thereof, the method comprising administering to each subject in the population an immunotherapy comprising a LAG-3 antagonist, wherein a sample of each subject’s tumor in the population is FGL-1 positive. In some aspects, the method further comprises determining the level of FGL-1 expression in the sample prior to administering the immunotherapy.

[0145] Provided herein is a method of selecting a tumor in a human subject for an immunotherapy comprising a LAG-3 antagonist, comprising: (a) determining the level of FGL-1 expression in a sample of the subject’s tumor; and (b) administering the immunotherapy to the subject if the sample is FGL-1 positive.

[0146] Provided herein is a method of selecting tumors in a population of human subjects for an immunotherapy comprising a LAG-3 antagonist, comprising: (a) determining thelevel of FGL-1 expression in a sample of each subject’s tumor in the population; and (b) administering the immunotherapy to the subject if the sample is FGL-1 positive.

[0147] Provided herein is a method of selecting a human subject afflicted with a tumor for an immunotherapy comprising a LAG-3 antagonist, comprising: (a) determining the level of FGL-1 expression in a sample of the subject’s tumor; and (b) administering the immunotherapy to the subject if the sample is FGL-1 positive.

[0148] Provided herein is a method of selecting a population of human subjects afflicted with tumors for an immunotherapy comprising a LAG-3 antagonist, comprising: (a) determining the level of FGL-1 expression in a sample of a tumor from a human subject, wherein the subject is a member of the population selected for the immunotherapy if the sample is FGL-1 positive; and (b) administering the immunotherapy to each subject in the population.

[0149] Provided herein is a method of treating a tumor in a human subject in need thereof, the method comprising administering to the subject an immunotherapy comprising a lymphocyte activation gene-3 (LAG-3) antagonist, wherein a sample of the subject’s plasma or serum is fibrinogen-like protein 1 (FGL-1) positive. In some aspects, the method further comprises determining the level of FGL-1 expression in the sample prior to administering the immunotherapy.

[0150] Provided herein is a method of treating tumors in a population of human subjects in need thereof, the method comprising administering to each subject in the population an immunotherapy comprising a LAG-3 antagonist, wherein a sample of each subject’s plasma or serum in the population is FGL-1 positive. In some aspects, the method further comprises determining the level of FGL-1 expression in the sample prior to administering the immunotherapy.

[0151] Provided herein is a method of selecting a tumor in a human subject for an immunotherapy comprising a LAG-3 antagonist, comprising: (a) determining the level of FGL-1 expression in a sample of the subject’s plasma or serum; and (b) administering the immunotherapy to the subject if the sample is FGL-1 positive.

[0152] Provided herein is a method of selecting tumors in a population of human subjects for an immunotherapy comprising a LAG-3 antagonist, comprising: (a) determining the level of FGL-1 expression in a sample of each subject’s plasma or serum in the population; and (b) administering the immunotherapy to the subject if the sample is FGL-1 positive.

[0153] Provided herein is a method of selecting a human subject afflicted with a tumor for an immunotherapy comprising a LAG-3 antagonist, comprising: (a) determining the level of FGL-1 expression in a sample of the subject’s plasma or serum; and (b) administering the immunotherapy to the subject if the sample is FGL-1 positive.

[0154] Provided herein is a method of selecting a population of human subjects afflicted with tumors for an immunotherapy comprising a LAG-3 antagonist, comprising: (a) determining the level of FGL-1 expression in a sample of plasma or serum from a human subject, wherein the subject is a member of the population selected for the immunotherapy if the sample is FGL-1 positive; and (b) administering the immunotherapy to each subject in the population. II.A Samples

[0155] Unless otherwise noted, a sample in the methods described herein can be a sample of the subject’s tumor or a sample of the subject's plasma or serum.

[0156] The sample of the subject's tumor can include any clinically relevant tumor tissue sample, such as a tumor biopsy, a core biopsy, an incisional biopsy, an excisional biopsy, a surgical specimen, or a fine needle aspirate.

[0157] In some aspects, the sample is from a primary tumor.

[0158] In some aspects, the sample is from a metastasis.

[0159] In some aspects, the sample comprises multiple samples from multiple time points, for example, before treatment, during treatment, and / or after treatment.

[0160] In some aspects, the sample comprises multiple samples from different locations in the subject, for example, from a primary tumor and from a metastasis.

[0161] In some aspects, the sample comprises a paraffin-embedded fixed tissue sample.

[0162] In some aspects, the sample comprises a formalin-fixed paraffin-embedded (FFPE) tissue sample.

[0163] In some aspects, the sample comprises a fresh tissue (e.g., tumor) sample.

[0164] In some aspects, the sample comprises a frozen tissue sample.

[0165] In some aspects, the sample comprises a fresh frozen (FF) tissue (e.g., tumor) sample.

[0166] In some aspects, the sample comprises circulating tumor cells (CTCs).

[0167] In some aspects, the sample comprises tumor-infiltrating lymphocytes (TILs).

[0168] In some aspects, the sample comprises tumor cells and TILs.

[0169] In some aspects, the sample comprises circulating lymphocytes.

[0170] In some aspects, the sample comprises an archival tissue sample.

[0171] In some aspects, the sample comprises an archival tissue sample with known diagnosis, treatment, and / or outcome history.

[0172] In some aspects, the sample comprises a block of tissue. II.B FGL-1 Expression

[0173] In some aspects, FGL-1 expression in the sample of a subject’s tumor, plasma, or serum has been determined by an assay that detects the presence of FGL-1 polypeptide. In some aspects, any of the methods disclosed herein comprise performing an assay to detect the presence of FGL-1 polypeptide in the sample. In some aspects, the assay comprises immunohistochemistry (IHC), enzyme-linked immunosorbent assay (ELISA), in vivo imaging, or flow cytometry.

[0174] In some aspects, the sample is from the subject’s tumor and FGL-1 expression in the sample has been determined by an assay that detects the presence of FGL-1 RNA. In some aspects, any of the methods disclosed herein comprise performing an assay to detect the presence of FGL-1 RNA in the sample. In some aspects, the assay comprises RT-PCR, in situ hybridization, or RNase protection.

[0175] In some aspects, the assay is a monoplex assay (e.g., a monoplex IHC assay). In some aspects, the assay is a multiplex assay. In some aspects, the multiplex assay is capable of detecting the presence of FGL-1 as well as, for example, LAG-3, PD-L1, a known mutation affecting treatment of the tumor (e.g., a BRAF mutation), or any combination thereof.

[0176] In any of the methods disclosed herein, it should be understood that "obtaining the sample from the subject" can be an optional step. That is, in some aspects, the method can comprise the "obtaining" step, and in some aspects, the "obtaining" step is not included in the method. It also should be understood that, in some aspects, "determining the level of FGL-1 expression in the sample" is performed by directly "assaying" the sample for FGL- 1 expression, for example, by performing a reverse transcriptase-polymerase chain reaction (RT-PCR) assay or an IHC assay, while in some aspects directly "assaying" the sample is not involved, and FGL-1 expression is determined, for example, by "reviewing" a report of test results from a laboratory, such as test results of an RT-PCR or IHC assay.

[0177] In some aspects, the sample is from the subject’s tumor and at least about 1% of tumor cells in the sample express FGL-1.

[0178] In some aspects, the sample is from the subject’s tumor and less than about 95%, less than about 90%, less than about 85%, less than about 80%, less than about 75%, less than about 70%, less than about 65%, less than about 60%, less than about 55%, less than about 50%, less than about 45%, less than about 40%, less than about 35%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, or less than about 5% of tumor cells in the sample express FGL-1.

[0179] In some aspects, the sample is from the subject’s tumor and about 1% to about 100%, about 1% to about 95%, about 1% to about 90%, about 1% to about 85%, about 1% to about 80%, about 1% to about 75%, about 1% to about 70%, about 1% to about 65%, about 1% to about 60%, about 1% to about 55%, about 1% to about 50%, about 1% to about 45%, about 1% to about 40%, about 1% to about 35%, about 1% to about 30%, about 1% to about 25%, about 1% to about 20%, about 1% to about 15%, about 1% to about 10%, or about 1% to about 5% of tumor cells in the sample express FGL-1.

[0180] In some aspects, the sample is from the subject’s tumor and about 5% to about 100%, about 5% to about 95%, about 5% to about 90%, about 5% to about 85%, about 5% to about 80%, about 5% to about 75%, about 5% to about 70%, about 5% to about 65%, about 5% to about 60%, about 5% to about 55%, about 5% to about 50%, about 5% to about 45%, about 5% to about 40%, about 5% to about 35%, about 5% to about 30%, about 5% to about 25%, about 5% to about 20%, about 5% to about 15%, or about 5% to about 10% of tumor cells in the sample express FGL-1.

[0181] In some aspects, the sample is from the subject’s tumor and about 10% to about 100%, about 10% to about 95%, about 10% to about 90%, about 10% to about 85%, about 10% to about 80%, about 10% to about 75%, about 10% to about 70%, about 10% to about 65%, about 10% to about 60%, about 10% to about 55%, about 10% to about 50%, about 10% to about 45%, about 10% to about 40%, about 10% to about 35%, about 10% to about 30%, about 10% to about 25%, about 10% to about 20%, or about 10% to about 15% of tumor cells in the sample express FGL-1.

[0182] In some aspects, the sample is from the subject’s tumor and about 15% to about 100%, about 15% to about 95%, about 15% to about 90%, about 15% to about 85%, about 15% to about 80%, about 15% to about 75%, about 15% to about 70%, about 15% to about65%, about 15% to about 60%, about 15% to about 55%, about 15% to about 50%, about 15% to about 45%, about 15% to about 40%, about 15% to about 35%, about 15% to about 30%, about 15% to about 25%, or about 15% to about 20% of tumor cells in the sample express FGL-1.

[0183] In some aspects, the sample is from the subject’s tumor and about 20% to about 100%, about 20% to about 95%, about 20% to about 90%, about 20% to about 85%, about 20% to about 80%, about 20% to about 75%, about 20% to about 70%, about 20% to about 65%, about 20% to about 60%, about 20% to about 55%, about 20% to about 50%, about 20% to about 45%, about 20% to about 40%, about 20% to about 35%, about 20% to about 30%, or about 20% to about 25% of tumor cells in the sample express FGL-1.

[0184] In some aspects, the sample is from the subject’s tumor and about 25% to about 100%, about 25% to about 95%, about 25% to about 90%, about 25% to about 85%, about 25% to about 80%, about 25% to about 75%, about 25% to about 70%, about 25% to about 65%, about 25% to about 60%, about 25% to about 55%, about 25% to about 50%, about 25% to about 45%, about 25% to about 40%, about 25% to about 35%, or about 25% to about 30% of tumor cells in the sample express FGL-1.

[0185] In some aspects, the sample is from the subject’s tumor and about 50% to about 100%, about 50% to about 95%, about 50% to about 90%, about 50% to about 85%, about 50% to about 80%, about 50% to about 75%, about 50% to about 70%, about 50% to about 65%, about 50% to about 60%, or about 50% to about 55% of tumor cells in the sample express FGL-1.

[0186] In some aspects, the sample is from the subject’s tumor and about 75% to about 100%, about 75% to about 95%, about 75% to about 90%, about 75% to about 85%, or about 75% to about 80% of tumor cells in the sample express FGL-1.

[0187] In some aspects, the sample is from the subject’s tumor and about 1% to about 100%, about 5% to about 100%, about 10% to about 100%, about 15% to about 100%, about 20% to about 100%, about 25% to about 100%, about 30% to about 100%, about 35% to about 100%, about 40% to about 100%, about 45% to about 100%, about 50% to about 100%, about 55% to about 100%, about 60% to about 100%, about 65% to about 100%, about 70% to about 100%, about 75% to about 100%, about 80% to about 100%, about 85% to about 100%, about 90% to about 100%, or about 95% to about 100% of tumor cells in the sample express FGL-1.

[0188] In some aspects, FGL-1 expression in the sample is determined from an IHC assay. In some aspects, the IHC assay comprises contacting the sample with an anti-human FGL- 1 monoclonal antibody. In some aspects, the anti-human FGL-1 monoclonal antibody is a rabbit anti-human FGL-1 IgG monoclonal antibody, such as, for example, EPR9937 (ab170922) (ABCAM, Boston, MA, USA).

[0189] In some aspects, a histoscore (H-score) is calculated for a sample of a subject’s tumor as a measure of the overall intensity of FGL-1 expression in a subject’s tumor. The histoscore is calculated according to the following formula:

[0190] Histoscore = (1 × percentage of tumor cells in the sample with weak FGL-1 expression) + (2 × percentage of tumor cells in the sample with moderate FGL-1 expression) + (3 × percentage of tumor cells in the sample with strong FGL-1 expression)

[0191] The final histoscore range is 0 (minimum score, no FGL-1 expression in any tumor cells in the sample) to 300 (maximum score, strong FGL-1 expression in all tumor cells in the sample).

[0192] In some aspects, the H-score indicates weak FGL-1 expression.

[0193] In some aspects, the H-score indicates weak to moderate FGL-1 expression.

[0194] In some aspects, the H-score indicates moderate FGL-1 expression.

[0195] In some aspects, the H-score indicates moderate to strong FGL-1 expression.

[0196] In some aspects, the H-score indicates strong FGL-1 expression.

[0197] In some aspects, the sample of a subject’s tumor in any of the methods disclosed herein comprises an H-score of less than about 300. In some aspects, the sample comprises an H-score of less than about 295, less than about 290, less than about 285, less than about 280, less than about 275, less than about 270, less than about 265, less than about 260, less than about 255, less than about 250, less than about 245, less than about 240, less than about 235, less than about 230, less than about 225, less than about 220, less than about 215, less than about 210, less than about 205, less than about 200, less than about 195, less than about 190, less than about 185, less than about 180, less than about 175, less than about 170, less than about 165, less than about 160, less than about 155, less than about 150, less than about 145, less than about 140, less than about 135, less than about 130, less than about 125, less than about 120, less than about 115, less than about 110, less than about 105, less than about 100, less than about 95, less than about 90, less than about 85, less than about 80, less than about 75, less than about 70, less than about 65, less than about 60, less than about 55, lessthan about 50, less than about 45, less than about 40, less than about 35, less than about 30, less than about 25, less than about 20, less than about 15, less than about 10, less than about 9, less than about 8, less than about 7, less than about 6, or less than about 5. In some aspects, the sample comprises an H-score of less than about 250 (e.g., a sample from a subject having a hepatocellular carcinoma as described herein). In some aspects, the sample comprises an H-score of less than about 140 (e.g., a sample from a subject having a hepatocellular carcinoma as described herein).

[0198] In some aspects, the sample of a subject’s tumor in any of the methods disclosed herein comprises an H-score of less than or equal to about 300. In some aspects, the sample comprises an H-score of less than or equal to about 295, less than or equal to about 290, less than or equal to about 285, less than or equal to about 280, less than or equal to about 275, less than or equal to about 270, less than or equal to about 265, less than or equal to about 260, less than or equal to about 255, less than or equal to about 250, less than or equal to about 245, less than or equal to about 240, less than or equal to about 235, less than or equal to about 230, less than or equal to about 225, less than or equal to about 220, less than or equal to about 215, less than or equal to about 210, less than or equal to about 205, less than or equal to about 200, less than or equal to about 195, less than or equal to about 190, less than or equal to about 185, less than or equal to about 180, less than or equal to about 175, less than or equal to about 170, less than or equal to about 165, less than or equal to about 160, less than or equal to about 155, less than or equal to about 150, less than or equal to about 145, less than or equal to about 140, less than or equal to about 135, less than or equal to about 130, less than or equal to about 125, less than or equal to about 120, less than or equal to about 115, less than or equal to about 110, less than or equal to about 105, less than or equal to about 100, less than or equal to about 95, less than or equal to about 90, less than or equal to about 85, less than or equal to about 80, less than or equal to about 75, less than or equal to about 70, less than or equal to about 65, less than or equal to about 60, less than or equal to about 55, less than or equal to about 50, less than or equal to about 45, less than or equal to about 40, less than or equal to about 35, less than or equal to about 30, less than or equal to about 25, less than or equal to about 20, less than or equal to about 15, less than or equal to about 10, less than or equal to about 9, less than or equal to about 8, less than or equal to about 7, less than or equal to about 6, or less than or equal to about 5. In some aspects, the sample comprises an H-score of less than or equal to about10 (e.g., a sample from a subject having a non-small cell lung cancer comprising a non- squamous histology as described herein).

[0199] In some aspects, the sample of a subject’s tumor in any of the methods disclosed herein comprises an H-score of greater than about 1. In some aspects, the sample comprises an H-score of greater than about 5, greater than about 10, greater than about 15, greater than about 20, greater than about 25, greater than about 30, greater than about 35, greater than about 40, greater than about 45, greater than about 50, greater than about 75, greater than about 100, greater than about 125, greater than about 150, greater than about 175, or greater than about 200. In some aspects, the sample comprises an H-score of greater than about 45 (e.g., a sample from a subject having a non-small cell lung cancer comprising a non-squamous histology as described herein).

[0200] In some aspects, the sample of a subject’s tumor in any of the methods disclosed herein comprises an H-score of about 1 to about 300. In some aspects, the sample comprises an H-score of about 1 to about 295, about 1 to about 290, about 1 to about 285, about 1 to about 280, about 1 to about 275, about 1 to about 270, about 1 to about 265, about 1 to about 260, about 1 to about 255, about 1 to about 250, about 1 to about 245, about 1 to about 240, about 1 to about 235, about 1 to about 230, about 1 to about 225, about 1 to about 220, about 1 to about 215, about 1 to about 210, about 1 to about 205, about 1 to about 200, about 1 to about 195, about 1 to about 190, about 1 to about 185, about 1 to about 180, about 1 to about 175, about 1 to about 170, about 1 to about 165, about 1 to about 160, about 1 to about 155, about 1 to about 150, about 1 to about 145, about 1 to about 140, about 1 to about 135, about 1 to about 130, about 1 to about 125, about 1 to about 120, about 1 to about 115, about 1 to about 110, about 1 to about 105, about 1 to about 100, about 1 to about 95, about 1 to about 90, about 1 to about 85, about 1 to about 80, about 1 to about 75, about 1 to about 70, about 1 to about 65, about 1 to about 60, about 1 to about 55, about 1 to about 50, about 1 to about 45, about 1 to about 40, about 1 to about 35, about 1 to about 30, about 1 to about 25, about 1 to about 20, about 1 to about 15, about 1 to about 10, about 1 to about 9, about 1 to about 8, about 1 to about 7, about 1 to about 6, about 1 to about 5, about 5 to about 300, about 5 to about 250, about 5 to about 245, about 5 to about 240, about 5 to about 235, about 5 to about 230, about 5 to about 225, about 5 to about 200, about 5 to about 150, about 5 to about 145, about 5 to about 140, about 5 to about 135, about 5 to about 130, about 5 to about 125, about 5 to about 100, about 5 toabout 50, about 5 to about 25, about 5 to about 20, about 5 to about 15, about 5 to about 10, about 10 to about 300, about 10 to about 250, about 10 to about 245, about 10 to about 240, about 10 to about 235, about 10 to about 230, about 10 to about 225, about 10 to about 200, about 10 to about 150, about 10 to about 145, about 10 to about 140, about 10 to about 135, about 10 to about 130, about 10 to about 125, about 10 to about 100, about 10 to about 50, about 10 to about 25, about 10 to about 20, about 20 to about 300, about 20 to about 250, about 20 to about 240, about 20 to about 235, about 20 to about 230, about 20 to about 225, about 20 to about 200, about 20 to about 150, about 20 to about 145, about 20 to about 140, about 20 to about 135, about 20 to about 130, about 20 to about 125, about 20 to about 100, about 20 to about 50, about 20 to about 25, about 25 to about 300, about 25 to about 250, about 25 to about 240, about 25 to about 235, about 25 to about 230, about 25 to about 225, about 25 to about 200, about 25 to about 150, about 25 to about 145, about 25 to about 140, about 25 to about 135, about 25 to about 130, about 25 to about 125, about 25 to about 100, about 25 to about 50, about 50 to about 300, about 50 to about 295, 50 to about 290, 50 to about 285, 50 to about 280, about 50 to about 275, about 50 to about 270, about 50 to about 265, about 50 to about 260, about 50 to about 255, about 50 to about 250, about 50 to about 240, about 50 to about 235, about 50 to about 230, about 50 to about 225, about 50 to about 200, about 50 to about 150, about 50 to about 145, about 50 to about 140, about 50 to about 135, about 50 to about 130, about 50 to about 125, about 50 to about 100, about 100 to about 300, about 100 to about 275, about 100 to about 270, about 100 to about 265, about 100 to about 260, about 100 to about 255, about 100 to about 250, about 100 to about 240, about 100 to about 235, about 100 to about 230, about 100 to about 225, about 100 to about 200, about 100 to about 150, about 100 to about 145, about 100 to about 140, about 100 to about 135, about 100 to about 130, about 100 to about 125, about 200 to about 300, about 200 to about 275, about 200 to about 270, about 200 to about 265, about 200 to about 260, about 200 to about 255, about 200 to about 250, about 200 to about 240, about 200 to about 235, about 200 to about 230, or about 200 to about 225. In some aspects, the sample comprises an H-score of about 1 to about 250. In some aspects, the sample comprises an H-score of about 1 to about 10 (e.g., a sample from a subject having a non-small cell lung cancer comprising a non-squamous histology as described herein).

[0201] In some aspects, the sample of a subject’s tumor in any of the methods disclosed herein comprises an H-score of about 1 to less than about 300. In some aspects, the samplecomprises an H-score of about 1 to less than about 295, about 1 to less than about 290, about 1 to less than about 280, about 1 to less than about 275, about 1 to less than about 270, about 1 to less than about 265, about 1 to less than about 260, about 1 to less than about 255, about 1 to less than about 250, about 1 to less than about 245, about 1 to less than about 240, about 1 to less than about 235, about 1 to less than about 230, about 1 to less than about 225, about 1 to less than about 220, about 1 to less than about 215, about 1 to less than about 210, about 1 to less than about 200, about 1 to less than about 195, about 1 to less than about 190, about 1 to less than about 185, about 1 to less than about 180, about 1 to less than about 175, about 1 to less than about 170, about 1 to less than about 165, about 1 to less than about 160, about 1 to less than about 155, about 1 to less than about 150, about 1 to less than about 145, about 1 to less than about 140, about 1 to less than about 135, about 1 to less than about 130, about 1 to less than about 125, about 1 to less than about 120, about 1 to less than about 115, about 1 to less than about 110, about 1 to less than about 105, about 1 to less than about 100, about 1 to less than about 95, about 1 to less than about 90, about 1 to less than about 85, about 1 to less than about 80, about 1 to less than about 75, about 1 to less than about 70, about 1 to less than about 65, about 1 to less than about 60, about 1 to less than about 55, about 1 to less than about 50, about 1 to less than about 45, about 1 to less than about 40, about 1 to less than about 35, about 1 to less than about 30, about 1 to less than about 25, about 1 to less than about 20, about 1 to less than about 15, about 1 to less than about 10, about 1 to less than about 5, about 5 to less than about 300, about 5 to less than about 250, about 5 to less than about 245, about 5 to less than about 240, about 5 to less than about 235, about 5 to less than about 230, about 5 to less than about 225, about 5 to less than about 200, about 5 to less than about 150, about 5 to less than about 145, about 5 to less than about 140, about 5 to less than about 135, about 5 to less than about 130, about 5 to less than about 125, about 5 to less than about 100, about 5 to less than about 75, about 5 to less than about 50, about 10 to less than about 250, about 10 to less than about 240, about 10 to less than about 235, about 10 to less than about 230, about 10 to less than about 225, about 10 to less than about 200, about 10 to less than about 150, about 10 to less than about 145, about 10 to less than about 140, about 10 to less than about 135, about 10 to less than about 130, about 10 to less than about 125, about 10 to less than about 100, about 10 to less than about 75, about 10 to less than about 50, about 25 to less than about 250, about 25 to less than about 240, about 25 to lessthan about 235, about 25 to less than about 230, about 25 to less than about 225, about 25 to less than about 200, about 25 to less than about 150, about 25 to less than about 145, about 25 to less than about 140, about 25 to less than about 135, about 25 to less than about 130, about 25 to less than about 125, about 25 to less than about 100, about 25 to less than about 75, about 25 to less than about 50, about 50 to less than about 250, about 50 to less than about 240, about 50 to less than about 235, about 50 to less than about 230, about 50 to less than about 225, about 50 to less than about 200, about 50 to less than about 150, about 50 to less than about 145, about 50 to less than about 140, about 50 to less than about 135, about 50 to less than about 130, about 50 to less than about 125, about 50 to less than about 100, about 50 to less than about 75, about 100 to less than about 250, about 100 to less than about 240, about 100 to less than about 235, about 100 to less than about 230, about 100 to less than about 225, about 100 to less than about 200, about 100 to less than about 150, about 100 to less than about 145, about 100 to less than about 140, about 100 to less than about 135, about 100 to less than about 130, about 100 to less than about 125, about 150 to less than about 250, about 155 to less than about 250, about 160 to less than about 250, about 165 to less than about 250, about 170 to less than about 250, about 175 to less than about 250, about 180 to less than about 250, about 185 to less than about 250, about 190 to less than about 250, about 195 to less than about 250, or about 200 to less than about 250. In some aspects, the sample comprises an H-score of about 1 to less than about 250 (e.g., a sample from a subject having a hepatocellular carcinoma as described herein). In some aspects, the sample comprises an H-score of about 1 to less than about 140 (e.g., a sample from a subject having a hepatocellular carcinoma as described herein).

[0202] In some aspects, the H-score is determined by estimating the percentage of stained cells in each intensity category (i.e., weak, moderate, and strong) in a sample of a subject’s tumor.

[0203] In some aspects, the H-score is a manual calculation (e.g., a pathologist determines the percentages of stained cells in each intensity category (i.e., weak, moderate, and strong) in a sample).

[0204] In some aspects, the H-score is an automatic calculation. An automatic calculation can be interchangeably referred to herein as a calculation by a digital algorithm, an H-score determined by a digital algorithm, or an H-score that is digitally calculated.

[0205] In some aspects, the H-score is an automatic calculation by image analysis software.

[0206] In some aspects, the sample of a subject’s plasma or serum in any of the methods disclosed herein comprises a concentration of soluble FGL-1 (sFGL-1) of less than about 2000 ng / mL. In some aspects, the sample comprises a concentration of SFGL-1 of less than about 1990 ng / mL, less than about 1980 ng / mL, less than about 1970 ng / mL, less than about 1960 ng / mL, less than about 1950 ng / mL, less than about 1940 ng / mL, less than about 1930 ng / mL, less than about 1920 ng / mL, less than about 1910 ng / mL, less than about 1900 ng / mL, less than about 1890 ng / mL, less than about 1880 ng / mL, less than about 1870 ng / mL, less than about 1860 ng / mL, less than about 1850 ng / mL, less than about 1840 ng / mL, less than about 1830 ng / mL, less than about 1820 ng / mL, less than about 1810 ng / mL, less than about 1800 ng / mL, less than about 1790 ng / mL, less than about 1780 ng / mL, less than about 1770 ng / mL, less than about 1760 ng / mL, less than about 1750 ng / mL, less than about 1740 ng / mL, less than about 1730 ng / mL, less than about 1720 ng / mL, less than about 1710 ng / mL, less than about 1700 ng / mL, less than about 1690 ng / mL, less than about 1680 ng / mL, less than about 1670 ng / mL, less than about 1660 ng / mL, less than about 1650 ng / mL, less than about 1640 ng / mL, less than about 1630 ng / mL, less than about 1620 ng / mL, less than about 1610 ng / mL, less than about 1600 ng / mL, less than about 1590 ng / mL, less than about 1580 ng / mL, less than about 1570 ng / mL, less than about 1560 ng / mL, less than about 1550 ng / mL, less than about 1540 ng / mL, less than about 1530 ng / mL, less than about 1520 ng / mL, less than about 1510 ng / mL, less than about 1500 ng / mL, less than about 1490 ng / mL, less than about 1480 ng / mL, less than about 1470 ng / mL, less than about 1460 ng / mL, less than about 1450 ng / mL, less than about 1440 ng / mL, less than about 1430 ng / mL, less than about 1420 ng / mL, less than about 1410 ng / mL, less than about 1400 ng / mL, less than about 1390 ng / mL, less than about 1380 ng / mL, less than about 1370 ng / mL, less than about 1360 ng / mL, less than about 1350 ng / mL, less than about 1340 ng / mL, less than about 1330 ng / mL, less than about 1320 ng / mL, less than about 1310 ng / mL, less than about 1300 ng / mL, less than about 1290 ng / mL, less than about 1280 ng / mL, less than about 1270 ng / mL, less than about 1260 ng / mL, less than about 1250 ng / mL, less than about 1240 ng / mL, less than about 1230 ng / mL, less than about 1220 ng / mL, less than about 1210 ng / mL, less than about 1200 ng / mL, less than about 1190 ng / mL, less than about 1180 ng / mL, less than about 1170 ng / mL, less than about 1160 ng / mL, less than about 1150 ng / mL, less than about 1140 ng / mL, less than about 1130 ng / mL, less thanabout 1120 ng / mL, less than about 1110 ng / mL, less than about 1100 ng / mL, less than about 1090 ng / mL, less than about 1080 ng / mL, less than about 1070 ng / mL, less than about 1060 ng / mL, less than about 1050 ng / mL, less than about 1040 ng / mL, less than about 1030 ng / mL, less than about 1020 ng / mL, less than about 1010 ng / mL, less than about 1000 ng / mL, less than about 990 ng / mL, less than about 980 ng / mL, less than about 970 ng / mL, less than about 960 ng / mL, less than about 950 ng / mL, less than about 940 ng / mL, less than about 930 ng / mL, less than about 920 ng / mL, less than about 910 ng / mL, less than about 900 ng / mL, less than about 890 ng / mL, less than about 880 ng / mL, less than about 870 ng / mL, less than about 860 ng / mL, less than about 850 ng / mL, less than about 840 ng / mL, less than about 830 ng / mL, less than about 820 ng / mL, less than about 810 ng / mL, less than about 800 ng / mL, less than about 790 ng / mL, less than about 780 ng / mL, less than about 770 ng / mL, less than about 760 ng / mL, less than about 750 ng / mL, less than about 740 ng / mL, less than about 730 ng / mL, less than about 720 ng / mL, less than about 710 ng / mL, less than about 700 ng / mL, less than about 690 ng / mL, less than about 680 ng / mL, less than about 670 ng / mL, less than about 660 ng / mL, less than about 650 ng / mL, less than about 640 ng / mL, less than about 630 ng / mL, less than about 620 ng / mL, less than about 610 ng / mL, less than about 600 ng / mL, less than about 590 ng / mL, less than about 580 ng / mL, less than about 570 ng / mL, less than about 560 ng / mL, less than about 550 ng / mL, less than about 540 ng / mL, less than about 530 ng / mL, less than about 520 ng / mL, less than about 510 ng / mL, less than about 500 ng / mL, less than about 490 ng / mL, less than about 480 ng / mL, less than about 470 ng / mL, less than about 460 ng / mL, less than about 450 ng / mL, less than about 440 ng / mL, less than about 430 ng / mL, less than about 420 ng / mL, less than about 410 ng / mL, less than about 400 ng / mL, less than about 390 ng / mL, less than about 380 ng / mL, less than about 370 ng / mL, less than about 360 ng / mL, less than about 350 ng / mL, less than about 340 ng / mL, less than about 330 ng / mL, less than about 320 ng / mL, less than about 310 ng / mL, less than about 300 ng / mL, less than about 290 ng / mL, less than about 280 ng / mL, less than about 270 ng / mL, less than about 260 ng / mL, less than about 250 ng / mL, less than about 240 ng / mL, less than about 230 ng / mL, less than about 220 ng / mL, less than about 210 ng / mL, less than about 200 ng / mL, less than about 190 ng / mL, less than about 180 ng / mL, less than about 170 ng / mL, less than about 160 ng / mL, less than about 150 ng / mL, less than about 140 ng / mL, less than about 130 ng / mL, less than about 120 ng / mL, less than about 110 ng / mL, or less than about 100 ng / mL. Insome aspects, the sample of a subject’s plasma or serum is less than about 360 ng / mL (e.g., a sample from a subject having a non-small cell lung cancer comprising a non-squamous histology as described herein).

[0207] In some aspects, the sample of a subject’s plasma or serum in any of the methods disclosed herein comprises a concentration of sFGL-1 of about 1 ng / mL to about 2000 ng / mL. In some aspects, the sample comporises a concentration of sFGL-1 of about 1 ng / mL to about 1900 ng / mL, about 1 ng / mL to about 1800 ng / mL, about 1 ng / mL to about 1700 ng / mL, about 1 ng / mL to about 1600 ng / mL, about 1 ng / mL to about 1500 ng / mL, about 1 ng / mL to about 1400 ng / mL, about 1 ng / mL to about 1300 ng / mL, about 1 ng / mL to about 1200 ng / mL, about 1 ng / mL to about 1100 ng / mL, about 1 ng / mL to about 1000 ng / mL, about 1 ng / mL to about 900 ng / mL, about 1 ng / mL to about 800 ng / mL, about 1 ng / mL to about 700 ng / mL, about 1 ng / mL to about 600 ng / mL, about 1 ng / mL to about 500 ng / mL, about 1 ng / mL to about 490 ng / mL, about 1 ng / mL to about 480 ng / mL, about 1 ng / mL to about 470 ng / mL, about 1 ng / mL to about 460 ng / mL, about 1 ng / mL to about 450 ng / mL, about 1 ng / mL to about 440 ng / mL, about 1 ng / mL to about 430 ng / mL, about 1 ng / mL to about 420 ng / mL, about 1 ng / mL to about 410 ng / mL, about 1 ng / mL to about 400 ng / mL, about 1 ng / mL to about 390 ng / mL, about 1 ng / mL to about 380 ng / mL, about 1 ng / mL to about 370 ng / mL, about 1 ng / mL to about 360 ng / mL, about 1 ng / mL to about 350 ng / mL, about 1 ng / mL to about 340 ng / mL, about 1 ng / mL to about 330 ng / mL, about 1 ng / mL to about 320 ng / mL, about 1 ng / mL to about 310 ng / mL, about 1 ng / mL to about 300 ng / mL, about 1 ng / mL to about 290 ng / mL, about 1 ng / mL to about 280 ng / mL, about 1 ng / mL to about 270 ng / mL, about 1 ng / mL to about 260 ng / mL, about 1 ng / mL to about 250 ng / mL, about 1 ng / mL to about 240 ng / mL, about 1 ng / mL to about 230 ng / mL, about 1 ng / mL to about 220 ng / mL, about 1 ng / mL to about 210 ng / mL, about 1 ng / mL to about 200 ng / mL, about 1 ng / mL to about 190 ng / mL, about 1 ng / mL to about 180 ng / mL, about 1 ng / mL to about 170 ng / mL, about 1 ng / mL to about 160 ng / mL, about 1 ng / mL to about 150 ng / mL, about 1 ng / mL to about 140 ng / mL, about 1 ng / mL to about 130 ng / mL, about 1 ng / mL to about 120 ng / mL, about 1 ng / mL to about 110 ng / mL, about 1 ng / mL to about 100 ng / mL, about 1 ng / mL to about 90 ng / mL, about 1 ng / mL to about 80 ng / mL, about 1 ng / mL to about 70 ng / mL, about 1 ng / mL to about 60 ng / mL, about 1 ng / mL to about 50 ng / mL, about 1 ng / mL to about 40 ng / mL, about 1 ng / mL to about 30 ng / mL, about 1 ng / mL to about 20 ng / mL, about 1 ng / mL to about 10 ng / mL, about 10 ng / mL to about 500ng / mL, about 10 ng / mL to about 490 ng / mL, about 10 ng / mL to about 480 ng / mL, about 10 ng / mL to about 470 ng / mL, about 10 ng / mL to about 460 ng / mL, about 10 ng / mL to about 450 ng / mL, about 10 ng / mL to about 440 ng / mL, about 10 ng / mL to about 430 ng / mL, about 10 ng / mL to about 420 ng / mL, about 10 ng / mL to about 410 ng / mL, about 10 ng / mL to about 400 ng / mL, about 10 ng / mL to about 390 ng / mL, about 10 ng / mL to about 380 ng / mL, about 10 ng / mL to about 370 ng / mL, about 10 ng / mL to about 360 ng / mL, about 10 ng / mL to about 350 ng / mL, about 10 ng / mL to about 340 ng / mL, about 10 ng / mL to about 330 ng / mL, about 10 ng / mL to about 320 ng / mL, about 10 ng / mL to about 310 ng / mL, about 10 ng / mL to about 300 ng / mL, about 10 ng / mL to about 290 ng / mL, about 10 ng / mL to about 280 ng / mL, about 10 ng / mL to about 270 ng / mL, about 10 ng / mL to about 260 ng / mL, about 10 ng / mL to about 250 ng / mL, about 10 ng / mL to about 240 ng / mL, about 10 ng / mL to about 230 ng / mL, about 10 ng / mL to about 220 ng / mL, about 10 ng / mL to about 210 ng / mL, about 10 ng / mL to about 200 ng / mL, about 10 ng / mL to about 190 ng / mL, about 10 ng / mL to about 180 ng / mL, about 10 ng / mL to about 170 ng / mL, about 10 ng / mL to about 160 ng / mL, about 10 ng / mL to about 150 ng / mL, about 10 ng / mL to about 140 ng / mL, about 10 ng / mL to about 130 ng / mL, about 10 ng / mL to about 120 ng / mL, about 10 ng / mL to about 110 ng / mL, about 10 ng / mL to about 100 ng / mL, about 10 ng / mL to about 50 ng / mL, about 50 ng / mL to about 490 ng / mL, about 50 ng / mL to about 480 ng / mL, about 50 ng / mL to about 470 ng / mL, about 50 ng / mL to about 460 ng / mL, about 50 ng / mL to about 450 ng / mL, about 50 ng / mL to about 440 ng / mL, about 50 ng / mL to about 430 ng / mL, about 50 ng / mL to about 420 ng / mL, about 50 ng / mL to about 410 ng / mL, about 50 ng / mL to about 400 ng / mL, about 50 ng / mL to about 390 ng / mL, about 50 ng / mL to about 380 ng / mL, about 50 ng / mL to about 370 ng / mL, about 50 ng / mL to about 360 ng / mL, about 50 ng / mL to about 350 ng / mL, about 50 ng / mL to about 340 ng / mL, about 50 ng / mL to about 330 ng / mL, about 50 ng / mL to about 320 ng / mL, about 50 ng / mL to about 310 ng / mL, about 50 ng / mL to about 300 ng / mL, about 50 ng / mL to about 290 ng / mL, about 50 ng / mL to about 280 ng / mL, about 50 ng / mL to about 270 ng / mL, about 50 ng / mL to about 260 ng / mL, about 50 ng / mL to about 250 ng / mL, about 50 ng / mL to about 240 ng / mL, about 50 ng / mL to about 230 ng / mL, about 50 ng / mL to about 220 ng / mL, about 50 ng / mL to about 210 ng / mL, about 50 ng / mL to about 200 ng / mL, about 50 ng / mL to about 190 ng / mL, about 50 ng / mL to about 180 ng / mL, about 50 ng / mL to about 170 ng / mL, about 50 ng / mL to about 160ng / mL, about 50 ng / mL to about 150 ng / mL, about 50 ng / mL to about 140 ng / mL, about 50 ng / mL to about 130 ng / mL, about 50 ng / mL to about 120 ng / mL, about 50 ng / mL to about 110 ng / mL, about 50 ng / mL to about 100 ng / mL, about 100 ng / mL to about 500 ng / mL, about 100 ng / mL to about 490 ng / mL, about 100 ng / mL to about 480 ng / mL, about 100 ng / mL to about 470 ng / mL, about 100 ng / mL to about 460 ng / mL, about 100 ng / mL to about 450 ng / mL, about 100 ng / mL to about 440 ng / mL, about 100 ng / mL to about 430 ng / mL, about 100 ng / mL to about 420 ng / mL, about 100 ng / mL to about 410 ng / mL, about 100 ng / mL to about 400 ng / mL, about 100 ng / mL to about 390 ng / mL, about 100 ng / mL to about 380 ng / mL, about 100 ng / mL to about 370 ng / mL, about 100 ng / mL to about 360 ng / mL, about 100 ng / mL to about 350 ng / mL, about 100 ng / mL to about 340 ng / mL, about 100 ng / mL to about 330 ng / mL, about 100 ng / mL to about 320 ng / mL, about 100 ng / mL to about 310 ng / mL, about 100 ng / mL to about 300 ng / mL, about 100 ng / mL to about 290 ng / mL, about 100 ng / mL to about 280 ng / mL, about 100 ng / mL to about 270 ng / mL, about 100 ng / mL to about 260 ng / mL, about 100 ng / mL to about 250 ng / mL, about 100 ng / mL to about 240 ng / mL, about 100 ng / mL to about 230 ng / mL, about 100 ng / mL to about 220 ng / mL, about 100 ng / mL to about 210 ng / mL, about 100 ng / mL to about 200 ng / mL, about 200 ng / mL to about 2000 ng / mL, about 300 ng / mL to about 2000 ng / mL, about 400 ng / mL to about 2000 ng / mL, about 500 ng / mL to about 2000 ng / mL, about 600 ng / mL to about 2000 ng / mL, about 700 ng / mL to about 2000 ng / mL, about 800 ng / mL to about 2000 ng / mL, about 900 ng / mL to about 2000 ng / mL, about 1000 ng / mL to about 2000 ng / mL, about 1100 ng / mL to about 2000 ng / mL, about 1200 ng / mL to about 2000 ng / mL, about 1300 ng / mL to about 2000 ng / mL, about 1400 ng / mL to about 2000 ng / mL, about 1500 ng / mL to about 2000 ng / mL, about 1600 ng / mL to about 2000 ng / mL, about 1700 ng / mL to about 2000 ng / mL, about 1800 ng / mL to about 2000 ng / mL, or about 1900 ng / mL to about 2000 ng / mL.

[0208] In some aspects, the sample of a subject’s plasma or serum in any of the methods disclosed herein comprises a concentration of sFGL-1 of greater than about 100 ng / mL. In some aspects, the sample comprises a concentration of sFGL-1 of greater than about 200 ng / mL, greater than about 300 ng / mL, greater than about 400 ng / mL, greater than about 500 ng / mL, greater than about 600 ng / mL, greater than about 700 ng / mL, greater than about 800 ng / mL, greater than about 900 ng / mL, greater than about 1000 ng / mL, greater than about 1100 ng / mL, greater than about 1200 ng / mL, greater than about 1300 ng / mL, greaterthan about 1400 ng / mL, greater than about 1500 ng / mL, greater than about 1600 ng / mL, greater than about 1700 ng / mL, greater than about 1710 ng / mL, greater than about 1720 ng / mL, greater than about 1730 ng / mL, greater than about 1740 ng / mL, greater than about 1750 ng / mL, greater than about 1760 ng / mL, greater than about 1770 ng / mL, greater than about 1780 ng / mL, greater than about 1790 ng / mL, or greater than about 1800 ng / mL.

[0209] In some aspects, the FGL-1 expression, concentration, and / or H-score is predictive of a subject’s responsiveness to an immunotherapy comprising a LAG-3 antagonist. In some aspects, the FGL-1 expression, concentration, and / or H-score of moderate FGL-1 expression is predictive of a subject being responsive to an immunotherapy comprising a LAG-3 antagonist. In some aspects, the FGL-1 expression, concentration, and / or H-score of strong FGL-1 expression is predictive of reduced responsiveness or non-responsiveness of a subject to an immunotherapy comprising a LAG-3 antagonist.

[0210] In some aspects, the dose of an immunotherapy comprising a LAG-3 antagonist is determined by the FGL-1 expression, concentration, and / or H-score. In some aspects, the dose of a LAG-3 antagonist (e.g., an anti-LAG-3 antibody), the dose of a PD-1 pathway inhibitor (e.g., an anti-PD-1 pathway inhibitor), or the doses of a LAG-3 antagonist and a PD-1 pathway inhibitor are determined by the FGL-1 expression, concentration, and / or H- score. In some aspects, the dose of the immunotherapy is the standard dose administered for the tumor when the FGL-1 expression, concentration, and / or H-score indicates weak FGL-1 expression. In some aspects, the dose of the immunotherapy is the standard dose administered for the tumor when the FGL-1 expression, concentration, and / or H-score indicates weak to moderate FGL-1 expression. In some aspects, the dose of the immunotherapy is the standard dose administered for the tumor when the FGL-1 expression, concentration, and / or H-score indicates moderate FGL-1 expression. In some aspects, the dose of the immunotherapy is increased above the standard dose administered for the tumor when the FGL-1 expression, concentration, and / or H-score is indicative of strong FGL-1 expression. II.C Tumors

[0211] In some aspects of any of the methods disclosed herein, the tumor comprises a hepatocellular carcinoma, colorectal carcinoma, gastric cancer, small-cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), squamous NSCLC, non-squamous NSCLC, solid cancer with liver metastatic disease, cervical cancer, breast cancer, triple-negativebreast cancer, pancreatic cancer, urothelial cancer, prostate cancer, hormone refractory prostate adenocarcinoma, hematological cancer, squamous cell carcinoma, glioma, gastrointestinal cancer, renal cancer, clear cell carcinoma, ovarian cancer, liver cancer, endometrial cancer, kidney cancer, renal cell carcinoma (RCC), thyroid cancer, neuroblastoma, glioblastoma, glioblastoma multiforme, stomach cancer, bladder cancer, hepatoma, colon cancer, head and neck cancer, gastroesophageal cancer, germ cell tumor, pediatric sarcoma, sinonasal natural killer T-cell lymphoma, melanoma, bone cancer, skin cancer, uterine cancer, cancer of the anal region, testicular cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, rectal cancer, solid tumor of childhood, cancer of the ureter, carcinoma of the renal pelvis, neoplasm of the central nervous system (CNS), primary CNS lymphoma, spinal axis tumor, brain cancer, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid cancer, environmentally- induced cancer, virus-related cancer or cancer of viral origin, or any combination thereof.

[0212] In some aspects, the tumor comprises a hepatocellular carcinoma, colorectal cancer, lung cancer, gastric cancer, renal cancer, prostate cancer, melanoma, hematological cancer, breast cancer, head and neck cancer, or a combination thereof.

[0213] In some aspects, the tumor comprises a breast cancer.

[0214] In some aspects, the tumor comprises a triple-negative breast cancer. As used herein, the term "triple-negative breast cancer" refers to a breast cancer that is characterized by a lack of detectable expression of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor type 2 (HER2 or ErbB2).

[0215] In some aspects, the tumor comprises a head and neck cancer.

[0216] In some aspects, the tumor is unresectable, advanced, and / or metastatic.

[0217] In some aspects, the tumor is a malignant tumor.

[0218] In some aspects, the method is a first line therapy.

[0219] In some aspects, the method is a second line therapy.

[0220] In some aspects, the method is a third line therapy.

[0221] In some aspects, the subject has progressed on or is intolerant of a prior therapy (e.g., a standard of care therapy). For example, the National Comprehensive CancerNetwork (NCCN), an alliance of 21 major cancer centers in the USA, publishes the NCCN Clinical Practice Guidelines in Oncology (NCCN GUIDELINES®) that provide detailed up-to-date information on the standard of care treatments for a wide variety of cancers. See NCCN GUIDELINES®, 2023-2024, www.nccn.org / guidelines / category_1, last accessed May 3, 2024.

[0222] In some aspects, the subject is naïve to prior systemic therapy.

[0223] In some aspects, the subject is naïve to prior immuno-oncology therapy, the subject is naïve to prior immuno-oncology for the tumor, or the tumor is naïve to prior immuno- oncology therapy. II.C.1 Hepatocellular Carcinoma

[0224] In some aspects, the tumor comprises a hepatocellular carcinoma (HCC). The term "HCC" as used herein is interchangeable with any of the terms "liver cancer," "liver cell carcinoma," and "hepatoma."

[0225] In some aspects, the tumor comprises a HCC, and the sample of a subject's tumor as described herein comprises an H-score as described herein. In some aspects, the sample comprises an H-score of less than about 250. In some aspects, the sample comprises an H- score of about 1 to less than about 250. In some aspects, the sample comprises an H-score of less than about 140. In some aspects, the sample comprises an H-score of about 1 to less than about 140. In some aspects, the H-score is a manual calculation (e.g., an H-score of less than about 250 or about 1 to less than about 250). In some aspects, the H-score is an automated calculation by image analysis software (e.g., an H-score of less than about 140 or about 1 to less than about 140).

[0226] In some aspects, the subject has progressed on or is intolerant to a prior therapy (e.g., a standard of care therapy, including a standard of care 1L or 2L therapy). In some aspects, the prior therapy and / or standard of care therapy comprises a tyrosine kinase inhibitor, an anti-angiogenesis agent, a checkpoint inhibitor, a checkpoint stimulator, a chemotherapeutic agent, an immunotherapeutic agent (e.g., an agent used in immuno- oncology therapy), a platinum agent, an alkylating agent, a taxane, a nucleoside analog, an antimetabolite, a topisomerase inhibitor, an anthracycline, a vinca alkaloid, or any combination thereof. In some aspects, the prior therapy comprises sorafenib (e.g., sorafenib tosylate, also known as NEXAVAR®, which is indicated for the treatment of patients with unresectable HCC), lenvatinib (e.g., lenvatinib mesylate, also known as LENVIMA®,which is indicated for 1L treatment of patients with unresectable HCC), regorafenib (e.g., STIVARGA®, which is indicated for the treatment of patients with HCC who have been previously treated with sorafenib) and / or cabozantinib (e.g., cabozantinib S-malate, also known as CABOMETYX®, which is indicated for the treatment of patients with HCC who have been previously treated with sorafenib). In some aspects, the prior therapy comprises the combination of an anti-PD-L1 antibody (e.g., atezolizumab, also known as TECENTRIQ®) and an anti-VEGF antibody (e.g., bevacizumab, also known as AVASTIN®). The combination of atezolizumab and bevacizumab is indicated for the treatment of patients with unresectable or metastatic HCC who have not received prior systemic therapy. In some aspects, the prior therapy comprises an anti-VEGFR-2 antibody (e.g., ramucirumab, also known as CYRAMZA®, which is indicated as a single agent, for the treatment of patients with HCC who have an alpha fetoprotein of ≥400 ng / mL and have been treated with sorafenib). In some aspects, the prior therapy is an anti-PD-1 antibody (e.g., nivolumab, also known as OPDIVO®, or pembrolizumab, also known as KEYTRUDA®, each indicated as a single agent for the treatment of patients with HCC who have been previously treated with sorafenib). In some aspects, the prior therapy is the combination of an anti-PD-1 antibody (e.g., nivolumab / OPDIVO®) in combination with an anti-CTLA-4 antibody (e.g., ipilimumab, also known as YERVOY®). The combination of nivolumab and ipilimumab is indicated for the treatment of patients who have been previously treated with sorafenib.

[0227] In some aspects, the subject is naïve to prior immuno-oncology (I-O) therapy. In some aspects, the subject has never received I-O therapy, has received I-O therapy for a cancer other than HCC, or has received I-O therapy for a previous HCC but not a current HCC. In some aspects, the subject is naïve to prior I-O therapy, the subject is naïve to prior I-O therapy for HCC, or the HCC is naïve to prior I-O therapy. In some aspects, the prior I-O therapy is an antibody. In some aspects, the antibody binds to a checkpoint inhibitor. In some aspects, the prior I-O therapy is an anti-PD-1 antibody and / or the combination of an anti-PD-1 antibody and an anti-CTLA-4 antibody.

[0228] In some aspects, the methods of the disclosure comprise administering to the subject an immunotherapy comprising a LAG-3 antagonist based on the subject's performance status, liver function, and / or cancer stage. Performance status, liver function, and / or cancer stage can be indicated by any one or more systems in the art. In some aspects, the systemis Child-Pugh score or status, Eastern Cooperative Oncology Group Performance Status (ECOG PS), and / or Barcelona Clinic Liver Cancer (BCLC) stage. In some aspects, the subject has a Child-Pugh score of 5-6, 7-9, or 10-15. In some aspects, the subject has a Child-Pugh status of A, B, or C. In some aspects, the subject has a Child-Pugh score of 5- 6 and / or has Child-Pugh A status. In some aspects, the subject has a Child-Pugh score of 7-9 and / or has Child-Pugh B status. In some aspects, the subject has a Child-Pugh score of 10-15 and / or has Child-Pugh C status. In some aspects, the subject has an ECOG PS of 0, 1, 2, 3, or 4. In some aspects, the subject has a BCLC status of 0, A, B, C, or D. In some aspects, the subject has an ECOG PS of 0, a Child-Pugh score of 5-6, a Child-Pugh A (or Class A) status, and / or a BCLC stage of 0. In some aspects, the subject has an ECOG PS of 0, a Child-Pugh score of 5 or 6, a Child-Pugh A (or Class A) status, and / or a BCLC stage of A. In some aspects, the subject has an ECOG PS of 0, a Child-Pugh score of 7-9, a Child- Pugh B (or Class B) status, and / or a BCLC stage of B. In some aspects, the subject has an ECOG PS of 1 or 2, a Child-Pugh score of 5-6 or 7-9, a Child-Pugh A or B (Class A or Class B) status, and / or a BCLC stage of C. In some aspects, the subject has an ECOG PS of 3 or 4, a Child-Pugh score of 10-15, a Child-Pugh C (or Class C) status, and / or a BCLC stage of D.

[0229] In some aspects, the subject has microvascular invasion of HCC and / or extrahepatic spread of HCC. In some aspects, the subject lacks microvascular invasion of HCC and / or extrahepatic spread of HCC.

[0230] In some aspects, the HCC has an etiology associated with chronic liver disease, chronic liver inflammation, an infection, a toxin, aflatoxin B1, alcoholic liver disease, tobacco use, metabolic syndrome, diabetes, obesity, and / or non-alcoholic fatty liver disease. In some aspects, the HCC is viral HCC (i.e., the cause of HCC is a viral infection). In some aspects, the HCC is non-viral HCC (i.e., the cause of HCC is any cause other than viral infection). In some aspects, the subject has an HBV infection. In some aspects, the subject has an HCV infection. In some aspects, the subject has an HBV infection and an HCV infection. In some aspects, the subject has an HIV infection and a HBV and / or HCV infection. In some aspects, the subject has alcoholic liver disease. In some aspects, the subject has metabolic syndrome, diabetes, and / or non-alcoholic fatty liver disease.

[0231] In some aspects, any of the methods described herein comprises administering (e.g., intravenously administering) about 480 mg of an anti-LAG-3 antibody as described herein(e.g., relatlimab or an antibody comprising the sequences of relatlimab), and about 480 mg of an anti-PD-1 antibody as described herein (e.g., nivolumab, or an antibody comprising the sequences of nivolumab) to a subject having a tumor comprising an HCC.

[0232] In some aspects, any of the methods described herein further comprises administering a PDCT as described herein to a subject having a tumor comprising an HCC. II.C.2 Lung Cancer

[0233] In some aspects, the tumor comprises a lung cancer.

[0234] In some aspects, the lung cancer is recurrent following multi-modal therapy for locally advanced lung cancer.

[0235] In some aspects, the subject has not received a prior local or systemic anticancer therapy given as primary therapy for locally advanced disease.

[0236] In some aspects, the subject has not received a prior systemic therapy for cancer, the subject has not received a prior systemic therapy for lung cancer, or the subject has not received a prior systemic therapy for advanced or metastatic lung cancer.

[0237] In some aspects, the subject is naïve to prior immuno-oncology (I-O) therapy. In some aspects, the subject has never received I-O therapy, has received I-O therapy for a cancer other than lung cancer, or has received I-O therapy for a previous lung cancer but not a current lung cancer. In some aspects, the subject is naïve to prior I-O therapy, the subject is naïve to prior I-O therapy for lung cancer, or the lung cancer is naïve to prior I- O therapy. In some aspects, the prior I-O therapy is an antibody. In some aspects, the antibody binds to a checkpoint inhibitor. In some aspects, the prior I-O therapy is an anti- PD-1 antibody and / or the combination of an anti-PD-1 antibody and an anti-CTLA-4 antibody.

[0238] In some aspects the subject has an ECOG PS of 0, 1, 2, 3, or 4. In some aspects, the subject has an ECOG PS of ≤ 3. In some aspects, the subject has an ECOG PS of ≤ 2. In some aspects, the subject has an ECOG PS of ≤ 1.

[0239] In some aspects, lung cancer is staged based on a tumor (T) / node (N) / metastasis (M) staging system (T / N / M) such as the American Joint Committee on Cancer (AJCC) classification. See, e.g., https: / / www.cancer.org / cancer / lung-cancer / detection-diagnosis- staging / staging-nsclc.html, last accessed December 20, 2022.

[0240] Stages for lung cancer (e.g., NSCLC) include: occult (hidden) stage, Stage 0 (carcinoma in situ), Stage I (e.g., Stage IA1, Stage IA2, Stage IA3, and Stage IB NSCLC),Stage II (e.g., Stage IIA and Stage IIB NSCLC), Stage III (e.g., Stage IIIA, Stage IIIB, and Stage IIIC NSCLC), and Stage IV (e.g., Stage IVA and Stage IVB NSCLC).

[0241] In some aspects the subject is afflicted with an occult (hidden) stage lung cancer (e.g., NSCLC). In the occult stage, the cancer cannot be seen by imaging or bronchoscopy (TX), has not spread to lymph nodes (N0), and has not metastasized (M0) (TX / N0 / M0).

[0242] In some aspects the subject is afflicted with a Stage 0 lung cancer (e.g., NSCLC). In Stage 0 (Tis / N0 / M0), cancer cells are found only in the lining of the airways and have not invaded deeper into other lung tissues (Tis). N0 and M0 are as described above.

[0243] In some aspects, the subject is afflicted with a Stage I lung cancer (e.g., NSCLC). Stage I lung cancer is divided, e.g., into Stage IA1, Stage IA2, Stage IA3, and Stage IB for NSCLC. N0 and M0 are as described above. In Stage IA1 (T1mi / N0 / M0), the cancer is a minimally invasive adenocarcinoma, and the tumor is no larger than 3 centimeters (cm) across, with the part invading into deeper lung tissues not larger than 0.5 cm across (T1mi). In Stage IA1 (T1a / N0 / M0), the tumor is not larger than 1 cm across, has not grown into the membranes surrounding the lungs, and does not affect the main branches of the bronchi (T1a). In Stage IA2 (T1b / N0 / M0), the tumor is larger than 1 cm across but not larger than 2 cm across, has not grown into the membranes surrounding the lungs, and does not affect the main branches of the bronchi (T1b). In Stage IA3 (T1c / N0 / M0), the tumor is larger than 2 cm across but not larger than 3 cm across, has not grown into the membranes surrounding the lungs, and does not affect the main branches of the bronchi (T1c). In Stage IB (T2a / N0 / M0), one or more of the following is true: 1) the tumor is larger than 3 cm across but not larger than 4 cm across; 2) the cancer has spread to the main bronchus and is at least 2 cm below where the trachea joins the bronchus; 3) the cancer has spread to the innermost layer of the membrane that covers the lung and is not larger than 4 cm across; or 4) the tumor is not larger than 4 cm across but is partially clogging the airways (T2a).

[0244] In some aspects, the subject is afflicted with a Stage II lung cancer (e.g., NSCLC). Stage II is divided, e.g., into Stage IIA (T2b / N0 / M0) and IIB (T1a / T1b / T1c / N1 / M0 or T2a / T2b / N1 / M0 or T3 / N0 / M0) for NSCLC. N0 and M0 are as described above. In Stage IIA, one or more of the following is true: 1) the tumor is larger than 4 cm across but not larger than 5 cm across; 2) the cancer has spread to the main bronchus, is at least 2 centimeters below where the trachea joins the bronchus, and the tumor is larger than 4 cm across but not larger than 5 cm across; 3) the cancer has spread to the innermost layer ofthe membrane that covers the lung, and the tumor is larger than 4 cm across but not larger than 5 cm across; or 4) the tumor is larger than 4 cm across but not larger than 5 cm across and is partially clogging the airways (T2b). In stage IIB, the cancer has either spread to the lymph nodes or not. If the cancer has spread to the lymph nodes, then the cancer can only have spread to the lymph nodes on the same side of the chest as the tumor, and the lymph nodes with cancer are within the lung or near the bronchus (N1). For T1a / T1b / T1c / N1 / M0, the tumor is no larger than 3 cm across, has not grown into the membranes surrounding the lungs, and does not affect the main branches of the bronchi (T1a / T1b / T1c). For T2a / T2b / N1 / M0, one or more of the following is true: 1) the tumor is larger than 3 cm across but not larger than 5 cm across; 2) the cancer has spread to the main bronchus, is at least 2 centimeters below where the trachea joins the bronchus, and the tumor is not larger than 5 cm across; 3) the cancer has spread to the innermost layer of the membrane that covers the lung and is not larger than 5 cm across; or 4) the tumor is not larger than 5 cm across and is partially clogging the airways (T2a / T2b). In T3 / N0 / M0, the cancer has not spread to the lymph nodes or metastasized but one or more of the following is true: 1) the cancer is larger than 5 cm across but not larger than 7 cm across; 2) the cancer has grown into the chest wall, the parietal pleura, the phrenic nerve, or the parietal pericardium; or 3) the same lobe of a lung has 2 or more separate tumor nodules (T3).

[0245] In some aspects, the subject is afflicted with a Stage III lung cancer (e.g., NSCLC). Stage III is divided, e.g., into Stage IIIA (T1a / T1b / T1c / N2 / M0 or T2a / T2b / N2 / M0 or T3 / N1 / M0 or T4 / N0 or N1 / M0), IIIB (T1a / T1b / T1c / N3 / M0 or T2a / T2b / N3 / M0 or T3 / N2 / M0 or T4 / N2 / M0), and IIIC (T3 / N3 / M0 or T4 / N3 / M0) for NSCLC. T1a / T1b / T1c, T2a / T2b, T3, N0, N1, and M0 are as described above. For N2, the cancer has spread to lymph nodes around the carina or in the mediastinum on the same side as the tumor. For N3, the cancer has spread to lymph nodes on either side of the body near the collarbone, and / or has spread on the other side of the body from the main tumor to hilar or mediastinal lymph nodes. For T4, one or more of the following is true: 1) the tumor is larger than 7 cm across; 2) the tumor has grown into the mediastinum, the heart, the large blood vessels near the heart (e.g., the aorta), the trachea, the esophagus, the diaphragm, the backbone, or the carina; or 3) 2 or more tumor nodules are present in different lobes of the same lung.

[0246] In some aspects, the subject is afflicted with a Stage IV lung cancer (e.g., NSCLC). Stage IV is divided, e.g., into Stage IVA (Any T / Any N / M1a or Any T / Any N / M1b) andIVB (Any T / Any N / M1c) for NSCLC. For Any T, the tumor can be of any size and can have grown into nearby structures or not have grown into them. For Any N, the cancer can have reached nearby lymph nodes or not have reached them. For M1a, one or more of the following is true: 1) the cancer has spread to both lungs; 2) cancer cells are found in the fluid around the lung; 3) cancer cells are found in the fluid around the heart. For M1b, the cancer has spread as a single tumor to a distant lymph node or another organ (e.g., the liver, bones, or brain). For M1c, the cancer has spread as two or more tumors to distant lymph nodes and / or another organ (e.g., the liver, bones, or brain).

[0247] In some aspects, the lung cancer is small cell lung cancer (SCLC). In some aspects, staging of the SCLC is by T / N / M staging. In some aspects, rather than T / N / M staging, the SCLC is staged as either limited stage or extensive stage. Limited stage SCLC is confined to one lung and / or the local lymph nodes. Extensive stage SCLC is found in both lungs and / or distant sites in the body.

[0248] In some aspects, the lung cancer is non-small cell lung cancer (NSCLC). NSCLC includes NSCLC with a histology that is “not otherwise specified” (NOS), NSCLC with a squamous histology (SQ), and NSCLC with a non-squamous histology (NSQ, including adenocarcinoma, large cell, and undifferentiated carcinoma). In some aspects, the NSCLC has a squamous histology. In some aspects, the NSCLC has a non-squamous histology. In some aspects, staging of the NSCLC is by T / N / M staging. In some aspects, the NSCLC comprises locally advanced Stage IIIA, IIIB, or IIIC NSCLC.

[0249] Surgery (i.e., surgical resection), radiotherapy (RT, also interchangeably referred to herein as radiation therapy), and chemotherapy are three modalities commonly used to treat NSCLC patients. As a class, NSCLCs are relatively insensitive to chemotherapy and RT, compared to small cell carcinoma. In general, for patients with Stage I or II disease, surgical resection has provided the best chance for cure, with chemotherapy often used both pre- operatively and post-operatively. RT can also be used as adjuvant therapy for patients with resectable NSCLC, the primary local treatment, or as palliative therapy for patients with incurable NSCLC. Patients with advanced or metastatic disease (e.g., Stage IV NSCLC) who have a good performance status (PS) can benefit from chemotherapy.

[0250] Specific targeted therapies have also been developed for the treatment of advanced or metastatic NSCLC in subjects with sensitizing mutations in genes for epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), ROS-1, neurotrophin receptortyrosine kinase (NTRK), and B-rapidly accelerated fibrosarcoma proto-oncogene (BRAF, e.g., the BRAF V600E mutation).

[0251] In some aspects, the subject has an EGFR, ALK, NTRK, ROS-1, or BRAF mutation sensitive to targeted inhibitor therapy.

[0252] In some aspects, the subject has no EGFR, ALK, NTRK, ROS-1, or BRAF mutation sensitive to targeted inhibitor therapy.

[0253] In some aspects, the tumor comprises a NSCLC, and a sample of a subject's tumor as described herein comprises an H-score as described herein. In some aspects, the sample comprises an H-score of less than or equal to about 10. In some aspects, the sample comprises an H-score of about 1 to less than or equal to about 10. In some aspects, the sample comprises an H-score of greater than about 45. In some aspects, the sample comprises an H-score of about 1 to less than about 140. In some aspects, the H-score is a manual calculation. In some aspects, the H-score is an automated calculation by image analysis software. In some aspects, the NSCLC comprises non-squamous NSCLC.

[0254] In some aspects, any of the methods described herein comprises administering (e.g., intravenously administering) about 360 mg of an anti-LAG-3 antibody as described herein (e.g., relatlimab or an antibody comprising the sequences of relatlimab), and about 360 mg of an anti-PD-1 antibody as described herein (e.g., nivolumab, or an antibody comprising the sequences of nivolumab) to a subject having a tumor comprising an NSCLC. In some aspects, the NSCLC comprises non-squamous NSCLC. II.C.3 Colorectal Carcinoma

[0255] In some aspects, the tumor comprises a colorectal carcinoma (CRC).

[0256] In some aspects, the CRC is a colon cancer, a rectal cancer, or a combination thereof.

[0257] Colon cancer presents in five stages: Stage 0 (Carcinoma in Situ), Stage I, Stage II, Stage III and Stage IV. Standard of care treatments for colon cancer include: 1) surgery, including a local excision, resection of the colon with anastomosis, or resection of the colon with colostomy; 2) radiofrequency ablation; 3) cryosurgery; 4) chemotherapy; 5) radiation therapy; and 6) targeted therapies, including monoclonal antibodies and angiogenesis inhibitors. In some aspects, a method of the disclosure further comprises administering a standard of care therapy for the treatment of colon cancer.

[0258] Rectal cancer presents in five stages: Stage 0 (Carcinoma in Situ), Stage I, Stage II, Stage III and Stage IV. Standard of care treatments for rectal cancer include: 1) Surgery, including polypectomy, local excision, resection, radiofrequency ablation, cryosurgery, and pelvic exenteration; 2) radiation therapy; 3) chemotherapy; and 4) targeted therapy, including monoclonal antibody therapy. In some aspects, a method of the disclosure further comprises administering a standard of care therapy for the treatment of rectal cancer.

[0259] In some aspects, the subject has progressed on or is intolerant to a prior therapy (e.g., a standard of care therapy, including a standard of care 1L or 2L therapy).

[0260] In some aspects, the prior therapy comprises a fluoropyrimidine, oxaliplatin, irinotecan, anti-vascular endothelial growth factor (VEGF) therapy, anti-epidermal growth factor receptor (EGFR) therapy (e.g., cetuximab or panitumumab) for CRC comprising a Kristen Rat Sarcoma Viral Oncogene Homologue (KRAS) mutation, regorafenib, TAS- 102, or any combination thereof.

[0261] In some aspects, the subject has received one, two, three, four, or more prior therapies.

[0262] In some aspects, the subject is naïve to prior systemic therapy for advanced and / or metastatic CRC.

[0263] In some aspects, the subject is naïve to prior immuno-oncology (I-O) therapy. In some aspects, the subject has never received I-O therapy, has received I-O therapy for a cancer other than CRC, or has received I-O therapy for a previous CRC but not a current CRC. In some aspects, the subject is naïve to prior I-O therapy, the subject is naïve to prior I-O therapy for CRC, or the CRC is naïve to prior I-O therapy. In some aspects, the prior I-O therapy is an antibody. In some aspects, the antibody binds to a checkpoint inhibitor. In some aspects, the prior I-O therapy is an anti-PD-1 antibody and / or the combination of an anti-PD-1 antibody and an anti-CTLA-4 antibody.

[0264] In some aspects, the CRC comprises adenocarcinoma histology.

[0265] Approximately 4% of CRCs are associated with high microsatellite instability (MSI-H), which is a condition of genetic hypermutability that results from deficient DNA mismatch repair (dMMR). The presence of MSI-H represents phenotypic evidence of dMMR. In most cases, the genetic basis for MSI-H CRC is an inherited germline alteration in any one or more of the five human MMR genes: MLH1, MSH2, MSH6, PMS1, or PMS2.

[0266] In contrast to MSI-H, microsatellite stability (MSS) is the molecular fingerprint of a proficient mismatch repair (pMMR) system. The term MSS is widely accepted as a surrogate terminology for pMMR tumors. Approximately 85% CRCs display MSS without novel microsatellite alleles.

[0267] In colorectal cancer, MSI-H is associated with increases in immune infiltration and expression of immune checkpoint regulators, while MSS is typically associated with an immunosuppressive tumor microenvironment that blunts activation of anti-tumor immune responses. But, a subset of MSS CRC patients displays a MSI-like tumor immune contexture, characterized by high T cell activation and LAG-3 upregulation.

[0268] Patients with MSI-H mCRC are less likely to benefit from conventional chemotherapy than patients with MSS mCRC. But, studies have confirmed that MSS identification can be prognostic in that MSS CRC has a worse prognosis than MSI-H CRC.

[0269] There are several well-established methods to differentiate MSS from MSI-H. One is immunohistochemistry (IHC) for MMR. IHC MMR testing consists of staining of tumor tissue for loss of expression of four mismatch repair proteins known to be mutated in Lynch syndrome: MLH1, MSH2, MSH6, and PMS2. If at least one of these is not normally expressed, then the testing indicates the dMMR (MSI-H) phenotype. Polymerase chain reaction (PCR) amplification of a set of mono- and / or di-nucleotide repeats on tumor and normal DNA, followed by comparison of the peak patterns by capillary electrophoresis, can also assess for MSI with three categories: MSI-H, MSI-Low, and MSS. The clinicopathologic and most molecular characteristics in MSI-Low tumors do not seem to differ from MSS tumors. Therefore, unless otherwise noted, MSS CRC in a method of the disclosure includes MSI-Low CRC.

[0270] In some aspects, the CRC is MSS CRC.

[0271] In some aspects the MSS CRC comprises high T cell activation and LAG-3 upregulation.

[0272] In some aspects, the MSS CRC does not include MSI-Low CRC (i.e., the MSS CRC excludes MSI-Low CRC).

[0273] In some aspects, the CRC comprises normal expression of MMR proteins (e.g., as compared to a reference expressing the corresponding wildtype MMR proteins). In some aspects, the MMR proteins are MLH1, MSH2, MSH6, and PMS2. In some aspects, the MMR proteins are MLH1, MSH2, MSH6, PMS1, and PMS2.

[0274] In some aspects, the CRC is MSI-H CRC.

[0275] In some aspects, the CRC comprises reduced expression of a MMR protein (e.g., as compared to a reference expressing the corresponding wildtype MMR protein). In some aspects, the MMR protein is MLH1, MSH2, MSH6, PMS2, or a combination thereof. In some aspects, the MMR protein is MLH1, MSH2, MSH6, PMS1, PMS2, or a combination thereof.

[0276] In some aspects, the CRC comprises a KRAS mutation, a NRAS mutation, a B- rapidly accelerated fibrosarcoma proto-oncogene (BRAF) mutation, or a combination thereof.

[0277] In some aspects, the CRC comprises wild-type KRAS, wild-type NRAS, wild-type BRAF, or a combination thereof.

[0278] In some aspects, the methods of the disclosure comprise administering to the subject an immunotherapy comprising a LAG-3 antagonist based on the subject's performance status. In some aspects, the subject has an ECOG PS of 0 or 1. In some aspects, the subject has an ECOG PS of 0, 1, or 2. In some aspects, the subject has an ECOG PS of 0, 1, 2, or 3. In some aspects, the subject has an ECOG PS of 0, 1, 2, 3, or 4. II.C.4 Melanoma

[0279] In some aspects, the tumor comprises a melanoma.

[0280] In some aspects, the melanoma is staged based on a tumor / node / metastasis (TNM) staging system such as the American Joint Committee on Cancer (AJCC) classification.

[0281] In some aspects, the patient has stage I melanoma, also known as melanoma in situ. In stage I, the cancer is confined to the epidermis. It has not spread to nearby lymph nodes or to distant parts of the body. In some aspects, the patient has histologically confirmed unresectable stage I melanoma.

[0282] In some aspects, the patient has stage II melanoma. In stage II, the tumor is more than 1 mm thick and can be thicker than 4 mm. It can be ulcerated or not. The cancer has not spread to nearby lymph nodes or to distant parts of the body. In some aspects, the patient has histologically confirmed unresectable stage II melanoma.

[0283] In some aspects, the patient has stage III melanoma. In some aspects, the patient has histologically confirmed unresectable stage III melanoma. Stage III is divided into stages IIIA, IIIB, IIIC, and IIID.

[0284] In stage IIIA, the tumor is no more than 2 mm thick and can be ulcerated or not. The cancer has spread to 1 to 3 nearby lymph nodes, but it is so small that it is only seen under the microscope. It has not spread to distant parts of the body. In some aspects, the patient has histologically confirmed unresectable stage IIIA melanoma.

[0285] In stage IIIB, (1) there is no sign of the primary tumor and: (a) the cancer has spread to only one nearby lymph node, or (b) the cancer has spread to very small areas of nearby skin (satellite tumors) or to skin lymphatic channels around the tumor (without reaching the nearby lymph nodes), or (2) the tumor is no more than 4 mm thick and can be ulcerated or not and: (a) the cancer has spread to only one nearby lymph node, or (b) the cancer has spread to very small areas of nearby skin (satellite tumors) or to skin lymphatic channels around the tumor (without reaching the nearby lymph nodes), or (c) the cancer has spread to 2 or 3 nearby lymph nodes. In stage IIIB, the cancer has not spread to distant parts of the body. In some aspects, the patient has histologically confirmed unresectable stage IIIB melanoma.

[0286] In stage IIIC, (1) there is no sign of the primary tumor, and: (a) the cancer has spread to 2 or more nearby lymph nodes, at least one of which could be seen or felt, or (b) the cancer has spread to very small areas of nearby skin (satellite tumors) or to skin lymphatic channels around the tumor, and it has reached the nearby lymph nodes, or (c) the cancer has spread to nearby lymph nodes that are clumped together, or (2) the tumor is no more than 4 mm thick, and can be ulcerated or not, and: (a) the cancer has spread to very small areas of nearby skin (satellite tumors) or to skin lymphatic channels around the tumor, and it has reached nearby lymph nodes, or (b) the cancer has spread to 4 or more nearby lymph nodes, or it has spread to nearby lymph nodes that are clumped together, or (3) the tumor is more than 2 mm but no more than 4 mm thick and is ulcerated or it is thicker than 4 mm but is not ulcerated, and: (a) the cancer has spread to one or more nearby lymph nodes, and / or (b) the cancer has spread to very small areas of nearby skin (satellite tumors) or to skin lymphatic channels around the tumor, or (4) the tumor is thicker than 4 mm and is ulcerated, and: (a) the cancer has spread to 1 to 3 nearby lymph nodes, which are not clumped together, or (b) the cancer has spread to very small areas of nearby skin (satellite tumors) or to skin lymphatic channels around the tumor, and it may or may not have reached 1 nearby lymph node. In stage IIIC, the cancer has not spread to distant parts of the body. In some aspects, the patient has histologically confirmed unresectable stage IIIC melanoma.

[0287] In stage IIID, the tumor is thicker than 4 mm and is ulcerated, and: (a) the cancer has spread to 4 or more nearby lymph nodes, or (b) the cancer has spread to nearby lymph nodes that are clumped together, or (c) the cancer has spread to very small areas of nearby skin (satellite tumors) or to skin lymphatic channels around the tumor, and the cancer has spread to at least 2 nearby lymph nodes, or to lymph nodes that are clumped together. In stage IIID, the cancer has not spread to distant parts of the body.

[0288] In stage IV, the tumor can be any thickness, can be ulcerated or not, and may or may not have spread to nearby lymph nodes. In stage IV, the cancer has spread to distant lymph nodes or to organs such as the lungs, liver, or brain. In some aspects, the patient has histologically confirmed stage IV melanoma.

[0289] In some aspects, the patient has histologically confirmed unresectable stage III or stage IV melanoma.

[0290] In some aspects the patient has an ECOG PS of 0, 1, 2, 3, or 4. In some aspects, the patient has an ECOG PS of ≤ 3. In some aspects, the patient has an ECOG PS of ≤ 2. In some aspects, the patient has an ECOG PS of ≤ 1. In some aspects, the patient has an ECOG PS of 0 or 1.

[0291] In some aspects, the patient has a B-rapidly accelerated fibrosarcoma proto- oncogene (BRAF, e.g., a BRAF V600 mutation such as BRAF V600E or BRAF V600K), mitogen-activated extracellular signal-regulated kinase (MEK), neuroblastoma RAS viral oncogene homolog (NRAS), and / or proto-oncogene c-KIT (KIT) mutation sensitive to targeted inhibitor therapy.

[0292] In some aspects, the patient has a BRAF mutation. In some aspects, the BRAF mutation is a BRAF V600 mutation. In some aspects, the BRAF mutation is a BRAF V600E mutation. In some aspects, the BRAF mutation is a BRAF V600K mutation.

[0293] In some aspects, the patient has no BRAF, MEK, NRAS, and / or KIT mutation sensitive to targeted inhibitor therapy. In some aspects, the targeted inhibitor therapy comprises a tyrosine kinase inhibitor of BRAF and / or MEK. In some aspects, the targeted inhibitor therapy comprises dabrafenib, vemurafenib, encorafenib, trametinib, cobimetinib, and / or binimetinib.

[0294] In some aspects, a method as described herein comprises subcutaneously administering about 320 mg of an anti-LAG-3 antibody as described herein (e.g., relatlimab or an antibody comprising the sequences of relatlimab) once about every four weeks, andabout 960 mg of an anti-PD-1 antibody as described herein (e.g., nivolumab, or an antibody comprising the sequences of nivolumab) about once every four weeks in combination with about 1 mg / kg of an anti-CTLA-4 antibody as described herein (e.g., ipilimumab or an antibody comprising the sequences of ipilimumab) once about every 8 weeks to a subject having a tumor comprising an melanoma. II.C.5 Hematological Cancer

[0295] In some aspects, the tumor comprises a hematological cancer.

[0296] In some aspects, the hematological cancer comprises a leukemia, lymphoma, or myeloma.

[0297] In some aspects, the hematological cancer comprises a B-cell lymphoma (e.g., a mature B-cell lymphoma), T-cell lymphoma, or natural killer-cell lymphoma

[0298] In some aspects, the hematological cancer comprises a Hodgkin lymphoma.

[0299] In some aspects, the Hodgkin lymphoma comprises nodular lymphocyte- predominant Hodgkin lymphoma.

[0300] In some aspects, the Hodgkin lymphoma comprises a classical Hodgkin lymphoma (cHL). cHL can be characterized by rare, malignant Reed Sternberg cells surrounded by an extensive but ineffective inflammatory immune cell infiltrate.

[0301] In some aspects, the cHL comprises nodular sclerosis Hodgkin lymphoma, mixed cellularity Hodgkin lymphoma, lymphocyte-depleted Hodgkin lymphoma, or lymphocyte- rich classical Hodgkin lymphoma.

[0302] In some aspects, the cHL is a recurrent or refractory cHL characterized by early relapse, B-symptoms at relapse, extensive disease at a contraindicated radiotherapy field, relapse at a prior radiotherapy field, or a combination thereof.

[0303] In some aspects, the cHL is staged according to the Lugano 2014 Classification. See, e.g., Cheson et al., J. Clin. Oncol.32(27):3059-3067 (2014).

[0304] In some aspects, the cHL is stage IIB with bulky disease, IIIA with E-lesions with or without bulky disease, IIIB, or IV, where E-lesions are defined as localized involvement of extralymphatic tissue (by contiguous growth from, or in close anatomic relation to, an involved lymph node) that is treatable by irradiation.

[0305] In some aspects, the hematological cancer comprises a non-Hodgkin lymphoma (NHL).

[0306] In some aspects, the NHL comprises diffuse large B-cell lymphoma, anaplastic large cell lymphoma, Burkitt lymphoma, Burkitt-like lymphoma, lymphoblastic lymphoma, mantle cell lymphoma, peripheral T-cell lymphoma, follicular lymphoma, cutaneous T-cell lymphoma, lymphoplasmactyic lymphoma, marginal zone lymphoma, mucosa-associated lymphoid tissue lymphoma, central nervous system lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, primary mediastinal large B-cell lymphoma, adult T-cell lymphoma, angioimmunoblastic T-cell lymphoma, Waldenström macroglobulinemia, mycosis fungoides, or Sézary syndrome.

[0307] In some aspects, the NHL comprises a Burkitt lymphoma, Burkitt-like lymphoma, diffuse large B-cell lymphoma, lymphoblastic lymphoma, or anaplastic large cell lymphoma.

[0308] In some aspects, the NHL is a recurrent or refractory NHL characterized by two or more of a decreased performance status, elevated serum lactate dehydrogenase, and stage III or IV. In some aspects, the NHL is staged according to the Lugano 2014 Classification.

[0309] In some aspects, the NHL is stage III or IV.

[0310] In some aspects, the hematological cancer comprises acute myeloid leukemia, chronic lymphocytic leukemia, hairy cell leukemia, acute lymphocytic leukemia, acute promyelocytic leukemia, chronic myeloid leukemia, chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia, myeloproliferative neoplasms, systemic mastocytosis, prolymphocytic leukemia, large granular lymphocytic leukemia, or blastic plasmacytoid dendritic cell neoplasm. II.D LAG-3 antagonists

[0311] A LAG-3 antagonist for use in the methods of the disclosure includes, but is not limited to, LAG-3 binding agents and soluble LAG-3 polypeptides. LAG-3 binding agents include antibodies that specifically bind to LAG-3 (i.e., an "anti-LAG-3 antibody"). The term "LAG-3 antagonist" as used herein is interchangeable with the term "LAG-3 inhibitor."

[0312] In some aspects, the LAG-3 antagonist comprises an anti-LAG-3 antibody.

[0313] Antibodies that bind to LAG-3 have been disclosed, for example, in Int'l Publ. Nos. WO / 2015 / 042246, WO / 2021 / 092380, WO / 2022 / 047189, WO / 2023 / 147371, WO / 2023 / 077090, WO / 2023 / 164638, or WO / 2022 / 087402; Int’l Appl. No.PCT / US2023 / 085070, and U.S. Publ. Nos. 2014 / 0093511 and 2011 / 0150892, each of which is incorporated by reference herein in its entirety.

[0314] An exemplary LAG-3 antibody useful in the present disclosure comprises 25F7 (described in U.S. Publ. No. 2011 / 0150892). An additional exemplary LAG-3 antibody useful in the present disclosure comprises BMS-986016 (relatlimab). In some aspects, an anti-LAG-3 antibody useful in the present disclosure cross-competes with 25F7 or BMS- 986016. In some aspects, an anti-LAG-3 antibody useful in the present disclosure binds to the same epitope as 25F7 or BMS-986016. In some aspects, an anti-LAG-3 antibody comprises six CDRs of 25F7 or BMS-986016.

[0315] Other art-recognized anti-LAG-3 antibodies that can be used in the methods of the disclosure include IMP731 (H5L7BW) described in US 2011 / 007023, MK-4280 (28G-10, favezelimab) described in WO2016 / 028672 and U.S. Publication No. 2020 / 0055938, REGN3767 (fianlimab) described in Burova E, et al., J. Immunother. Cancer (2016); 4(Supp. 1):P195 and U.S. Patent No. 10,358,495, humanized BAP050 described in WO2017 / 019894, GSK2831781, IMP-701 (LAG525; ieramilimab) described in U.S. Patent No. 10,711,060 and U.S. Publ. No. 2020 / 0172617, aLAG3(0414), aLAG3(0416), Sym022, TSR-033, TSR-075, XmAb841 (previously XmAb22841), MGD013 (tebotelimab), BI754111, FS118, P 13B02-30, AVA-017, AGEN1746, RO7247669, INCAGN02385, IBI-110, EMB-02, IBI-323, LBL-007, and ABL501. These and other anti-LAG-3 antibodies useful in the claimed invention can be found in, for example: US 10,188,730, WO 2016 / 028672, WO 2017 / 106129, WO2017 / 062888, WO2009 / 044273, WO2018 / 069500, WO2016 / 126858, WO2014 / 179664, WO2016 / 200782, WO2015 / 200119, WO2017 / 019846, WO2017 / 198741, WO2017 / 220555, WO2017 / 220569, WO2018 / 071500, WO2017 / 015560, WO2017 / 025498, WO2017 / 087589, WO2017 / 087901, WO2018 / 083087, WO2017 / 149143, WO2017 / 219995, US2017 / 0260271, WO2017 / 086367, WO2017 / 086419, WO2018 / 034227, WO2018 / 185046, WO2018 / 185043, WO2018 / 217940, WO19 / 011306, WO2018 / 208868, WO2014 / 140180, WO2018 / 201096, WO2018 / 204374, and WO2019 / 018730. The contents of each of these references are incorporated by reference in their entirety.

[0316] Anti-LAG-3 antibodies that can be used in the methods of the disclosure also include isolated antibodies that bind specifically to human LAG-3 and cross-compete forbinding to human LAG-3 with any anti-LAG-3 antibody disclosed herein, e.g., relatlimab. In some aspects, the anti-LAG-3 antibody binds the same epitope as any of the anti-LAG- 3 antibodies described herein, e.g., relatlimab.

[0317] In some aspects, the antibodies that cross-compete for binding to human LAG-3 with, or bind to the same epitope region as, any anti-LAG-3 antibody disclosed herein, e.g., relatlimab, are monoclonal antibodies. For administration to human subjects, these cross- competing antibodies are chimeric antibodies, engineered antibodies, or humanized or human antibodies. Such chimeric, engineered, humanized or human monoclonal antibodies can be prepared and isolated by methods well known in the art.

[0318] Anti-LAG-3 antibodies that can be used in the methods of the disclosure also include antigen binding portions of any of the above full-length antibodies.

[0319] In some aspects, the anti-LAG-3 antibody comprises a full-length antibody.

[0320] In some aspects, the anti-LAG-3 antibody comprises a monoclonal, human, humanized, chimeric, or multispecific antibody. In some aspects, the multispecific antibody comprises a dual-affinity re-targeting antibody (DART), a dual variable domain immunoglobulin (DVD-IG), or a bispecific antibody.

[0321] In some aspects, the anti-LAG-3 antibody comprises a F(ab')2fragment, a Fab' fragment, a Fab fragment, a Fv fragment, a scFv fragment, a dsFv fragment, a dAb fragment, or a single chain binding polypeptide.

[0322] In some aspects, the anti-LAG-3 antibody comprises BMS-986016 (relatlimab), IMP731 (H5L7BW), MK4280 (28G-10, favezelimab), REGN3767 (fianlimab), GSK2831781, humanized BAP050, IMP-701 (LAG525, ieramilimab), aLAG3(0414), aLAG3(0416), Sym022, TSR-033, TSR-075, XmAb841 (XmAb22841), MGD013 (tebotelimab), BI754111, FS118, P 13B02-30, AVA-017, 25F7, AGEN1746, RO7247669, INCAGN02385, IBI-110, EMB-02, IBI-323, LBL-007, ABL501, or an antigen binding portion thereof.

[0323] In some aspects, the anti-LAG-3 antibody is formulated for intravenous administration.

[0324] In some aspects, the anti-LAG-3 antibody is administered intravenously for about 30 minutes.

[0325] In some aspects, the anti-LAG-3 antibody comprises relatlimab, or an antigen binding portion thereof.

[0326] In some aspects, relatlimab, or an antigen binding portion thereof, is administered intravenously at a dose of about 240 mg once about every 4 weeks.

[0327] In some aspects, relatlimab, or an antigen binding portion thereof, is administered intravenously at a dose of about 360 mg once about every 4 weeks.

[0328] In some aspects, relatlimab, or an antigen binding portion thereof, is administered intravenously at a dose of about 480 mg once about every 4 weeks.

[0329] In some aspects, relatlimab, or an antigen binding portion thereof, is administered intravenously at a dose of about 240 mg for about 30 minutes on Day 1 of a four-week cycle.

[0330] In some aspects, relatlimab, or an antigen binding portion thereof, is administered intravenously at a dose of about 360 mg for about 30 minutes on Day 1 of a four-week cycle.

[0331] In some aspects, relatlimab, or an antigen binding portion thereof, is administered intravenously at a dose of about 480 mg for about 30 minutes on Day 1 of a four-week cycle.

[0332] In some aspects, relatlimab, or an antigen binding portion thereof, is administered subcutaneously at a dose of about 320 mg once about every 4 weeks.

[0333] In some aspects, relatlimab, or an antigen binding portion thereof, is administered subcutaneously at a dose of about 720 mg once about every 4 weeks.

[0334] In some aspects, relatlimab, or an antigen binding portion thereof, is administered subcutaneously at a dose of about 960 mg once about every 4 weeks.

[0335] In some aspects, relatlimab, or an antigen binding portion thereof, is administered subcutaneously at a dose of about 320 mg for about 30 minutes on Day 1 of a four-week cycle.

[0336] In some aspects, relatlimab, or an antigen binding portion thereof, is administered subcutaneously at a dose of about 720 mg for about 30 minutes on Day 1 of a four-week cycle.

[0337] In some aspects, relatlimab, or an antigen binding portion thereof, is administered subcutaneously at a dose of about 960 mg for about 30 minutes on Day 1 of a four-week cycle.

[0338] In some aspects, the methods of the disclosure comprise an anti-LAG-3 antibody comprising CDR1, CDR2 and CDR3 domains of the heavy chain variable region havingthe sequence set forth in SEQ ID NO:3, and CDR1, CDR2 and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID NO:4.

[0339] In some aspects, the methods of the disclosure comprise an anti-LAG-3 antibody comprising: (a) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO:5; (b) a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO:6; (c) a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO:7; (d) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO:8; (e) a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO:9; and (f) a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO:10.

[0340] In some aspects, the methods of the disclosure comprise an anti-LAG-3 antibody comprising heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs:3 and 4, respectively.

[0341] In some aspects, the methods of the disclosure comprise an anti-LAG-3 antibody comprising heavy and light chains comprising the sequences set forth in SEQ ID NOs:1 and 2, respectively.

[0342] In some aspects, the methods of the disclosure comprise an anti-LAG-3 antibody comprising heavy and light chains comprising the sequences set forth in SEQ ID NOs:21 and 2, respectively.

[0343] In some aspects, the anti-LAG-3 antibody comprises MGD013 (tebotelimab), which is a bispecific PD-1 × LAG-3 DART, or an antigen binding portion thereof. In some aspects, tebotelimab, or an antigen binding portion thereof, is administered intravenously at a dose of about 300 mg or about 600 mg once about every 2 or 3 weeks. In some aspects, tebotelimab, or an antigen binding portion thereof, is administered intravenously at a dose of about 300 mg once about every 2 weeks. In some aspects, tebotelimab, or an antigen binding portion thereof, is administered intravenously at a dose of about 600 mg once about every 3 weeks.

[0344] In some aspects, the anti-LAG-3 antibody comprises REGN3767 (fianlimab), or an antigen binding portion thereof. In some aspects, fianlimab, or an antigen binding portion thereof, is administered intravenously at a dose of about 1 mg / kg, about 3 mg / kg, about 10 mg / kg, or about 20 mg / kg once about every 3 weeks. In some aspects, fianlimab, or anantigen binding portion thereof, is administered intravenously at a dose of about 1600 mg once about every 3 weeks.

[0345] In some aspects, the methods of the disclosure comprise an anti-LAG-3 antibody comprising CDR1, CDR2 and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID NO:25, and CDR1, CDR2 and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID NO:26.

[0346] In some aspects, the methods of the disclosure comprise an anti-LAG-3 antibody comprising: (a) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO:27; (b) a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO:28; (c) a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO:29; (d) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO:30; (e) a light chain variable region CDR2 comprising the sequence DAS; and (f) a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO:31.

[0347] In some aspects, the methods of the disclosure comprise an anti-LAG-3 antibody comprising heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs:25 and 26, respectively.

[0348] In some aspects, the methods of the disclosure comprise an anti-LAG-3 antibody comprising heavy and light chains comprising the sequences as set forth in SEQ ID NOs:23 and 24, respectively.

[0349] In some aspects, the anti-LAG-3 antibody comprises LAG525 (ieramilimab), or an antigen binding portion thereof. In some aspects, ieramilimab, or an antigen binding portion thereof, is administered intravenously at a dose of about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, or about 1300 mg once about every 2, 3, or 4 weeks.

[0350] In some aspects, the methods of the disclosure comprise an anti-LAG-3 antibody comprising CDR1, CDR2 and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID NO:45, and CDR1, CDR2 and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID NO:47.

[0351] In some aspects, the methods of the disclosure comprise an anti-LAG-3 antibody comprising CDR1, CDR2 and CDR3 domains of the heavy chain variable region havingthe sequence set forth in SEQ ID NO:46, and CDR1, CDR2 and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID NO:48.

[0352] In some aspects, the methods of the disclosure comprise an anti-LAG-3 antibody comprising: (a) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO:49; (b) a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO:50; (c) a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO:51; (d) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO:52; (e) a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO:53; and (f) a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO:54.

[0353] In some aspects, the methods of the disclosure comprise an anti-LAG-3 antibody comprising heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs:45 and 47, respectively.

[0354] In some aspects, the methods of the disclosure comprise an anti-LAG-3 antibody comprising heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs:46 and 48, respectively.

[0355] In some aspects, the methods of the disclosure comprise an anti-LAG-3 antibody comprising heavy and light chains comprising the sequences as set forth in SEQ ID NOs:41 and 43, respectively.

[0356] In some aspects, the methods of the disclosure comprise an anti-LAG-3 antibody comprising heavy and light chains comprising the sequences as set forth in SEQ ID NOs:42 and 44, respectively.

[0357] In some aspects, the anti-LAG-3 antibody comprises MK4280 (favezelimab), or an antigen binding portion thereof. In some aspects, favezelimab, or an antigen binding portion thereof, is administered intravenously at a dose of about 7 mg, about 21 mg, about 70 mg, about 210 mg, about 700 mg, or about 800 mg once about every 3 weeks or once about every 6 weeks. In some aspects, favezelimab, or an antigen binding portion thereof, is administered intravenously at a dose of about 200 mg once about every 3 weeks. In some aspects, favezelimab, or an antigen binding portion thereof, is administered intravenously at a dose of about 800 mg once about every 6 weeks. In some aspects, favezelimab is administered intravenously at a dose of about 800 mg on Day 1, then once about every 3 weeks. In some aspects, favezelimab, or an antigen binding portion thereof, is administeredfor up to 35 cycles. In some aspects, favezelimab, or an antigen binding portion thereof, is administered intravenously at a dose of about 800 mg for about 30 minutes on Day 1 of a three-week cycle for up to 35 cycles.

[0358] In some aspects, the methods of the disclosure comprise an anti-LAG-3 antibody comprising CDR1, CDR2 and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID NO:67, and CDR1, CDR2 and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID NO:68.

[0359] In some aspects, the methods of the disclosure comprise an anti-LAG-3 antibody comprising: (a) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO:69; (b) a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO:70; (c) a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO:71; (d) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO:72; (e) a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO:73; and (f) a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO:74.

[0360] In some aspects, the methods of the disclosure comprise an anti-LAG-3 antibody comprising heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs:67 and 68, respectively.

[0361] In some aspects, the methods of the disclosure comprise an anti-LAG-3 antibody comprising heavy and light chains comprising the sequences as set forth in SEQ ID NOs:65 and 66, respectively.

[0362] In some aspects, an anti-LAG-3 antibody is used to determine LAG-3 expression. In some aspects, an anti-LAG-3 antibody is selected for its ability to bind to LAG-3 in formalin-fixed, paraffin-embedded (FFPE) tissue specimens. In some aspects, an anti- LAG-3 antibody is capable of binding to LAG-3 in frozen tissues. In some aspects, an anti- LAG-3 antibody is capable of distinguishing membrane bound, cytoplasmic, and / or soluble forms of LAG-3.

[0363] In some aspects, an anti-LAG-3 antibody useful for assaying, detecting, and / or quantifying LAG-3 expression in accordance with the methods disclosed herein is the 17B4 mouse IgG1 anti-human LAG-3 monoclonal antibody. See, e.g., Matsuzaki, J et al., PNAS (2010); 107:7875.

[0364] In some aspects, the LAG-3 antagonist comprises a soluble LAG-3 polypeptide. In some aspects, the soluble LAG-3 polypeptide is a fusion polypeptide, e.g., a fusion protein comprising the extracellular portion of LAG-3. In some aspects, the soluble LAG-3 polypeptide is a LAG-3-Fc fusion polypeptide capable of binding to MHC Class II. In some aspects, the soluble LAG-3 polypeptide comprises a ligand binding fragment of the LAG- 3 extracellular domain. In some aspects, the ligand binding fragment of the LAG-3 extracellular domain comprises an amino acid sequence with at least about 90%, at least about 95%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO:22. In some aspects, the soluble LAG-3 polypeptide further comprises a half-life extending moiety. In some aspects, the half-life extending moiety comprises an immunoglobulin constant region or a portion thereof, an immunoglobulin-binding polypeptide, an immunoglobulin G (IgG), albumin-binding polypeptide (ABP), a PASylation moiety, a HESylation moiety, XTEN, a PEGylation moiety, an Fc region, or any combination thereof. In some aspects, the soluble LAG-3 polypeptide comprises IMP321 (eftilagimod alpha). See, e.g., Brignone C, et al., J. Immunol. (2007); 179:4202- 4211 and WO2009 / 044273. In some aspects, eftilagimod alpha is administered at a dose of about 30 mg. In some aspects, eftilagimod alpha is administered subcutaneously at a dose of about 30 mg once about every 2 weeks.

[0365] In some aspects, the LAG-3 antagonist is formulated for parenteral administration.

[0366] In some aspects, the LAG-3 antagonist is formulated for intravenous, intraperitoneal, intramuscular, intrathecal, or subcutaneous administration.

[0367] In some aspects, the LAG-3 antagonist is administered at a flat dose.

[0368] In some aspects, the LAG-3 antagonist is administered at a dose of from at least about 0.25 mg to about 2000 mg, about 0.25 mg to about 1600 mg, about 0.25 mg to about 1200 mg, about 0.25 mg to about 800 mg, about 0.25 mg to about 400 mg, about 0.25 mg to about 100 mg, about 0.25 mg to about 50 mg, about 0.25 mg to about 40 mg, about 0.25 mg to about 30 mg, about 0.25 mg to about 20 mg, about 20 mg to about 2000 mg, about 20 mg to about 1600 mg, about 20 mg to about 1200 mg, about 20 mg to about 800 mg, about 20 mg to about 400 mg, about 20 mg to about 100 mg, about 100 mg to about 2000 mg, about 100 mg to about 1800 mg, about 100 mg to about 1600 mg, about 100 mg to about 1400 mg, about 100 mg to about 1200 mg, about 100 mg to about 1000 mg, about 100 mg to about 800 mg, about 100 mg to about 600 mg, about 100 mg to about 400 mg,about 400 mg to about 2000 mg, about 400 mg to about 1800 mg, about 400 mg to about 1600 mg, about 400 mg to about 1400 mg, about 400 mg to about 1200 mg, or about 400 mg to about 1000 mg.

[0369] In some aspects, the LAG-3 antagonist is administered at a dose of about 0.25 mg, about 0.5 mg, about 0.75 mg, about 1 mg, about 1.25 mg, about 1.5 mg, about 1.75 mg, about 2 mg, about 2.25 mg, about 2.5 mg, about 2.75 mg, about 3 mg, about 3.25 mg, about 3.5 mg, about 3.75 mg, about 4 mg, about 4.25 mg, about 4.5 mg, about 4.75 mg, about 5 mg, about 5.25 mg, about 5.5 mg, about 5.75 mg, about 6 mg, about 6.25 mg, about 6.5 mg, about 6.75 mg, about 7 mg, about 7.25 mg, about 7.5 mg, about 7.75 mg, about 8 mg, about 8.25 mg, about 8.5 mg, about 8.75 mg, about 9 mg, about 9.25 mg, about 9.5 mg, about 9.75 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, about 800 mg, about 810 mg, about 820 mg, about 830 mg, about 840 mg, about 850 mg, about 860 mg, about 870 mg, about 880 mg, about 890 mg, about 900 mg, about 910 mg, about 920 mg, about 930 mg, about 940 mg, about 950 mg, about 960 mg, about 970 mg, about 980 mg, about 990 mg, about 1000 mg, about 1040 mg, about 1080 mg, about 1100 mg, about 1140 mg, about 1180 mg, about 1200 mg, about 1240 mg, about 1280 mg, about 1300 mg, about 1340 mg, about 1380 mg, about 1400 mg, about 1440 mg, about 1480 mg, about 1500 mg, about 1540 mg, about 1580 mg, about 1600 mg, about 1640 mg, about 1680 mg, about 1700 mg, about 1740 mg, about 1780 mg, about1800 mg, about 1840 mg, about 1880 mg, about 1900 mg, about 1940 mg, about 1980 mg, or about 2000 mg.

[0370] In some aspects, the LAG-3 antagonist is administered at a weight-based dose.

[0371] In some aspects, the LAG-3 antagonist is administered at a dose of from about 0.003 mg / kg to about 25 mg / kg, about 0.003 mg / kg to about 20 mg / kg, about 0.003 mg / kg to about 15 mg / kg, about 0.003 mg / kg to about 10 mg / kg, about 0.003 mg / kg to about 5 mg / kg, about 0.003 mg / kg to about 1 mg / kg, about 0.003 mg / kg to about 0.9 mg / kg, about 0.003 mg / kg to about 0.8 mg / kg, about 0.003 mg / kg to about 0.7 mg / kg, about 0.003 mg / kg to about 0.6 mg / kg, about 0.003 mg / kg to about 0.5 mg / kg, about 0.003 mg / kg to about 0.4 mg / kg, about 0.003 mg / kg to about 0.3 mg / kg, about 0.003 mg / kg to about 0.2 mg / kg, about 0.003 mg / kg to about 0.1 mg / kg, about 0.1 mg / kg to about 25 mg / kg, about 0.1 mg / kg to about 20 mg / kg, about 0.1 mg / kg to about 15 mg / kg, about 0.1 mg / kg to about 10 mg / kg, about 0.1 mg / kg to about 5 mg / kg, about 0.1 mg / kg to about 1 mg / kg, about 1 mg / kg to about 25 mg / kg, about 1 mg / kg to about 20 mg / kg, about 1 mg / kg to about 15 mg / kg, about 1 mg / kg to about 10 mg / kg, about 1 mg / kg to about 5 mg / kg, about 5 mg / kg to about 25 mg / kg, about 5 mg / kg to about 20 mg / kg, about 5 mg / kg to about 15 mg / kg, about 5 mg / kg to about 10 mg / kg, about 10 mg / kg to about 25 mg / kg, about 10 mg / kg to about 20 mg / kg, about 10 mg / kg to about 15 mg / kg, about 15 mg / kg to about 25 mg / kg, about 15 mg / kg to about 20 mg / kg, or about 20 mg / kg to about 25 mg / kg.

[0372] In some aspects, the LAG-3 antagonist is administered at a dose of about 0.003 mg / kg, about 0.004 mg / kg, about 0.005 mg / kg, about 0.006 mg / kg, about 0.007 mg / kg, about 0.008 mg / kg, about 0.009 mg / kg, about 0.01 mg / kg, about 0.02 mg / kg, about 0.03 mg / kg, about 0.04 mg / kg, about 0.05 mg / kg, about 0.06 mg / kg, about 0.07 mg / kg, about 0.08 mg / kg, about 0.09 mg / kg, about 0.1 mg / kg, about 0.2 mg / kg, about 0.3 mg / kg, about 0.4 mg / kg, about 0.5 mg / kg, about 0.6 mg / kg, about 0.7 mg / kg, about 0.8 mg / kg, about 0.9 mg / kg, about 1.0 mg / kg, about 2.0 mg / kg, about 3.0 mg / kg, about 4.0 mg / kg, about 5.0 mg / kg, about 6.0 mg / kg, about 7.0 mg / kg, about 8.0 mg / kg, about 9.0 mg / kg, about 10.0 mg / kg, about 11.0 mg / kg, about 12.0 mg / kg, about 13.0 mg / kg, about 14.0 mg / kg, about 15.0 mg / kg, about 16.0 mg / kg, about 17.0 mg / kg, about 18.0 mg / kg, about 19.0 mg / kg, about 20.0 mg / kg, about 21.0 mg / kg, about 22.0 mg / kg, about 23.0 mg / kg, about 24.0 mg / kg, or about 25.0 mg / kg.

[0373] In some aspects, the dose is administered once about every one week, once about every two weeks, once about every three weeks, once about every four weeks, once about every five weeks, once about every six weeks, once about every seven weeks, once about every eight weeks, once about every nine weeks, once about every ten weeks, once about every eleven weeks, or once about every twelve weeks. II.E PD-1 pathway inhibitors

[0374] In some aspects, an immunotherapy of any of the methods disclosed herein further comprises a PD-1 pathway inhibitor.

[0375] In some aspects, the PD-1 pathway inhibitor is a PD-1 inhibitor and / or a PD-L1 inhibitor.

[0376] In some aspects, the PD-1 inhibitor and / or PD-L1 inhibitor is a small molecule.

[0377] In some aspects, the PD-1 inhibitor and / or PD-L1 inhibitor is a millamolecule.

[0378] In some aspects, the PD-1 inhibitor and / or PD-L1 inhibitor is a macrocyclic peptide.

[0379] In some aspects, the PD-1 inhibitor and / or PD-L1 inhibitor comprises BMS- 986189.

[0380] In some aspects, the PD-1 inhibitor is an inhibitor disclosed in International Publication No. WO2014 / 151634, which is incorporated by reference herein in its entirety.

[0381] In some aspects, the PD-1 inhibitor is INCMGA00012 (Insight Pharmaceuticals).

[0382] In some aspects, the PD-1 inhibitor comprises a combination of an anti-PD-1 antibody disclosed herein and a PD-1 small molecule inhibitor.

[0383] In some aspects, the PD-L1 inhibitor comprises a millamolecule having a formula set forth in formula (I):wherein R1-R13are amino acid side chains, Ra-Rnare hydrogen, methyl, or form a ring with a vicinal R group, and R14is –C(O)NHR15, wherein R15is hydrogen, or a glycine residue optionally substituted with additional glycine residues and / or tails which can improve pharmacokinetic properties. In some aspects, the PD-L1 inhibitor comprises a compound disclosed in International Publication No. WO2014 / 151634, which is incorporated by reference herein in its entirety. In some aspects, the PD-L1 inhibitor comprises a compound disclosed in International Publication No. WO2016 / 039749, WO2016 / 149351, WO2016 / 077518, WO2016 / 100285, WO2016 / 100608, WO2016 / 126646, WO2016 / 057624, WO2017 / 151830, WO2017 / 176608, WO2018 / 085750, WO2018 / 237153, or WO2019 / 070643, each of which is incorporated by reference herein in its entirety.

[0384] In some aspects, the PD-L1 inhibitor comprises a small molecule PD-L1 inhibitor disclosed in International Publication No. WO2015 / 034820, WO2015 / 160641, WO2018 / 044963, WO2017 / 066227, WO2018 / 009505, WO2018 / 183171, WO2018 / 118848, WO2019 / 147662, or WO2019 / 169123, each of which is incorporated by reference herein in its entirety.

[0385] In some aspects, the PD-1 pathway inhibitor comprises a soluble PD-L2 polypeptide. In some aspects, the soluble PD-L2 polypeptide is a fusion polypeptide. In some aspects, the soluble PD-L2 polypeptide comprises a ligand binding fragment of the PD-L2 extracellular domain. In some aspects, the soluble PD-L2 polypeptide furthercomprises a half-life extending moiety. In some aspects, the half-life extending moiety comprises an immunoglobulin constant region or a portion thereof, an immunoglobulin- binding polypeptide, an immunoglobulin G (IgG), albumin-binding polypeptide (ABP), a PASylation moiety, a HESylation moiety, XTEN, a PEGylation moiety, an Fc region, or any combination thereof. In some aspects, the soluble PD-L2 polypeptide comprises AMP- 224 (see, e.g., US 2013 / 0017199).

[0386] In some aspects, the PD-1 pathway inhibitor comprises an anti-PD-1 antibody and / or an anti-PD-L1 antibody.

[0387] In some aspects, the PD-1 pathway inhibitor is formulated for parenteral administration.

[0388] In some aspects, the PD-1 pathway inhibitor is formulated for intravenous, intraperitoneal, intramuscular, intrathecal, or subcutaneous administration.

[0389] In some aspects, the PD-1 pathway inhibitor is administered at a flat dose.

[0390] In some aspects, the PD-1 pathway inhibitor is administered at a dose of from at least about 0.25 mg to about 2000 mg, about 0.25 mg to about 1600 mg, about 0.25 mg to about 1200 mg, about 0.25 mg to about 800 mg, about 0.25 mg to about 400 mg, about 0.25 mg to about 100 mg, about 0.25 mg to about 50 mg, about 0.25 mg to about 40 mg, about 0.25 mg to about 30 mg, about 0.25 mg to about 20 mg, about 20 mg to about 2000 mg, about 20 mg to about 1600 mg, about 20 mg to about 1200 mg, about 20 mg to about 800 mg, about 20 mg to about 400 mg, about 20 mg to about 100 mg, about 100 mg to about 2000 mg, about 100 mg to about 1800 mg, about 100 mg to about 1600 mg, about 100 mg to about 1400 mg, about 100 mg to about 1200 mg, about 100 mg to about 1000 mg, about 100 mg to about 800 mg, about 100 mg to about 600 mg, about 100 mg to about 400 mg, about 400 mg to about 2000 mg, about 400 mg to about 1800 mg, about 400 mg to about 1600 mg, about 400 mg to about 1400 mg, about 400 mg to about 1200 mg, or about 400 mg to about 1000 mg.

[0391] In some aspects, the PD-1 pathway inhibitor is administered at a dose of about 0.25 mg, about 0.5 mg, about 0.75 mg, about 1 mg, about 1.25 mg, about 1.5 mg, about 1.75 mg, about 2 mg, about 2.25 mg, about 2.5 mg, about 2.75 mg, about 3 mg, about 3.25 mg, about 3.5 mg, about 3.75 mg, about 4 mg, about 4.25 mg, about 4.5 mg, about 4.75 mg, about 5 mg, about 5.25 mg, about 5.5 mg, about 5.75 mg, about 6 mg, about 6.25 mg, about 6.5 mg, about 6.75 mg, about 7 mg, about 7.25 mg, about 7.5 mg, about 7.75 mg, about 8mg, about 8.25 mg, about 8.5 mg, about 8.75 mg, about 9 mg, about 9.25 mg, about 9.5 mg, about 9.75 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, about 800 mg, about 810 mg, about 820 mg, about 830 mg, about 840 mg, about 850 mg, about 860 mg, about 870 mg, about 880 mg, about 890 mg, about 900 mg, about 910 mg, about 920 mg, about 930 mg, about 940 mg, about 950 mg, about 960 mg, about 970 mg, about 980 mg, about 990 mg, about 1000 mg, about 1040 mg, about 1080 mg, about 1100 mg, about 1140 mg, about 1180 mg, about 1200 mg, about 1240 mg, about 1280 mg, about 1300 mg, about 1340 mg, about 1380 mg, about 1400 mg, about 1440 mg, about 1480 mg, about 1500 mg, about 1540 mg, about 1580 mg, about 1600 mg, about 1640 mg, about 1680 mg, about 1700 mg, about 1740 mg, about 1780 mg, about 1800 mg, about 1840 mg, about 1880 mg, about 1900 mg, about 1940 mg, about 1980 mg, or about 2000 mg.

[0392] In some aspects, the PD-1 pathway inhibitor is administered at a weight-based dose.

[0393] In some aspects, the PD-1 pathway inhibitor is administered at a dose of from about 0.003 mg / kg to about 25 mg / kg, about 0.003 mg / kg to about 20 mg / kg, about 0.003 mg / kg to about 15 mg / kg, about 0.003 mg / kg to about 10 mg / kg, about 0.003 mg / kg to about 5 mg / kg, about 0.003 mg / kg to about 1 mg / kg, about 0.003 mg / kg to about 0.9 mg / kg, about 0.003 mg / kg to about 0.8 mg / kg, about 0.003 mg / kg to about 0.7 mg / kg, about 0.003 mg / kg to about 0.6 mg / kg, about 0.003 mg / kg to about 0.5 mg / kg, about 0.003 mg / kg to about 0.4 mg / kg, about 0.003 mg / kg to about 0.3 mg / kg, about 0.003 mg / kg to about 0.2 mg / kg, about0.003 mg / kg to about 0.1 mg / kg, about 0.1 mg / kg to about 25 mg / kg, about 0.1 mg / kg to about 20 mg / kg, about 0.1 mg / kg to about 15 mg / kg, about 0.1 mg / kg to about 10 mg / kg, about 0.1 mg / kg to about 5 mg / kg, about 0.1 mg / kg to about 1 mg / kg, about 1 mg / kg to about 25 mg / kg, about 1 mg / kg to about 20 mg / kg, about 1 mg / kg to about 15 mg / kg, about 1 mg / kg to about 10 mg / kg, about 1 mg / kg to about 5 mg / kg, about 5 mg / kg to about 25 mg / kg, about 5 mg / kg to about 20 mg / kg, about 5 mg / kg to about 15 mg / kg, about 5 mg / kg to about 10 mg / kg, about 10 mg / kg to about 25 mg / kg, about 10 mg / kg to about 20 mg / kg, about 10 mg / kg to about 15 mg / kg, about 15 mg / kg to about 25 mg / kg, about 15 mg / kg to about 20 mg / kg, or about 20 mg / kg to about 25 mg / kg.

[0394] In some aspects, the PD-1 pathway inhibitor is administered at a dose of about 0.003 mg / kg, about 0.004 mg / kg, about 0.005 mg / kg, about 0.006 mg / kg, about 0.007 mg / kg, about 0.008 mg / kg, about 0.009 mg / kg, about 0.01 mg / kg, about 0.02 mg / kg, about 0.03 mg / kg, about 0.04 mg / kg, about 0.05 mg / kg, about 0.06 mg / kg, about 0.07 mg / kg, about 0.08 mg / kg, about 0.09 mg / kg, about 0.1 mg / kg, about 0.2 mg / kg, about 0.3 mg / kg, about 0.4 mg / kg, about 0.5 mg / kg, about 0.6 mg / kg, about 0.7 mg / kg, about 0.8 mg / kg, about 0.9 mg / kg, about 1.0 mg / kg, about 2.0 mg / kg, about 3.0 mg / kg, about 4.0 mg / kg, about 5.0 mg / kg, about 6.0 mg / kg, about 7.0 mg / kg, about 8.0 mg / kg, about 9.0 mg / kg, about 10.0 mg / kg, about 11.0 mg / kg, about 12.0 mg / kg, about 13.0 mg / kg, about 14.0 mg / kg, about 15.0 mg / kg, about 16.0 mg / kg, about 17.0 mg / kg, about 18.0 mg / kg, about 19.0 mg / kg, about 20.0 mg / kg, about 21.0 mg / kg, about 22.0 mg / kg, about 23.0 mg / kg, about 24.0 mg / kg, or about 25.0 mg / kg.

[0395] In some aspects, the dose of the PD-1 pathway inhibitor is administered once about every one week, once about every two weeks, once about every three weeks, once about every four weeks, once about every five weeks, once about every six weeks, once about every seven weeks, once about every eight weeks, once about every nine weeks, once about every ten weeks, once about every eleven weeks, or once about every twelve weeks.

[0396] In some aspects, the PD-1 pathway inhibitor is administered before the LAG-3 antagonist.

[0397] In some aspects, the LAG-3 antagonist is administered before the PD-1 pathway inhibitor.

[0398] In some aspects, the LAG-3 antagonist and the PD-1 pathway inhibitor are administered concurrently.

[0399] In some aspects, the LAG-3 antagonist and the PD-1 pathway inhibitor are formulated separately.

[0400] In some aspects, the LAG-3 antagonist and the PD-1 pathway inhibitor are formulated together. II.E.1 Anti-PD-1 Antibodies

[0401] In some aspects, the PD-1 pathway inhibitor comprises an anti-PD-1 antibody.

[0402] Anti-PD-1 antibodies that are known in the art can be used in the methods of the disclosure. Various human monoclonal antibodies that bind specifically to PD-1 with high affinity have been disclosed in U.S. Patent No. 8,008,449. Anti-PD-1 human antibodies disclosed in U.S. Patent No.8,008,449 have been demonstrated to exhibit one or more of the following characteristics: (a) bind to human PD-1 with a KDof 1 x 10-7M or less, as determined by surface plasmon resonance using a BIACORE biosensor system; (b) do not substantially bind to human CD28, CTLA-4 or ICOS; (c) increase T-cell proliferation in a Mixed Lymphocyte Reaction (MLR) assay; (d) increase interferon-γ production in an MLR assay; (e) increase IL-2 secretion in an MLR assay; (f) bind to human PD-1 and cynomolgus monkey PD-1; (g) inhibit the binding of PD-L1 and / or PD-L2 to PD-1; (h) stimulate antigen-specific memory responses; (i) stimulate antibody responses; and (j) inhibit tumor cell growth in vivo. Anti-PD-1 antibodies usable in the present disclosure include monoclonal antibodies that bind specifically to human PD-1 and exhibit at least one, in some aspects, at least five, of the preceding characteristics.

[0403] Other anti-PD-1 monoclonal antibodies that can be used in the methods of the disclosure have been described in, for example, U.S. Patent Nos. 6,808,710, 7,488,802, 8,168,757 and 8,354,509, US Publication No. 2016 / 0272708, and PCT Publication Nos. WO 2012 / 145493, WO 2008 / 156712, WO 2015 / 112900, WO 2012 / 145493, WO 2015 / 112800, WO 2014 / 206107, WO 2015 / 35606, WO 2015 / 085847, WO 2014 / 179664, WO 2017 / 020291, WO 2017 / 020858, WO 2016 / 197367, WO 2017 / 024515, WO 2017 / 025051, WO 2017 / 123557, WO 2016 / 106159, WO 2014 / 194302, WO 2017 / 040790, WO 2017 / 133540, WO 2017 / 132827, WO 2017 / 024465, WO 2017 / 025016, WO 2017 / 106061, WO 2017 / 19846, WO 2017 / 024465, WO 2017 / 025016, WO 2017 / 132825, and WO 2017 / 133540 each of which is incorporated by reference in its entirety.

[0404] Anti-PD-1 antibodies that can be used in the methods of the disclosure include nivolumab (also known as OPDIVO®, 5C4, BMS-936558, MDX-1106, and ONO-4538),pembrolizumab (Merck; also known as KEYTRUDA®, lambrolizumab, and MK3475; see WO 2008 / 156712), PDR001 (Novartis; also known as spartalizumab; see WO 2015 / 112900 and U.S. Patent No. 9,683,048), MEDI-0680 (AstraZeneca; also known as AMP-514; see WO 2012 / 145493), TSR-042 (Tesaro Biopharmaceutical; also known as ANB011 or dostarlimab; see WO 2014 / 179664), cemiplimab (Regeneron; also known as LIBTAYO® or REGN2810; see WO 2015 / 112800 and U.S. Patent No.9,987,500), JS001 (TAIZHOU JUNSHI PHARMA; also known as toripalimab; see Si-Yang Liu et al., J. Hematol. Oncol. 10:136 (2017)), PF-06801591 (Pfizer; also known as sasanlimab; US 2016 / 0159905), BGB-A317 (Beigene; also known as tislelizumab; see WO 2015 / 35606 and US 2015 / 0079109), BI 754091 (Boehringer Ingelheim; see Zettl M et al., Cancer. Res. (2018);78(13 Suppl):Abstract 4558), INCSHR1210 (Jiangsu Hengrui Medicine; also known as SHR-1210 or camrelizumab; see WO 2015 / 085847; Si-Yang Liu et al., J. Hematol. Oncol. 10:136 (2017)), GLS-010 (Wuxi / Harbin Gloria Pharmaceuticals; also known as WBP3055; see Si-Yang Liu et al., J. Hematol. Oncol.10:136 (2017)), AM-0001 (Armo), STI-1110 (Sorrento Therapeutics; see WO 2014 / 194302), AGEN2034 (Agenus; see WO 2017 / 040790), MGA012 (Macrogenics, see WO 2017 / 19846), BCD-100 (Biocad; Kaplon et al., mAbs 10(2):183-203 (2018), IBI308 (Innovent; also known as sintilimab; see WO 2017 / 024465, WO 2017 / 025016, WO 2017 / 132825, and WO 2017 / 133540), and SSI- 361 (Lyvgen Biopharma Holdings Limited, US 2018 / 0346569).

[0405] Anti-PD-1 antibodies that can be used in the methods of the disclosure also include isolated antibodies that bind specifically to human PD-1 and cross-compete for binding to human PD-1 with any anti-PD-1 antibody disclosed herein, e.g., nivolumab (see, e.g., U.S. Patent No. 8,008,449 and 8,779,105; WO 2013 / 173223). In some aspects, the anti-PD-1 antibody binds the same epitope as any of the anti-PD-1 antibodies described herein, e.g., nivolumab.

[0406] In some aspects, the antibodies that cross-compete for binding to human PD-1 with, or bind to the same epitope region as, any anti-PD-1 antibody disclosed herein, e.g., nivolumab, are monoclonal antibodies. For administration to human subjects, these cross- competing antibodies are chimeric antibodies, engineered antibodies, or humanized or human antibodies. Such chimeric, engineered, humanized or human monoclonal antibodies can be prepared and isolated by methods well known in the art.

[0407] Anti-PD-1 antibodies that can be used in the methods of the disclosure also include antigen binding portions of any of the above full-length antibodies.

[0408] Anti-PD-1 antibodies that can be used in the methods of the disclosure are antibodies that bind to PD-1 with high specificity and affinity, block the binding of PD-L1 and or PD-L2, and inhibit the immunosuppressive effect of the PD-1 signaling pathway. In any of the compositions or methods disclosed herein, an anti-PD-1 "antibody" includes an antigen binding portion or fragment that binds to the PD-1 receptor and exhibits the functional properties similar to those of whole antibodies in inhibiting ligand binding and up-regulating the immune system. In some aspects, the anti-PD-1 antibody or antigen binding portion thereof cross-competes with nivolumab for binding to human PD-1.

[0409] In some aspects, the anti-PD-1 antibody comprises a full-length antibody. In some aspects, the anti-PD-1 antibody comprises a monoclonal, human, humanized, chimeric, or multispecific antibody. In some aspects, the multispecific antibody is a DART, a DVD-IG, or a bispecific antibody.

[0410] In some aspects, the anti-PD-1 antibody comprises a F(ab')2 fragment, a Fab' fragment, a Fab fragment, a Fv fragment, a scFv fragment, a dsFv fragment, a dAb fragment, or a single chain binding polypeptide.

[0411] In some aspects, the anti-PD-1 antibody comprises nivolumab, pembrolizumab, PDR001 (spartalizumab), MEDI-0680, TSR-042, cemiplimab, JS001, PF-06801591, BGB- A317, BI 754091, INCSHR1210, GLS-010, AM-001, STI-1110, AGEN2034, MGA012, BCD-100, IBI308, SSI-361, or an antigen binding portion thereof.

[0412] In some aspects, the anti-PD-1 antibody is formulated for parenteral administration.

[0413] In some aspects, the anti-PD-1 antibody is formulated for intravenous, intraperitoneal, intramuscular, intrathecal, or subcutaneous administration.

[0414] In some aspects, the anti-PD-1 antibody is administered intravenously for about 30 minutes.

[0415] In some aspects, the anti-PD-1 antibody is nivolumab, or an antigen binding portion thereof. Nivolumab is a fully human IgG4 (S228P) PD-1 immune checkpoint inhibitor antibody that selectively prevents interaction with PD-1 ligands (PD-L1 and PD-L2), thereby blocking the down-regulation of antitumor T-cell functions (U.S. Patent No. 8,008,449; Wang et al., 2014 Cancer Immunol Res.2(9):846-56).

[0416] In some aspects, nivolumab, or an antigen binding portion thereof, is administered intravenously at a dose of about 240 mg, about 360 mg, or about 480 mg once about every 2, 3, or 4 weeks. In some aspects, nivolumab, or an antigen binding portion thereof, is administered at a dose of about 240 mg once about every 2 weeks. In some aspects, nivolumab, or an antigen binding portion thereof, is administered at a dose of about 240 mg once about every 3 weeks. In some aspects, nivolumab, or an antigen binding portion thereof, is administered at a dose of about 360 mg once about every 3 weeks. In some aspects, nivolumab is administered at a dose of about 360 mg once about every 4 weeks. In some aspects, nivolumab is administered at a dose of about 480 mg once about every 4 weeks.

[0417] In some aspects, nivolumab is administered intravenously at a dose of about 240 mg for about 30 minutes on Day 1 of a two-week cycle.

[0418] In some aspects, nivolumab is administered intravenously at a dose of about 360 mg for about 30 minutes on Day 1 of a four-week cycle.

[0419] In some aspects, nivolumab is administered intravenously at a dose of about 480 mg for about 30 minutes on Day 1 of a four-week cycle.

[0420] In some aspects, nivolumab, or an antigen binding portion thereof, is administered subcutaneously at a dose of about 720 mg once about every 4 weeks.

[0421] In some aspects, nivolumab, or an antigen binding portion thereof, is administered subcutaneously at a dose of about 960 mg once about every 4 weeks.

[0422] In some aspects, nivolumab, or an antigen binding portion thereof, is administered subcutaneously at a dose of about 720 mg for about 30 minutes on Day 1 of a four-week cycle.

[0423] In some aspects, nivolumab, or an antigen binding portion thereof, is administered subcutaneously at a dose of about 960 mg for about 30 minutes on Day 1 of a four-week cycle.

[0424] In some aspects, the methods of the disclosure comprise an anti-PD-1 antibody comprising CDR1, CDR2 and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID NO:13, and CDR1, CDR2 and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID NO:14.

[0425] In some aspects, the methods of the disclosure comprise an anti-PD-1 antibody comprising: (a) a heavy chain variable region CDR1 comprising the sequence set forth inSEQ ID NO:15; (b) a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO:16; (c) a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO:17; (d) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO:18; (e) a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO:19; and (f) a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO:20.

[0426] In some aspects, the methods of the disclosure comprise an anti-PD-1 antibody comprising heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs:13 and 14, respectively.

[0427] In some aspects, the methods of the disclosure comprise an anti-PD-1 antibody comprising heavy and light chains comprising the sequences as set forth in SEQ ID NOs:11 and 12, respectively.

[0428] In some aspects, the methods of the disclosure comprise a combination of a LAG- 3 antagonist comprising relatlimab, or an antigen binding portion thereof, and a PD-1 pathway inhibitor comprising nivolumab, or an antigen binding portion thereof.

[0429] In some aspects, the LAG-3 antagonist comprises relatlimab intravenously administered between about 160 mg to about 480 mg once about every four weeks and the PD-1 pathway inhibitor comprises nivolumab intravenously administered between 240 mg to about 480 mg once about every four weeks.

[0430] In some aspects, the LAG-3 antagonist comprises relatlimab intravenously administered at about 160 mg once about every four weeks and the PD-1 pathway inhibitor comprises nivolumab intravenously administered at about 480 mg once about every four weeks.

[0431] In some aspects, the LAG-3 antagonist comprises relatlimab intravenously administered at about 360 mg once about every four weeks and the PD-1 pathway inhibitor comprises nivolumab intravenously administered at about 360 mg once about every four weeks.

[0432] In some aspects, the LAG-3 antagonist comprises relatlimab intravenously administered at about 480 mg once about every four weeks and the PD-1 pathway inhibitor comprises nivolumab intravenously administered at about 480 mg once about every four weeks.

[0433] In some aspects, the LAG-3 antagonist comprises relatlimab subcutaneously administered at about 320 mg once about every four weeks and the PD-1 pathway inhibitor comprises nivolumab subcutaneously administered at about 960 mg once about every four weeks.

[0434] In some aspects, the LAG-3 antagonist comprises relatlimab subcutaneously administered at about 960 mg once about every four weeks and the PD-1 pathway inhibitor comprises nivolumab subcutaneously administered at about 960 mg once about every four weeks.

[0435] The present disclosure is directed to a method of treating a tumor in a human subject in need thereof comprising intravenously administering to the subject relatlimab at about 480 mg once about every four weeks and nivolumab at about 480 mg once about every four weeks, wherein the subject’s tumor is identified as having a histoscore (H-score) of less than about 250 according to the formula: (1 × percentage of tumor cells in the sample with weak FGL-1 expression) + (2 × percentage of tumor cells in the sample with moderate FGL-1 expression) + (3 × percentage of tumor cells in the sample with strong FGL-1 expression). In some aspects, the tumor comprises a hepatocellular carcinoma. In some aspects, the H-score is less than about 140.

[0436] The present disclosure is directed to a method of treating a tumor in a human subject in need thereof comprising intravenously administering to the subject relatlimab at about 360 mg once about every four weeks and nivolumab at about 360 mg once about every four weeks, wherein the subject’s tumor is identified as having an H-score of less than or equal to about 10 according to the formula: (1 × percentage of tumor cells in the sample with weak FGL-1 expression) + (2 × percentage of tumor cells in the sample with moderate FGL-1 expression) + (3 × percentage of tumor cells in the sample with strong FGL-1 expression). In some aspects, the H-score is from about 1 to about 10. In some aspects, the tumor comprises a non-small cell lung cancer. In some aspects, the non-small lung cancer comprises non-squamous non-small cell lung cancer.

[0437] The present disclosure is directed to a method of treating a tumor in a human subject in need thereof comprising intravenously administering to the subject relatlimab at about 360 mg once about every four weeks and nivolumab at about 360 mg once about every four weeks, wherein the subject’s tumor is identified as having an H-score of greater than about 45 according to the formula: (1 × percentage of tumor cells in the sample with weak FGL-1 expression) + (2 × percentage of tumor cells in the sample with moderate FGL-1 expression) + (3 × percentage of tumor cells in the sample with strong FGL-1 expression). In some aspects, the tumor comprises a non-small cell lung cancer. In some aspects, the non-small lung cancer comprises non-squamous non-small cell lung cancer.

[0438] The present disclosure is directed to a method of treating a tumor in a human subject in need thereof comprising intravenously administering to the subject relatlimab at about 360 mg once about every four weeks and nivolumab at about 360 mg once about every four weeks, wherein a sample of the subject’s plasma or serum comprises less than about 360 ng / mL of soluble FGL-1. In some aspects, the tumor comprises a non-small cell lung cancer. In some aspects, the non-small lung cancer comprises non-squamous non-small cell lung cancer.

[0439] In some aspects, the methods of the disclosure comprise: (a) an anti-LAG-3 antibody comprising CDR1, CDR2 and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID NO:3, and CDR1, CDR2 and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID NO:4; and (b) an anti-PD-1 antibody comprising CDR1, CDR2 and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID NO:13, and CDR1, CDR2 and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID NO:14.

[0440] In some aspects, the methods of the disclosure comprise: (a) an anti-LAG-3 antibody comprising a heavy chain variable region CDR1, CDR2, and CDR3 comprising the sequence set forth in SEQ ID NO:5, SEQ ID NO:6, and SEQ ID NO:7, respectively, and a light chain variable region CDR1, CDR2, and CDR3 comprising the sequence set forth in SEQ ID NO:8, SEQ ID NO:9, and SEQ ID NO:10, respectively, and (b) an anti- PD-1 antibody comprising a heavy chain variable region CDR1, CDR2, and CDR3 comprising the sequence set forth in SEQ ID NO:15, SEQ ID NO:16, and SEQ ID NO:17, respectively, and a light chain variable region CDR1, CDR2, and CDR3 comprising the sequence set forth in SEQ ID NO:18, SEQ ID NO:19, and SEQ ID NO:20, respectively.

[0441] In some aspects, the methods of the disclosure comprise: (a) an anti-LAG-3 antibody comprising heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs:3 and 4, respectively, and (b) an anti-PD-1 antibody comprising heavyand light chain variable regions comprising the sequences set forth in SEQ ID NOs:13 and 14, respectively.

[0442] In some aspects, the methods of the disclosure comprise: (a) an anti-LAG-3 antibody comprising heavy and light chains comprising the sequences set forth in SEQ ID NOs:1 and 2, respectively, and (b) an anti-PD-1 antibody comprises heavy and light chains comprising the sequences as set forth in SEQ ID NOs:11 and 12, respectively.

[0443] In some aspects, the methods of the disclosure comprise: (a) an anti-LAG-3 antibody comprising heavy and light chains comprising the sequences set forth in SEQ ID NOs:21 and 2, respectively, and (b) an anti-PD-1 antibody comprises heavy and light chains comprising the sequences as set forth in SEQ ID NOs:11 and 12, respectively.

[0444] In some aspects, the anti-PD-1 antibody is pembrolizumab, or an antigen binding portion thereof. Pembrolizumab is a humanized monoclonal IgG4 (S228P) antibody directed against human cell surface receptor PD-1. Pembrolizumab is described, for example, in U.S. Patent Nos.8,354,509 and 8,900,587.

[0445] In some aspects, pembrolizumab, or an antigen binding portion thereof, is administered at a flat dose of about 200 mg once about every 2 weeks. In some aspects, pembrolizumab is administered at a flat dose of about 200 mg once about every 3 weeks. In some aspects, pembrolizumab, or an antigen binding portion thereof, is administered at a flat dose of about 400 mg once about every 6 weeks. In some aspects, pembrolizumab, or an antigen binding portion thereof, is administered at a flat dose of about 300 mg once about every 4-5 weeks.

[0446] In some aspects, pembrolizumab, or an antigen binding portion thereof, is administered intravenously at a dose of about 200 mg on Day 1, then once about every 3 weeks. In some aspects, pembrolizumab, or an antigen binding portion thereof, is administered for up to 35 cycles. In some aspects, pembrolizumab, or an antigen binding portion thereof, is administered intravenously at a dose of about 200 mg for about 30 minutes on Day 1 of a three-week cycle for up to 35 cycles.

[0447] In some aspects, the methods of the disclosure comprise an anti-PD-1 antibody comprising CDR1, CDR2 and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID NO:77, and CDR1, CDR2 and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID NO:78.

[0448] In some aspects, the methods of the disclosure comprise an anti-PD-1 antibody comprising: (a) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO:79; (b) a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO:80; (c) a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO:81; (d) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO:82; (e) a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO:83; and (f) a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO:84.

[0449] In some aspects, the methods of the disclosure comprise an anti-PD-1 antibody comprising heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs:77 and 78, respectively.

[0450] In some aspects, the methods of the disclosure comprise an anti-PD-1 antibody comprising heavy and light chains comprising the sequences as set forth in SEQ ID NOs:75 and 76, respectively.

[0451] In some aspects, the methods of the disclosure comprise a combination of favezelimab, or an antigen binding portion thereof, and pembrolizumab, or an antigen binding portion thereof. In some aspects, 800 mg of favezelimab, or an antigen binding portion thereof, and 200 mg of pembrolizumab, or an antigen binding portion thereof, are administered intravenously on Day 1, then once about every 3 weeks. In some aspects, the combination of favezelimab, or an antigen binding portion thereof, and pembrolizumab, or an antigen binding portion thereof, is administered for up to 35 cycles. In some aspects, 800 mg of favezelimab, or an antigen binding portion thereof, and 200 mg of pembrolizumab, or an antigen binding portion thereof, are administered intravenously for about 30 minutes on Day 1 of a three-week cycle for up to 35 cycles.

[0452] In some aspects, the methods of the disclosure comprise: (a) an anti-LAG-3 antibody comprising CDR1, CDR2 and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID NO:67, and CDR1, CDR2 and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID NO:68; and (b) an anti-PD-1 antibody comprising CDR1, CDR2 and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID NO:77, and CDR1, CDR2 and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID NO:78.

[0453] In some aspects, the methods of the disclosure comprise: (a) an anti-LAG-3 antibody comprising a heavy chain variable region CDR1, CDR2, and CDR3 comprising the sequence set forth in SEQ ID NO:69, SEQ ID NO:70, and SEQ ID NO:71, respectively, and a light chain variable region CDR1, CDR2, and CDR3 comprising the sequence set forth in SEQ ID NO:72, SEQ ID NO:73, and SEQ ID NO:74, respectively, and (b) an anti- PD-1 antibody comprising a heavy chain variable region CDR1, CDR2, and CDR3 comprising the sequence set forth in SEQ ID NO:79, SEQ ID NO:80, and SEQ ID NO:81, respectively, and a light chain variable region CDR1, CDR2, and CDR3 comprising the sequence set forth in SEQ ID NO:82, SEQ ID NO:83, and SEQ ID NO:84, respectively.

[0454] In some aspects, the methods of the disclosure comprise: (a) an anti-LAG-3 antibody comprising heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs:67 and 68, respectively, and (b) an anti-PD-1 antibody comprising heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs:77 and 78, respectively.

[0455] In some aspects, the methods of the disclosure comprise: (a) an anti-LAG-3 antibody comprising heavy and light chains comprising the sequences set forth in SEQ ID NOs:65 and 66, respectively, and (b) an anti-PD-1 antibody comprises heavy and light chains comprising the sequences as set forth in SEQ ID NOs:75 and 76, respectively.

[0456] In some aspects, the anti-PD-1 antibody is cemiplimab (REGN2810), or an antigen binding portion thereof. Cemiplimab is described, for example, in WO 2015 / 112800 and U.S. Patent No.9,987,500.

[0457] In some aspects, cemiplimab, or an antigen binding portion thereof, is administered intravenously at a dose of about 3 mg / kg or about 350 mg once about every 3 weeks.

[0458] In some aspects, the methods of the disclosure comprise an anti-PD-1 antibody comprising CDR1, CDR2 and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID NO:34, and CDR1, CDR2 and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID NO:35.

[0459] In some aspects, the methods of the disclosure comprise an anti-PD-1 antibody comprising: (a) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO:36; (b) a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO:37; (c) a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO:38; (d) a light chain variable region CDR1 comprising the sequenceset forth in SEQ ID NO:39; (e) a light chain variable region CDR2 comprising the sequence AAS; and (f) a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO:40.

[0460] In some aspects, the methods of the disclosure comprise an anti-PD-1 antibody comprising heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs:34 and 35, respectively.

[0461] In some aspects, the methods of the disclosure comprise an anti-PD-1 antibody comprising heavy and light chains comprising the sequences as set forth in SEQ ID NOs:32 and 33, respectively.

[0462] In some aspects, the methods of the disclosure comprise a combination of fianlimab, or an antigen binding portion thereof, and cemiplimab, or an antigen binding portion thereof.

[0463] In some aspects, the methods of the disclosure comprise: (a) an anti-LAG-3 antibody comprising CDR1, CDR2 and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID NO:25, and CDR1, CDR2 and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID NO:26; and (b) an anti-PD-1 antibody comprising CDR1, CDR2 and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID NO:34, and CDR1, CDR2 and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID NO:35.

[0464] In some aspects, the methods of the disclosure comprise: (a) an anti-LAG-3 antibody comprising a heavy chain variable region CDR1, CDR2, and CDR3 comprising the sequence set forth in SEQ ID NO:27, SEQ ID NO:28, and SEQ ID NO:29, respectively, and a light chain variable region CDR1, CDR2, and CDR3 comprising the sequence set forth in SEQ ID NO:30, the sequence DAS, and the sequence set forth in SEQ ID NO:31, respectively, and (b) an anti-PD-1 antibody comprising a heavy chain variable region CDR1, CDR2, and CDR3 comprising the sequence set forth in SEQ ID NO:36, SEQ ID NO:37, and SEQ ID NO:38, respectively, and a light chain variable region CDR1, CDR2, and CDR3 comprising the sequence set forth in SEQ ID NO:39, the sequence AAS, and SEQ ID NO:40, respectively.

[0465] In some aspects, the methods of the disclosure comprise: (a) an anti-LAG-3 antibody comprising heavy and light chain variable regions comprising the sequences setforth in SEQ ID NOs:25 and 26, respectively, and (b) an anti-PD-1 antibody comprising heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs:34 and 35, respectively.

[0466] In some aspects, the methods of the disclosure comprise: (a) an anti-LAG-3 antibody comprising heavy and light chains comprising the sequences set forth in SEQ ID NOs:23 and 24, respectively, and (b) an anti-PD-1 antibody comprises heavy and light chains comprising the sequences as set forth in SEQ ID NOs:32 and 33, respectively.

[0467] In some aspects, the anti-PD-1 antibody is spartalizumab (PDR001), or an antigen binding portion thereof. Spartalizumab is described, for example, in WO 2015 / 112900 and U.S. Patent No.9,683,048.

[0468] In some aspects, spartalizumab, or an antigen binding portion thereof, is administered intravenously at a dose of about 300 mg once about every 3 weeks or 400 mg once about every 4 weeks.

[0469] In some aspects, the methods of the disclosure comprise an anti-PD-1 antibody comprising CDR1, CDR2 and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID NO:57, and CDR1, CDR2 and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID NO:58.

[0470] In some aspects, the methods of the disclosure comprise an anti-PD-1 antibody comprising: (a) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO:59; (b) a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO:61; (c) a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO:61; (d) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO:62; (e) a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO:63; and (f) a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO:64.

[0471] In some aspects, the methods of the disclosure comprise an anti-PD-1 antibody comprising heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs:57 and 58, respectively.

[0472] In some aspects, the methods of the disclosure comprise an anti-PD-1 antibody comprising heavy and light chains comprising the sequences as set forth in SEQ ID NOs:55 and 56, respectively.

[0473] In some aspects, the methods of the disclosure comprise a combination of ieramilimab, or an antigen binding portion thereof, and spartalizumab, or an antigen binding portion thereof. In some aspects, ieramilimab, or an antigen binding portion thereof, is administered intravenously at a dose of about 400 mg once about every three weeks and spartalizumab, or an antigen binding portion thereof, is administered intravenously at a dose of about 300 mg once about every 3 weeks. In some aspects, ieramilimab, or an antigen binding portion thereof, is administered intravenously at a dose of about 600 mg once about every four weeks and spartalizumab, or an antigen binding portion thereof, is administered intravenously at a dose of about 400 mg once about every 4 weeks.

[0474] In some aspects, the methods of the disclosure comprise: (a) an anti-LAG-3 antibody comprising CDR1, CDR2 and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID NO:45, and CDR1, CDR2 and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID NO:47; and (b) an anti-PD-1 antibody comprising CDR1, CDR2 and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID NO:57, and CDR1, CDR2 and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID NO:58.

[0475] In some aspects, the methods of the disclosure comprise: (a) an anti-LAG-3 antibody comprising CDR1, CDR2 and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID NO:46, and CDR1, CDR2 and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID NO:48; and (b) an anti-PD-1 antibody comprising CDR1, CDR2 and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID NO:57, and CDR1, CDR2 and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID NO:58.

[0476] In some aspects, the methods of the disclosure comprise: (a) an anti-LAG-3 antibody comprising a heavy chain variable region CDR1, CDR2, and CDR3 comprising the sequence set forth in SEQ ID NO:49, SEQ ID NO:50, and SEQ ID NO:51, respectively, and a light chain variable region CDR1, CDR2, and CDR3 comprising the sequence set forth in SEQ ID NO:52, SEQ ID NO:53, and SEQ ID NO:54, respectively, and (b) an anti- PD-1 antibody comprising a heavy chain variable region CDR1, CDR2, and CDR3comprising the sequence set forth in SEQ ID NO:59, SEQ ID NO:60, and SEQ ID NO:61, respectively, and a light chain variable region CDR1, CDR2, and CDR3 comprising the sequence set forth in SEQ ID NO:62, SEQ ID NO:63, and SEQ ID NO:64, respectively.

[0477] In some aspects, the methods of the disclosure comprise: (a) an anti-LAG-3 antibody comprising heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs:45 and 47, respectively, and (b) an anti-PD-1 antibody comprising heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs:57 and 58, respectively.

[0478] In some aspects, the methods of the disclosure comprise: (a) an anti-LAG-3 antibody comprising heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs:46 and 48, respectively, and (b) an anti-PD-1 antibody comprising heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs:57 and 58, respectively.

[0479] In some aspects, the methods of the disclosure comprise: (a) an anti-LAG-3 antibody comprising heavy and light chains comprising the sequences set forth in SEQ ID NOs:41 and 43, respectively, and (b) an anti-PD-1 antibody comprises heavy and light chains comprising the sequences as set forth in SEQ ID NOs:55 and 56, respectively.

[0480] In some aspects, the methods of the disclosure comprise: (a) an anti-LAG-3 antibody comprising heavy and light chains comprising the sequences set forth in SEQ ID NOs:42 and 44, respectively, and (b) an anti-PD-1 antibody comprises heavy and light chains comprising the sequences as set forth in SEQ ID NOs:55 and 56, respectively.

[0481] The anti-LAG-3 antibody and the anti-PD-1 antibodies can be administered at any of the doses or combinations of doses described herein.

[0482] In some aspects, the dose of the anti-LAG-3 antibody is about 80 mg.

[0483] In some aspects, the dose of the anti-LAG-3 antibody is about 120 mg.

[0484] In some aspects, the dose of the anti-LAG-3 antibody is about 160 mg.

[0485] In some aspects, the dose of the anti-LAG-3 antibody is about 320 mg.

[0486] In some aspects, the dose of the anti-LAG-3 antibody is about 360 mg.

[0487] In some aspects, the dose of the anti-LAG-3 antibody is about 480 mg.

[0488] In some aspects, the dose of the anti-LAG-3 antibody is about 720 mg.

[0489] In some aspects, the dose of the anti-LAG-3 antibody is about 800 mg.

[0490] In some aspects, the dose of the anti-LAG-3 antibody is about 960 mg.

[0491] In some aspects, the dose of the anti-PD-1 antibody is about 200 mg.

[0492] In some aspects, the dose of the anti-PD-1 antibody is about 240 mg.

[0493] In some aspects, the dose of the anti-PD-1 antibody is about 360 mg.

[0494] In some aspects, the dose of the anti-PD-1 antibody is about 480 mg.

[0495] In some aspects, the dose of the anti-PD-1 antibody is about 960 mg.

[0496] In some aspects, the dose of the anti-LAG-3 antibody is about 80 mg and the dose of the anti-PD-1 antibody is about 240 mg.

[0497] In some aspects, the dose of the anti-LAG-3 antibody is about 80 mg and the dose of the anti-PD-1 antibody is about 480 mg.

[0498] In some aspects, the dose of the anti-LAG-3 antibody is about 120 mg and the dose of the anti-PD-1 antibody is about 360 mg.

[0499] In some aspects, the dose of the anti-LAG-3 antibody is about 160 mg and the dose of the anti-PD-1 antibody is about 480 mg.

[0500] In some aspects, the dose of the anti-LAG-3 antibody is about 320 mg and the dose of the anti-PD-1 antibody is about 960 mg.

[0501] In some aspects, the dose of the anti-LAG-3 antibody is about 360 mg and the dose of the anti-PD-1 antibody is about 360 mg.

[0502] In some aspects, the dose of the anti-LAG-3 antibody is about 480 mg and the dose of the anti-PD-1 antibody is about 480 mg.

[0503] In some aspects, the dose of the anti-LAG-3 antibody is about 720 mg and the dose of the anti-PD-1 antibody is about 360 mg.

[0504] In some aspects, the dose of the anti-LAG-3 antibody is about 800 mg and the dose of the anti-PD-1 antibody is about 200 mg.

[0505] In some aspects, the dose of the anti-LAG-3 antibody is about 960 mg and the dose of the anti-PD-1 antibody is about 480 mg.

[0506] In some aspects, the dose of the anti-LAG-3 antibody is about 2 mg / kg and the dose of the anti-PD-1 antibody is about 6 mg / kg.

[0507] In some aspects, the dose of the anti-LAG-3 antibody is about 1 mg / kg and the dose of the anti-PD-1 antibody is about 6 mg / kg.

[0508] In some aspects, the dose of the anti-LAG-3 antibody is about 26.7 mg / mL and the dose of the anti-PD-1 antibody is about 80 mg / mL.

[0509] In some aspects, the anti-LAG-3 antibody comprises heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs:3 and 4, respectively, and the anti-PD-1 antibody comprises heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs:13 and 14, respectively.

[0510] In some aspects, the anti-LAG-3 antibody comprises heavy and light chains comprising the sequences set forth in SEQ ID NOs:1 and 2, respectively, and the anti-PD- 1 antibody comprises heavy and light chains comprising the sequences as set forth in SEQ ID NOs:11 and 12, respectively.

[0511] In some aspects, the anti-LAG-3 antibody comprises heavy and light chains comprising the sequences set forth in SEQ ID NOs:21 and 2, respectively, and the anti-PD- 1 antibody comprises heavy and light chains comprising the sequences as set forth in SEQ ID NOs:11 and 12, respectively.

[0512] In some aspects, the anti-LAG-3 antibody and the anti-PD-1 antibody are administered about once every four weeks. In some aspects, the anti-LAG-3 antibody and the anti-PD-1 antibody are administered on Day 1 of every four-week cycle.

[0513] In some aspects, the anti-LAG-3 antibody is administered intravenously for about 30 minutes.

[0514] In some aspects, the anti-PD-1 antibody is administered intravenously for about 30 minutes.

[0515] In some aspects, a pharmaceutical composition comprising an anti-LAG-3 antibody and an anti-PD-1 antibody is administered intravenously for about 30 minutes. II.E.2 Anti-PD-L1 Antibodies

[0516] In some aspects, the PD-1 pathway inhibitor is an anti-PD-L1 antibody.

[0517] Anti-PD-L1 antibodies that are known in the art can be used in the methods of the disclosure. Examples of anti-PD-L1 antibodies useful in the compositions and methods of the present disclosure include the antibodies disclosed in US Patent No.9,580,507. Anti- PD-L1 human monoclonal antibodies disclosed in U.S. Patent No. 9,580,507 have been demonstrated to exhibit one or more of the following characteristics: (a) bind to human PD- L1 with a KD of 1 x 10-7M or less, as determined by surface plasmon resonance using a BIACORE biosensor system; (b) increase T-cell proliferation in a Mixed Lymphocyte Reaction (MLR) assay; (c) increase interferon-γ production in an MLR assay; (d) increase IL-2 secretion in an MLR assay; (e) stimulate antibody responses; and (f) reverse the effectof T regulatory cells on T cell effector cells and / or dendritic cells. Anti-PD-L1 antibodies usable in the present disclosure include monoclonal antibodies that bind specifically to human PD-L1 and exhibit at least one, in some aspects, at least five, of the preceding characteristics.

[0518] Anti-PD-L1 antibodies that can be used in the methods of the disclosure include BMS-936559 (also known as 12A4, MDX-1105; see, e.g., U.S. Patent No.7,943,743 and WO 2013 / 173223), atezolizumab (Roche; also known as TECENTRIQ®; MPDL3280A, RG7446; see US 8,217,149; see, also, Herbst et al. (2013) J Clin Oncol 31(suppl):3000), durvalumab (AstraZeneca; also known as IMFINZI™, MEDI-4736; see WO 2011 / 066389), avelumab (Pfizer; also known as BAVENCIO®, MSB-0010718C; see WO 2013 / 079174), STI-1014 (Sorrento; see WO2013 / 181634), CX-072 (Cytomx; see WO2016 / 149201), KN035 (3D Med / Alphamab; see Zhang et al., Cell Discov.7:3 (March 2017), LY3300054 (Eli Lilly Co.; see, e.g., WO 2017 / 034916), BGB-A333 (BeiGene; see Desai et al., JCO 36 (15suppl):TPS3113 (2018)), ICO 36, FAZ053 (Novartis), and CK-301 (Checkpoint Therapeutics; see Gorelik et al., AACR:Abstract 4606 (Apr 2016)).

[0519] Anti-PD-L1 antibodies that can be used in the methods of the disclosure also include isolated antibodies that bind specifically to human PD-L1 and cross-compete for binding to human PD-L1 with any anti-PD-L1 antibody disclosed herein, e.g., atezolizumab, durvalumab, and / or avelumab. In some aspects, the anti-PD-L1 antibody binds the same epitope as any of the anti-PD-L1 antibodies described herein, e.g., atezolizumab, durvalumab, and / or avelumab. In some aspects, the antibodies that cross-compete for binding to human PD-L1 with, or bind to the same epitope region as, any anti-PD-L1 antibody disclosed herein, e.g., atezolizumab, durvalumab, and / or avelumab, are monoclonal antibodies. For administration to human subjects, these cross-competing antibodies are chimeric antibodies, engineered antibodies, or humanized or human antibodies. Such chimeric, engineered, humanized or human monoclonal antibodies can be prepared and isolated by methods well known in the art.

[0520] Anti-PD-L1 antibodies that can be used in the methods of the disclosure also include antigen binding portions of any of the above full-length antibodies.

[0521] Anti-PD-L1 antibodies that can be used in the methods of the disclosure are antibodies that bind to PD-L1 with high specificity and affinity, block the binding of PD- 1, and inhibit the immunosuppressive effect of the PD-1 signaling pathway. In any of thecompositions or methods disclosed herein, an anti-PD-L1 "antibody" includes an antigen binding portion or fragment that binds to PD-L1 and exhibits the functional properties similar to those of whole antibodies in inhibiting receptor binding and up-regulating the immune system. In some aspects, the anti-PD-L1 antibody or antigen binding portion thereof cross-competes with atezolizumab, durvalumab, and / or avelumab for binding to human PD-L1.

[0522] In some aspects, an anti-PD-L1 antibody is substituted for the anti-PD-1 antibody in any of the methods disclosed herein.

[0523] In some aspects, the anti-PD-L1 antibody comprises a full-length antibody.

[0524] In some aspects, the anti-PD-L1 antibody comprises a monoclonal, human, humanized, chimeric, or multispecific antibody. In some aspects, the multispecific antibody is a DART, a DVD-IG, or a bispecific antibody.

[0525] In some aspects, the anti-PD-L1 antibody comprises a F(ab')2 fragment, a Fab' fragment, a Fab fragment, a Fv fragment, a scFv fragment, a dsFv fragment, a dAb fragment, or a single chain binding polypeptide.

[0526] In some aspects, the anti-PD-L1 antibody comprises BMS-936559, atezolizumab, durvalumab, avelumab, STI-1014, CX-072, KN035, LY3300054, BGB-A333, ICO 36, FAZ053, CK-301, or an antigen binding portion thereof.

[0527] In some aspects, the PD-L1 antibody is atezolizumab, or an antigen binding portion thereof. Atezolizumab is a fully humanized IgG1 monoclonal anti-PD-L1 antibody. In some aspects, atezolizumab, or an antigen binding portion thereof, is administered as a flat dose of about 800 mg once about every 2 weeks. In some aspects, atezolizumab, or an antigen binding portion thereof, is administered as a flat dose of about 840 mg once about every 2 weeks.

[0528] In some aspects, atezolizumab, or an antigen binding portion thereof, is administered intravenously at a dose of about 1,200 mg on Day 1 of a three-week cycle.

[0529] In some aspects, atezolizumab, or an antigen binding portion thereof, is administered intravenously at a dose of about 1,200 mg on Day 1 of a three-week cycle, and bevacizumab is administered at a dose of about 15 mg / kg on Day 1 of each cycle.

[0530] In some aspects, the PD-L1 antibody is durvalumab, or an antigen binding portion thereof. Durvalumab is a human IgG1 kappa monoclonal anti-PD-L1 antibody. In some aspects, durvalumab, or an antigen binding portion thereof, is administered at a dose ofabout 10 mg / kg once about every 2 weeks. In some aspects, durvalumab, or an antigen binding portion thereof, is administered at a dose of about 10 mg / kg once about every 2 weeks for up to 12 months. In some aspects, durvalumab, or an antigen binding portion thereof, is administered as a flat dose of about 800 mg / kg once about every 2 weeks. In some aspects, durvalumab, or an antigen binding portion thereof, is administered as a flat dose of about 1200 mg / kg once about every 3 weeks.

[0531] In some aspects, the PD-L1 antibody is avelumab, or an antigen binding portion thereof. Avelumab is a human IgG1 lambda monoclonal anti-PD-L1 antibody. In some aspects, avelumab, or an antigen binding portion thereof, is administered as a flat dose of about 800 mg once about every 2 weeks. II.F LAG-3 and / or PD-L1 expressions

[0532] In some aspects, the sample of any of the methods disclosed herein is LAG-3 positive. In some aspects, any of the methods disclosed herein further comprises determining the level of LAG-3 expression in the sample prior to administering the LAG- 3 therapy.

[0533] In some aspects, the sample of any of the methods disclosed herein is PD-L1 positive. In some aspects, any of the methods disclosed herein further comprises determining the level of PD-L1 expression in the sample prior to administering the LAG-3 therapy.

[0534] In some aspects, one or more immune cells in tumor tissue from the subject in the methods disclosed herein express LAG-3 (i.e., tumor tissue from the patient is LAG-3 positive) and / or one or more nucleated cells in tumor tissue from the subject express LAG- 3 (i.e., tumor tissue from the patient is LAG-3 positive) and / or one or more tumor cells in tumor tissue from the subject express PD-L1 (i.e., tumor tissue from the patient is PD-L1 positive).

[0535] In some aspects, one or more immune cells in tumor tissue from the subject express LAG-3. In some aspects, at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 7%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or about 100% of the immune cells express LAG-3. In some aspects, at least about 1% of the immune cells express LAG-3. In some aspects, greaterthan about 1% of the immune cells express LAG-3. In some aspects, at least about 5% of the immune cells express LAG-3. In some aspects, the immune cells comprise tumor- infiltrating lymphocytes. In some aspects, the tumor-infiltrating lymphocytes comprise CD8+cells.

[0536] In some aspects, one or more nucleated cells in tumor tissue from the subject express LAG-3. In some aspects, at least about 1%, at least about 3%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or about 100% of the nucleated cells express LAG-3. In some aspects, at least about 1% of the nucleated cells express LAG-3. In some aspects, greater than about 1% of the nucleated cells express LAG- 3. In some aspects, at least about 5% of the nucleated cells express LAG-3.

[0537] In some aspects, one or more tumor cells in tumor tissue from the subject express PD-L1. In some aspects, at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 7%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or about 100% of the tumor cells express PD-L1. In some aspects, at least about 1% of the tumor cells express PD-L1. In some aspects, at least about 1% of the tumor cells express PD-L1. In some aspects, greater than about 1% of the tumor cells express PD-L1. In some aspects, at least about 5% of the tumor cells express PD-L1. In some aspects, about 1% to about 49% of the tumor cells express PD-L1. In some aspects, greater than about 50% of the tumor cells express PD-L1.

[0538] In some aspects, one or more nucleated cells in tumor tissue from the subject express PD-L1. In some aspects, at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 7%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or about 100% of the nucleated cells express PD-L1. In some aspects, at least about 1% of the nucleated cells express PD-L1. In some aspects, at least about 1% of the nucleated cells express PD-L1. In some aspects, greater than about 1% of the nucleated cells express PD-L1. In some aspects, at least about 5% of the nucleatedcells express PD-L1. In some aspects, about 1% to about 49% of the nucleated cells express PD-L1. In some aspects, greater than about 50% of the nucleated cells express PD-L1.

[0539] In some aspects, the tumor tissue from the subject has a PD-L1 tumor proportion score (TPS) as defined herein and / or a combined positive score (CPS) as defined herein of at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 7%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or about 100%. In some aspects, the tumor tissue from the subject has a PD-L1 TPS and / or CPS of at least about 1%. In some aspects, the tumor tissue from the subject has a PD-L1 TPS and / or CPS of greater than about 1%. In some aspects, the tumor tissue from the subject has a PD-L1 TPS and / or CPS of at least about 5%. In some aspects, the tumor tissue from the subject has a PD-L1 TPS and / or CPS of about 1% to about 49%. In some aspects, the tumor tissue from the subject has a PD-L1 TPS and / or CPS of greater than about 50%.

[0540] In some aspects, any of the values of "at least about X%" is "≥X%").

[0541] In some aspects, tumor tissue from the patient is LAG-3 negative. In some aspects, the tumor tissue is LAG-3 negative when less than about 1% of the immune cells express LAG-3. In some aspects, the tumor tissue is LAG-3 negative when less than about 1% of the nucleated cells express LAG-3.

[0542] In some aspects, tumor tissue from the patient is PD-1 negative. In some aspects, the tumor tissue is PD-1 negative when less than about 1% of the immune cells express PD-1. In some aspects, the tumor tissue is PD-1 negative when less than about 1% of the nucleated cells express PD-1.

[0543] In some aspects, tumor tissue from the patient is PD-L1 negative. In some aspects, the tumor tissue is PD-L1 negative when less than about 1% of the tumor cells express PD- L1. In some aspects, the tumor tissue is PD-L1 negative when less than about 1% of the nucleated cells express PD-L1.

[0544] In some aspects, LAG-3, PD-1, and / or PD-L1 expression is assessed by performing an assay to detect the presence of LAG-3, PD-1, and / or PD-L1 RNA, respectively. In some aspects, the presence of LAG-3, PD-1, and / or PD-L1 RNA is detected by RT-PCR, in situ hybridization or RNase protection.

[0545] In some aspects, LAG-3, PD-1, and / or PD-L1 expression is assessed by performing an assay to detect the presence of LAG-3, PD-1, and / or PD-L1 polypeptide, respectively. In some aspects, the presence of LAG-3, PD-1, and / or PD-L1 polypeptide is detected by immunohistochemistry (IHC), enzyme-linked immunosorbent assay (ELISA), in vivo imaging, or flow cytometry. II.G. Additional Therapeutic Agents

[0546] The methods disclosed herein can comprise an additional therapeutic agent and / or anti-cancer therapy, which can comprise any known therapeutic agent or anti-cancer therapy, including a standard of care in the art for the treatment of a subject afflicted with a tumor. II.G.1. Therapeutic Agents

[0547] In some aspects, the additional therapeutic agent comprises an anti-cancer agent. In some aspects, the anti-cancer agent comprises a tyrosine kinase inhibitor, an anti- angiogenesis agent, a checkpoint inhibitor, a checkpoint stimulator, a chemotherapeutic agent, an immunotherapeutic agent, a platinum agent, an alkylating agent, a taxane, a nucleoside analog, an antimetabolite, a topisomerase inhibitor, an anthracycline, a vinca alkaloid, or any combination thereof.

[0548] In some aspects, the tyrosine kinase inhibitor comprises sorafenib (e.g., sorafenib tosylate, also known as NEXAVAR®), lenvatinib (e.g., lenvatinib mesylate, also known as LENVIMA®), regorafenib (e.g., STIVARGA®), cabozantinib (e.g., cabozantinib S- malate, also known as CABOMETYX®), sunitinib (e.g., sunitinib malate, also known as SUTENT®), brivanib, linifanib, pemigatinib (also known as PEMAZYRETM), everolimus (also known as AFINITOR® or ZORTRESS®), gefitinib (IRESSA®, a small-molecule TKI of EGFR), imatinib (e.g., imatinib mesylate), lapatinib (e.g., lapatinib ditosylate, also known as TYKERB®), nilotinib (e.g., nilotinib hydrochloride, also known as TASIGNA®), pazopanib (e.g., pazopanib hydrochloride, also known as VOTRIENT®), temsirolimus (also known as TORISEL®), erlotinib (e.g., erlotinib hydrochloride, also known as TARCEVA®, a small-molecule TKI of EGFR), afatinib (GILOTRIF®, a small- molecule TKI of EGFR), dacomitinib (VIZIMPRO®, a small-molecule TKI of EGFR), osimeritinb (TAGRISSO®, a small-molecule TKI of EGFR), alectinib (ALECENSA®, a small-molecule TKI of ALK), ceritinib (ZYKADIA®, a small-molecule TKI of ALK andROS-1), brigatinib (ALUNBRIG®, a small-molecule TKI of ALK), crizotinib (XALKORI®, a small-molecule TKI of ALK and ROS-1), lorlatinib (LORBRENA®, a small-molecule TKI of ALK and ROS-1), entrectinib (ROZLYTREK®, a small-molecule TKI of ROS-1 and NTRK), dabrafenib (TAFINLAR®, a small-molecule TKI of BRAF) trametinib (MEKINIST®, a small-molecule TKI of BRAF), vemurafenib (ZELBORAF®, a small-molecule TKI of BRAF), larotrectinib (ROZLYTREK®, a small-molecule TKI of NTRK), or any combination thereof.

[0549] In some aspects, the anti-angiogenesis agent comprises an inhibitor of a vascular endothelial growth factor (VEGF), VEGF receptor (VEGFR), platelet-derived growth factor (PDGF), PDGF receptor (PDGFR), angiopoietin (Ang), tyrosine kinase with Ig-like and EGF-like domains (Tie) receptor, hepatocyte growth factor (HGF), tyrosine-protein kinase Met (c-MET), C-type lectin family 14 member A (CLEC14A), multimerin 2 (MMRN2), shock protein 70-1A (HSP70-1A), a epidermal growth factor (EGF), EGFR, or any combination thereof. In some aspects, the anti-angiogenesis agent comprises bevacizumab (also known as AVASTIN®), ramucirumab (also known as CYRAMZA®), aflibercept (also known as EYLEA® or ZALTRAP®), tanibirumab, olaratumab (also known as LARTRUVOTM), nesvacumab, AMG780, MEDI3617, vanucizumab, rilotumumab, ficlatuzumab, TAK-701, onartuzumab, emibetuzumab, or any combination thereof.

[0550] In some aspects, the anti-angiogenesis agent is bevacizumab. In some aspects, bevacizumab is administered at a dose of about 15 mg / kg. In some aspects, bevacizumab is administered at a dose of about 15 mg / kg on Day 1 of a three-week cycle.

[0551] In some aspects, the checkpoint stimulator comprises an agonist of B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, GITR, inducible T cell co-stimulator (ICOS), ICOS-L, OX40, OX40L, CD70, CD27, CD40, death receptor 3 (DR3), CD28H, or any combination thereof.

[0552] In some aspects, the anti-cancer agent comprises a chemotherapeutic agent. In some aspects, the chemotherapeutic agent comprises an alkylating agent, an antimetabolite, an antineoplastic antibiotic, a mitotic inhibitor, a hormone or hormone modulator, a protein tyrosine kinase inhibitor, an epidermal growth factor inhibitor, a proteasome inhibitor, other neoplastic agent, or any combination thereof.

[0553] In some aspects, the chemotherapeutic agent comprises a platinum doublet chemotherapy (PDCT). In some aspects, the PDCT comprises a platinum agent in combination with a nucleoside analog, an antimetabolite, a taxane, a vinca alkaloid, or a topisomerase inhibitor. In some aspects, the platinum agent is cisplatin, carboplatin, oxaliplatin, satraplatin, picoplatin, nedaplatin, triplatin, lipoplatin, or phenanthriplatin. In some aspects, the platinum agent is cisplatin. In some aspects, the platinum agent is carboplatin. In some aspects, the nucleoside analog is cytarabine, gemcitabine, lamivudine, entecavir, or telbivudine. In some aspects, the nucleoside analog is gemcitabine. In some aspects, the antimetabolite is capecitabine, cladribine, clofarabine, cytarabine, floxuridine, fludarabine, fluorouracil, mercaptopurine, methotrexate, pemetrexed, pentostatin, pralatrexate, or thioguanine. In some aspects, the antimetabolite is pemetrexed. In some aspects, the taxane is paclitaxel, albumin-bound paclitaxel, docetaxel, or cabazitaxel. In some aspects, the vinca alkaloid is vinblastine, vincristine, vinorelbine, vindesine, vincaminol, vineridine, or vinburnine. In some aspects, the vinca alkaloid is vinorelbine or vinblastine. In some aspects, the topoisomerase inhibitor is etoposide, mitoxantrone, doxorubicin, irinotecan, topotecan, or camptothecin. In some aspects, the topoisomerase inhibitor is etoposide. In some aspects, the topoisomerase inhibitor is irinotecan. In some aspects, the PDCT comprises cisplatin or carboplatin in combination with gemcitabine, pemetrexed, paclitaxel, albumin-bound paclitaxel, docetaxel, vinorelbine, vinblastine, etoposide, or irinotecan. In some aspects, the PDCT comprises cisplatin or carboplatin in combination with paclitaxel or albumin-bound paclitaxel. In some aspects, the PDCT comprises cisplatin or carboplatin in combination with pemetrexed.

[0554] In some aspects, the tumor in any of the methods disclosed herein is a non-small cell lung cancer (NSCLC) as described herein, and the method further comprises administering a PDCT as described herein to the subject. In some aspects, the NSCLC comprises a squamous NSCLC, and the PDCT comprises: (i) a dose of carboplatin for a target area under the concentration-time curve of about 6 mg / mL•min, and (ii) a dose of about 200 mg / m2of paclitaxel, or (i) a dose of carboplatin for a target area under the concentration-time curve of about 6 mg / mL•min, and (ii) a dose of about 100 mg / m2of albumin-bound paclitaxel. In some aspects, the NSCLC comprises a non-squamous NSCLC, and the PDCT comprises: (i) a dose of carboplatin for a target area under the concentration-time curve of about 5 mg / mL•min or about 6 mg / mL•min, and (ii) a dose ofabout 500 mg / m2of pemetrexed, or (i) a dose of about 75 mg / m2of cisplatin, and (ii) a dose of about 500 mg / m2of pemetrexed. In some aspects, the PDCT is administered for 4 cycles, wherein each cycle is about once every 4 weeks. In some aspects, the PDCT is administered on Day 1 of each cycle.

[0555] In some aspects, the immunotherapeutic agent comprises an antibody that specifically binds to EGFR (e.g., cetuximab (ERBITUX®)), ALK, ROS-1, NTRK, BRAF, ICOS, CD137 (4-1BB), CD134 (OX40), NKG2A, CD27, CD96, GITR, Herpes Virus Entry Mediator (HVEM), PD-1, PD-L1, CTLA-4, BTLA, TIM-3, A2aR, Killer cell Lectin-like Receptor G1 (KLRG-1), Natural Killer Cell Receptor 2B4 (CD244), CD160, TIGIT, VISTA, KIR, TGFβ, IL-10, IL-8, B7-H4, Fas ligand, CSF1R, CXCR4, mesothelin, CEACAM-1, CD52, HER2, MICA, MICB, or any combination thereof.

[0556] In some aspects, the platinum agent comprises cisplatin, carboplatin, oxaliplatin, satraplatin, picoplatin, nedaplatin, triplatin (e.g., triplatin tetranitrate), lipoplatin, phenanthriplatin, or any combination thereof.

[0557] In some aspects, the alkylating agent comprises altretamine, bendamustine, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, ifosfamide, lomustine, mechlorethamine, melphalan, oxaliplatin, procarbazine, streptozocin, temozolomide, thiotepa, or any combination thereof.

[0558] In some aspects, the taxane comprises paclitaxel, albumin-bound paclitaxel (i.e., nab-paclitaxel), docetaxel, cabazitaxel, or any combination thereof.

[0559] In some aspects, the nucleoside analog comprises cytarabine, gemcitabine, lamivudine, entecavir, telbivudine, or any combination thereof.

[0560] In some aspects, the antimetabolite comprises capecitabine, cladribine, clofarabine, cytarabine, floxuridine, fludarabine, fluorouracil, mercaptopurine, methotrexate, pemetrexed, pentostatin, pralatrexate, thioguanine, or any combination thereof.

[0561] In some embodiments, the topoisomerase inhibitor comprises etoposide, mitoxantrone, doxorubicin, irinotecan, topotecan, camptothecin, or any combination thereof.

[0562] In some aspects, the anthracycline is doxorubicin, daunorubicin, epirubicin, idarubicin, or any combination thereof.

[0563] In some aspects, the vinca alkaloid is vinblastine, vincristine, vinorelbine, vindesine, vincaminol, vineridine, vinburnine, or any combination thereof.II.G.2. Checkpoint Inhibitors

[0564] In some aspects, the anti-cancer agent that is administered as an additional therapeutic agent in the methods of the disclosure is a checkpoint inhibitor.

[0565] In some aspects, the checkpoint inhibitor comprises a cytotoxic T-lymphocyte- associated protein 4 (CTLA-4) inhibitor, a T cell immunoglobulin and ITIM domain (TIGIT) inhibitor, a T cell immunoglobulin and mucin-domain containing-3 (TIM-3) inhibitor, a TIM-1 inhibitor, a TIM-4 inhibitor, a B7-H3 inhibitor, a B7-H4 inhibitor, a B and T cell lymphocyte attenuator (BTLA) inhibitor, a V-domain Ig suppressor of T cell activation (VISTA) inhibitor, an indoleamine 2,3-dioxygenase (IDO) inhibitor (e.g., an indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor, epacadostat (INCB24360), navoximod (GDC-0919), or linrodostat (BMS-986205), including a linrodostat salt such as, for example, linrodostat mesylate), a nicotinamide adenine dinucleotide phosphate oxidase isoform 2 (NOX2) inhibitor, a killer-cell immunoglobulin-like receptor (KIR) inhibitor, an adenosine A2a receptor (A2aR) inhibitor, a transforming growth factor beta (TGF-β) inhibitor, a phosphoinositide 3-kinase (PI3K) inhibitor, a CD47 inhibitor, a CD48 inhibitor, a CD73 inhibitor, a CD113 inhibitor, a sialic acid-binding immunoglobulin-like lectin-7 (SIGLEC-7) inhibitor, a SIGLEC-9 inhibitor, a SIGLEC-15 inhibitor, a glucocorticoid- induced TNFR-related protein (GITR) inhibitor, a galectin-1 inhibitor, a galectin-9 inhibitor, a carcinoembryonic antigen-related cell adhesion molecule-1 (CEACAM-1) inhibitor, a G protein-coupled receptor 56 (GPR56) inhibitor, a glycoprotein A repetitions predominant (GARP) inhibitor, a 2B4 inhibitor, a programmed death-1 homolog (PD1H) inhibitor, a leukocyte-associated immunoglobulin-like receptor 1 (LAIR1) inhibitor, or any combination thereof.

[0566] In some aspects, the checkpoint inhibitor is formulated for parenteral administration.

[0567] In some aspects, the checkpoint inhibitor is formulated for intravenous, intraperitoneal, intramuscular, intrathecal, or subcutaneous administration.

[0568] In some aspects, the checkpoint inhibitor is administered at a flat dose.

[0569] In some aspects, the checkpoint inhibitor is administered at a dose of from at least about 0.25 mg to about 2000 mg, about 0.25 mg to about 1600 mg, about 0.25 mg to about 1200 mg, about 0.25 mg to about 800 mg, about 0.25 mg to about 400 mg, about 0.25 mg to about 100 mg, about 0.25 mg to about 50 mg, about 0.25 mg to about 40 mg, about 0.25mg to about 30 mg, about 0.25 mg to about 20 mg, about 20 mg to about 2000 mg, about 20 mg to about 1600 mg, about 20 mg to about 1200 mg, about 20 mg to about 800 mg, about 20 mg to about 400 mg, about 20 mg to about 100 mg, about 100 mg to about 2000 mg, about 100 mg to about 1800 mg, about 100 mg to about 1600 mg, about 100 mg to about 1400 mg, about 100 mg to about 1200 mg, about 100 mg to about 1000 mg, about 100 mg to about 800 mg, about 100 mg to about 600 mg, about 100 mg to about 400 mg, about 400 mg to about 2000 mg, about 400 mg to about 1800 mg, about 400 mg to about 1600 mg, about 400 mg to about 1400 mg, about 400 mg to about 1200 mg, or about 400 mg to about 1000 mg.

[0570] In some aspects, the checkpoint inhibitor is administered at a dose of about 0.25 mg, about 0.5 mg, about 0.75 mg, about 1 mg, about 1.25 mg, about 1.5 mg, about 1.75 mg, about 2 mg, about 2.25 mg, about 2.5 mg, about 2.75 mg, about 3 mg, about 3.25 mg, about 3.5 mg, about 3.75 mg, about 4 mg, about 4.25 mg, about 4.5 mg, about 4.75 mg, about 5 mg, about 5.25 mg, about 5.5 mg, about 5.75 mg, about 6 mg, about 6.25 mg, about 6.5 mg, about 6.75 mg, about 7 mg, about 7.25 mg, about 7.5 mg, about 7.75 mg, about 8 mg, about 8.25 mg, about 8.5 mg, about 8.75 mg, about 9 mg, about 9.25 mg, about 9.5 mg, about 9.75 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, about 800 mg, about 810 mg, about 820 mg, about 830 mg, about 840 mg, about 850 mg, about 860 mg, about 870 mg, about 880 mg, about 890 mg, about 900 mg, about 910 mg, about 920 mg, about 930 mg, about 940 mg, about 950 mg, about960 mg, about 970 mg, about 980 mg, about 990 mg, about 1000 mg, about 1040 mg, about 1080 mg, about 1100 mg, about 1140 mg, about 1180 mg, about 1200 mg, about 1240 mg, about 1280 mg, about 1300 mg, about 1340 mg, about 1380 mg, about 1400 mg, about 1440 mg, about 1480 mg, about 1500 mg, about 1540 mg, about 1580 mg, about 1600 mg, about 1640 mg, about 1680 mg, about 1700 mg, about 1740 mg, about 1780 mg, about 1800 mg, about 1840 mg, about 1880 mg, about 1900 mg, about 1940 mg, about 1980 mg, or about 2000 mg.

[0571] In some aspects, the checkpoint inhibitor is administered as a weight-based dose.

[0572] In some aspects, the checkpoint inhibitor is administered at a dose of from about 0.003 mg / kg to about 25 mg / kg, about 0.003 mg / kg to about 20 mg / kg, about 0.003 mg / kg to about 15 mg / kg, about 0.003 mg / kg to about 10 mg / kg, about 0.003 mg / kg to about 5 mg / kg, about 0.003 mg / kg to about 1 mg / kg, about 0.003 mg / kg to about 0.9 mg / kg, about 0.003 mg / kg to about 0.8 mg / kg, about 0.003 mg / kg to about 0.7 mg / kg, about 0.003 mg / kg to about 0.6 mg / kg, about 0.003 mg / kg to about 0.5 mg / kg, about 0.003 mg / kg to about 0.4 mg / kg, about 0.003 mg / kg to about 0.3 mg / kg, about 0.003 mg / kg to about 0.2 mg / kg, about 0.003 mg / kg to about 0.1 mg / kg, about 0.1 mg / kg to about 25 mg / kg, about 0.1 mg / kg to about 20 mg / kg, about 0.1 mg / kg to about 15 mg / kg, about 0.1 mg / kg to about 10 mg / kg, about 0.1 mg / kg to about 5 mg / kg, about 0.1 mg / kg to about 1 mg / kg, about 1 mg / kg to about 25 mg / kg, about 1 mg / kg to about 20 mg / kg, about 1 mg / kg to about 15 mg / kg, about 1 mg / kg to about 10 mg / kg, about 1 mg / kg to about 5 mg / kg, about 5 mg / kg to about 25 mg / kg, about 5 mg / kg to about 20 mg / kg, about 5 mg / kg to about 15 mg / kg, about 5 mg / kg to about 10 mg / kg, about 10 mg / kg to about 25 mg / kg, about 10 mg / kg to about 20 mg / kg, about 10 mg / kg to about 15 mg / kg, about 15 mg / kg to about 25 mg / kg, about 15 mg / kg to about 20 mg / kg, or about 20 mg / kg to about 25 mg / kg.

[0573] In some aspects, the checkpoint inhibitor is administered at a dose of about 0.003 mg / kg, about 0.004 mg / kg, about 0.005 mg / kg, about 0.006 mg / kg, about 0.007 mg / kg, about 0.008 mg / kg, about 0.009 mg / kg, about 0.01 mg / kg, about 0.02 mg / kg, about 0.03 mg / kg, about 0.04 mg / kg, about 0.05 mg / kg, about 0.06 mg / kg, about 0.07 mg / kg, about 0.08 mg / kg, about 0.09 mg / kg, about 0.1 mg / kg, about 0.2 mg / kg, about 0.3 mg / kg, about 0.4 mg / kg, about 0.5 mg / kg, about 0.6 mg / kg, about 0.7 mg / kg, about 0.8 mg / kg, about 0.9 mg / kg, about 1.0 mg / kg, about 2.0 mg / kg, about 3.0 mg / kg, about 4.0 mg / kg, about 5.0 mg / kg, about 6.0 mg / kg, about 7.0 mg / kg, about 8.0 mg / kg, about 9.0 mg / kg, about 10.0mg / kg, about 11.0 mg / kg, about 12.0 mg / kg, about 13.0 mg / kg, about 14.0 mg / kg, about 15.0 mg / kg, about 16.0 mg / kg, about 17.0 mg / kg, about 18.0 mg / kg, about 19.0 mg / kg, about 20.0 mg / kg, about 21.0 mg / kg, about 22.0 mg / kg, about 23.0 mg / kg, about 24.0 mg / kg, or about 25.0 mg / kg.

[0574] In some aspects, the dose of the checkpoint inhibitor is administered every one week, every two weeks, every three weeks, every four weeks, every five weeks, every six weeks, every seven weeks, every eight weeks, every nine weeks, every ten weeks, every eleven weeks, or every twelve weeks. II.G.3 CTLA-4 inhibitors

[0575] In some aspects, the checkpoint inhibitor as disclosed herein comprises a CTLA-4 inhibitor. In some aspects, the CTLA-4 inhibitor comprises an anti-CTLA-4 antibody.

[0576] Anti-CTLA-4 antibodies that can be used in the methods of the disclosure bind to human CTLA-4 and disrupt the interaction of CTLA-4 with a human B7 receptor. Because the interaction of CTLA-4 with B7 transduces a signal leading to inactivation of T-cells bearing the CTLA-4 receptor, disruption of the interaction effectively induces, enhances, or prolongs the activation of such T cells, thereby inducing, enhancing or prolonging an immune response.

[0577] Human monoclonal antibodies that bind specifically to CTLA-4 with high affinity have been disclosed in U.S. Patent Nos. 6,984,720. Other anti-CTLA-4 monoclonal antibodies have been described in, for example, U.S. Patent Nos. 5,977,318, 6,051,227, 6,682,736, and 7,034,121 and International Publication Nos. WO 2012 / 122444, WO 2007 / 113648, WO 2016 / 196237, and WO 2000 / 037504, each of which is incorporated by reference herein in its entirety. The anti-CTLA-4 human monoclonal antibodies disclosed in U.S. Patent No. Nos.6,984,720 have been demonstrated to exhibit one or more of the following characteristics: (a) binds specifically to human CTLA-4 with a binding affinity reflected by an equilibrium association constant (Ka) of at least about 107M-1, or about 109M-1, or about 1010M-1to 1011M-1or higher, as determined by BIACORE analysis; (b) a kinetic association constant (ka) of at least about 103, about 104, or about 105m-1s-1; (c) a kinetic disassociation constant (kd) of at least about 103, about 104, or about 105m-1s-1; and (d) inhibits the binding of CTLA-4 to B7-1 (CD80) and B7-2 (CD86). Anti-CTLA-4 antibodies useful for the present disclosure include monoclonal antibodies that bindspecifically to human CTLA-4 and exhibit at least one, at least two, or at least three of the preceding characteristics.

[0578] Anti-CTLA-4 antibodies that can be used in the methods of the disclosure include ipilimumab (also known as YERVOY®, MDX-010, 10D1; see U.S. Patent No.6,984,720), MK-1308 (Merck), AGEN-1884 (Agenus Inc.; see WO 2016 / 196237), and tremelimumab (AstraZeneca; also known as ticilimumab, CP-675,206; see WO 2000 / 037504 and Ribas, Update Cancer Ther.2(3): 133-39 (2007)).

[0579] In some aspects, the anti-CTLA-4 antibody binds specifically to human CTLA-4 and cross-competes for binding to human CTLA-4 with any anti-CTLA-4 antibody disclosed herein, e.g., ipilimumab and / or tremelimumab. In some aspects, the anti-CTLA- 4 antibody binds the same epitope as any of the anti-CTLA-4 antibodies described herein, e.g., ipilimumab and / or tremelimumab.

[0580] In some aspects, the antibodies that cross-compete for binding to human CTLA-4 with, or bind to the same epitope region as, any anti-CTLA-4 antibody disclosed herein, e.g., ipilimumab and / or tremelimumab, are monoclonal antibodies. For administration to human subjects, these cross-competing antibodies are chimeric antibodies, engineered antibodies, or humanized or human antibodies.

[0581] Anti-CTLA-4 antibodies that can be used in the methods of the disclosure also include antigen binding portions of any of the above full-length antibodies.

[0582] In some aspects, the anti-CTLA-4 antibody comprises a full-length antibody. In some aspects, the anti-CTLA-4 antibody comprises a monoclonal, human, humanized, chimeric, or multispecific antibody. In some aspects, the multispecific antibody comprises a DART, a DVD-IG, or a bispecific antibody.

[0583] In some aspects, the anti-CTLA-4 antibody comprises a F(ab')2fragment, a Fab' fragment, a Fab fragment, a Fv fragment, a scFv fragment, a dsFv fragment, a dAb fragment, or a single chain binding polypeptide.

[0584] In some aspects, the anti-CTLA-4 antibody comprises ipilimumab, tremelimumab, MK-1308, AGEN-1884, or an antigen binding portion thereof.

[0585] In some aspects, the anti-CTLA-4 antibody comprises ipilimumab. Ipilimumab is a fully human, IgG1 monoclonal antibody that blocks the binding of CTLA-4 to its B7 ligands, thereby stimulating T cell activation. In some aspects, ipilimumab is administered at a dose of about 1 mg / kg once about every 8 weeks. In some aspects, ipilimumab isadministered at a dose of about 3 mg / kg once about every 3 weeks. In some aspects, ipilimumab is administered at a dose of about 10 mg / kg once about every 3 weeks. In some aspects, ipilimumab is administered at a dose of about 10 mg / kg once about every 12 weeks. In some aspects, the ipilimumab is administered for four doses. In some aspects, ipilimumab is administered on Day 1 of each cycle. III. Pharmaceutical Compositions

[0586] Therapeutic agents of the present disclosure can be constituted in a composition, e.g., a pharmaceutical composition containing an antagonist, inhibitor, antibody, and / or agent as disclosed herein and a pharmaceutically acceptable carrier. As used herein, a "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible.

[0587] In some aspects, the carrier for a composition containing an antagonist, inhibitor, antibody, and / or agent as disclosed herein is suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal or epidermal administration (e.g., by injection or infusion). In some aspects, the carrier is suitable for non-parenteral, e.g., oral, administration. In some aspects, a subcutaneous injection is based on Halozyme Therapeutics’ ENHANZE® drug- delivery technology (see U.S. Patent No. 7,767,429, which is incorporated by reference herein in its entirety). ENHANZE® uses a co-formulation of an antibody with recombinant human hyaluronidase enzyme (rHuPH20), which removes traditional limitations on the volume of biologics and drugs that can be delivered subcutaneously due to the extracellular matrix (see U.S. Patent No. 7,767,429). A pharmaceutical composition of the disclosure can include one or more pharmaceutically acceptable salts, anti-oxidant, aqueous and non- aqueous carriers, and / or adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. In some aspects, the pharmaceutical composition for the present disclosure can further comprise recombinant human hyaluronidase enzyme, e.g., rHuPH20.

[0588] All of the references cited above, as well as all references cited herein, are incorporated herein by reference in their entireties.

[0589] The following examples are offered by way of illustration and not by way of limitation.EXAMPLES EXAMPLE 1 - Clinical Studies

[0590] An anti-LAG-3 antibody (relatlimab) in combination with an anti-PD-1 antibody (nivolumab) is evaluated in a clinical study as a treatment of patients having a tumor as disclosed herein (e.g., a hepatocellular carcinoma or a lung cancer) in relation to expression of FGL-1 in tumor cells.

[0591] A tumor tissue sample is obtained from each patient for determination of FGL-1 expression (e.g., by an automated IHC assay). Patients are stratified as FGL-1 expressers or non-expressers based on FGL-1 expression in tissue samples of ≥ 1% or less than 1%, respectively. FGL-1 expressers are further stratified or alternatively stratified by H-score as described herein according to weak, moderate, or strong H-scores.

[0592] The objective response rate (ORR) is determined as the proportion of treated subjects with either a complete response (CR) or a partial response (PR). EXAMPLE 2 - FGL-1 Histoscores in Hepatocellular Carcinoma

[0593] Data was obtained from an ongoing Phase 2, randomized, open-label study (Trial ID CA224-073|NCT04567615) evaluating the safety and efficacy of relatlimab in combination with nivolumab as compared to nivolumab monotherapy in the second line treatment of hepatocellular carcinoma (HCC).

[0594] Key inclusion criteria for the study required participants to: (1) be an adult male or female ≥ 18 years old, (2) have a diagnosis of HCC based on histological confirmation, (3) have advanced / metastatic HCC, (4) be immunotherapy treatment-naive in the advanced / metastatic setting, (5) have experienced progression that was demonstrated radiographically on or after one or two prior tyrosine kinase inhibitor therapies, (6) have at least one Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 measurable untreated lesion, (7) have a Child-Pugh score of 5 or 6, and (8) have an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 for ECOG performance status scale.

[0595] Participants were randomized into study arms including: (1) Arm A, receiving 480 mg of nivolumab once every 4 weeks (Q4W), and (2) Arm B, receiving a co-administration of 480 mg of nivolumab Q4W and 480 mg of relatlimab Q4W.

[0596] Tumor samples obtained from the subjects prior to therapy were tested for baseline levels of FGL-1 by immunohistochemistry.

[0597] A histoscore for FGL-1 expression in the tumor samples was manually calculated according to the formula: (1 × percentage of tumor cells in the sample with weak FGL-1 expression) + (2 × percentage of tumor cells in the sample with moderate FGL-1 expression) + (3 × percentage of tumor cells in the sample with strong FGL-1 expression).

[0598] The relation between FGL-1 histoscores and responders (overall response rate (ORR) per BICR) in the treatment arms is shown below in Table 1. Table 1. FGL-1 Responders1 HS = histoscore 2 N = total number of subjects with the HS 3 A = 480 mg nivolumab Q4W 4 B = 480 mg nivolumab Q4W + 480 mg relatlimab Q4W

[0599] The data showed that FGL-1 histoscores of less than 250 were associated with higher ORR in the nivolumab+relatlimab treatment arm (Arm B) as compared to nivolumab (Arm A). The change in ORR between Arms B and A was +21% for histoscores of less than 250 (i.e., 24%-3%) versus -5% for histoscores of greater than or equal to 250 (i.e., 7%- 12%).

[0600] The relation between FGL-1 histoscores and progression free survival (PFS) per BICR is shown in FIG. 1 (histoscore of less than 250) and FIG. 2 (histoscore of greater than or equal to 250) and is summarized below in Table 2. Table 2. FGL-1 and PFS1 HS = histoscore 2 A = 480 mg nivolumab Q4W 3 B = 480 mg nivolumab Q4W + 480 mg relatlimab Q4W

[0601] The data showed that there was a trend for PFS benefit from treatment with relatlimab and nivolumab associated with FGL-1 histoscores of less than 250.

[0602] The relation between FGL-1 histoscores and overall survival (OS) is shown in FIG. 3 (histoscore of less than 250) and FIG.4 (histoscore of greater than or equal to 250) and is summarized below in Table 3. Table 3. FGL-1 and OS1 HS = histoscore 2 A = 480 mg nivolumab Q4W 3 B = 480 mg nivolumab Q4W + 480 mg relatlimab Q4W

[0603] The data showed that there was a trend for OS benefit from treatment with relatlimab and nivolumab associated with FGL-1 histoscores of less than 250.

[0604] Histoscores also were determined by a digital algorithm and image analysis software as a comparison to the manually calculated histoscores.

[0605] As shown in FIGs. 5A, the manually calculated histoscore of less than 250 was selected based on ORR benefit in a smoothing spline model, while the optimal range determined by the digital algorithm was less than 140 as shown in FIG.5B. The manual range was potentially overestimated due to 50% of the population identified as having a maximum histoscore of 300. The improved granularity of the digital approach resulted in a lowering of the manually calculated histoscore cutoff of 250.

[0606] FIGs. 5C and 5D provide a comparison of PFS survival probability based on manually calculated histoscores of less than 250 (FIG. 5C) and digitally calculated histoscores of less than 140 (FIG. 5D). Both methods demonstrate that there was PFS benefit from treatment with relatlimab and nivolumab in relation to FGL-1 histoscores. EXAMPLE 3 - FGL-1 Histoscores in Non-Small Cell Lung Cancer

[0607] Data is being obtained from an ongoing Phase 2, randomized, open-label study (Trial ID CA224-104|NCT04623775) evaluating the safety and efficacy of relatlimab plusnivolumab in combination with platinum doublet chemotherapy (PDCT) as compared to nivolumab in combination with PDCT in the first line treatment of stage IV or recurrent non-small cell lung cancer (NSCLC).

[0608] Key inclusion criteria for the study required participants to have: (1) histologically confirmed metastatic non-small cell lung cancer (NSCLC) of squamous (SQ) or non- squamous (NSQ) histology with Stage IV A / B (as defined by the 8th International Association for the Study of Lung Cancer Classification) or recurrent disease following multi-modal therapy for locally advanced disease, (2) an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of less than or equal to 1 at screening and confirmed prior to randomization, (3) measurable disease by computed tomography (CT) or magnetic resonance resources (MRI) per response evaluation criteria in solid tumor version 1.1 (RECIST 1.1) criteria, and (4) no prior systemic anti-cancer treatment (including epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) inhibitors) given as primary therapy for advanced or metastatic disease.

[0609] In part 1 of the study, participants were randomized 1:1 to experimental Arms A or B. The randomization was stratified by histology (SQ vs NSQ NSCLC).

[0610] Arm A: Nivolumab 360 mg administered every three weeks (Q3W) + relatlimab 720 mg Q3W + 4 cycles of histology-based PDCT.

[0611] Arm B: Nivolumab 360 mg Q3W + relatlimab 360 mg Q3W + 4 cycles of histology-based PDCT.

[0612] In part 2 of the study, participants were randomized 1:1 to experimental Arms C or D. Randomization included stratification by histology (SQ vs NSQ NSCLC).

[0613] Arm C: Nivolumab 360 mg Q3W + relatlimab 360 mg Q3W + 4 cycles of histology based PDCT.

[0614] Arm D: Nivolumab 360 mg Q3W + 4 cycles of histology-based PDCT.

[0615] Tumor samples obtained from the subjects prior to therapy were tested for baseline levels of FGL-1 by immunohistochemistry.

[0616] A histoscore for FGL-1 expression in the tumor samples is manually calculated according to the formula: (1 × percentage of tumor cells in the sample with weak FGL-1 expression) + (2 × percentage of tumor cells in the sample with moderate FGL-1 expression) + (3 × percentage of tumor cells in the sample with strong FGL-1 expression).

[0617] Evaluations will include: (1) baseline FGL-1 histoscores in SQ versus NSQ tumor samples, (2) distribution of baseline FGL-1 histoscores between lung and non-lung biopsies from the patients, (3) correlation of FGL-1 expression with other biomarkers, (4) association of FGL-1 histoscores and objective response rates for patients in treatment Arms C and D, and (5) association of FGL-1 histoscores and PFS for patients in treatment Arms C and D. EXAMPLE 4 - Soluble FGL-1

[0618] An electrochemiluninescence (ECL) immunoassay was performed to detect soluble FGL-1 in plasma.

[0619] A biotinylated, recombinant rabbit anti-human FGL-1 monoclonal capture antibody specific to soluble FGL-1 was coated onto an MSD Gold 96-well Streptavidin SECTOR Plate (Meso Scale Diagnostics, LLC, Rockville, Maryland, USA) and incubated for 1 hour at 23°C with shaking at 300-400 rpm. The plate was washed and a human FGL-1 protein with an Fc Tag (Acro Biosystems, Newark, Delaware, USA), quality controls, and samples diluted in assay buffer were added in duplicate wells to the plate. The plate was incubated for 2 hours at 23°C with shaking at 500-600 rpm. The plate was washed and a sulfo-tagged, recombinant rabbit anti-human FGL-1 monoclonal detection antibody specific to soluble FGL-1 was added to the plate. The plate was then incubated at 23°C for 1.5 hours with shaking at 500-600 rpm. The plate was washed and MSD Read Buffer T (4X) (Meso Scale Diagnostics, LLC, Rockville, Maryland, USA) was added to the plate. The plate was then read on an MESO SECTOR 600 plate imager (Meso Scale Diagnostics, LLC, Rockville, Maryland, USA). The assay was validated in plasma and serum.

[0620] Efficacy associations with soluble FGL-1 will be explored in the clinical trial described in Example 3. In particular, the following will be evaluated: (1) correlation of soluble FGL-1 in plasma and other biomarkers, including those expressed in tumor tissue, (2) change in ORR between treatment Arms C and D for soluble FGL-1 concentrations of less than 360 ng / mL, greater than or equal to 360 ng / mL, greater than or equal to 360 ng / mL and less than 1780 ng / mL, less than 900 ng / mL, greater than or equal to 900 ng / mL, less than 1780 ng / mL, and greater than or equal to 1780 ng / mL, (3) association of soluble FGL-1 concentrations of less than 360 ng / mL and PFS between treatment Arms C and D, and (4) change in soluble FGL-1 concentrations in responders from baseline to early on-treatment.SEQUENCES SEQ ID NO:1 Heavy Chain Amino Acid Sequence; Anti-LAG-3 mAb (BMS-986016) QVQLQQWGAGLLKPSETLSLTCAVYGGSFSDYYWNWIRQPPGKGLEWIGEINHRGSTNSNPSLKS RVTLSLDTSKNQFSLKLRSVTAADTAVYYCAFGYSDYEYNWFDPWGQGTLVTVSSASTKGPSVFP LAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSS LGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVT CVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSN KGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENN YKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO:2 Light Chain Amino Acid Sequence; Anti-LAG-3 mAb (BMS-986016) EIVLTQSPATLSLSPGERATLSCRASQSISSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGS GSGTDFTLTISSLEPEDFAVYYCQQRSNWPLTFGQGTNLEIKRTVAAPSVFIFPPSDEQLKSGTA SVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACE VTHQGLSSPVTKSFNRGEC SEQ ID NO:3 Heavy Chain Variable Region (VH) Amino Acid Sequence; Anti-LAG-3 mAb (BMS-986016) QVQLQQWGAGLLKPSETLSLTCAVYGGSFSDYYWNWIRQPPGKGLEWIGEINHRGSTNSNPSLKS RVTLSLDTSKNQFSLKLRSVTAADTAVYYCAFGYSDYEYNWFDPWGQGTLVTVSS SEQ ID NO:4 Light Chain Variable Region (VL) Amino Acid Sequence; Anti-LAG-3 mAb (BMS- 986016) EIVLTQSPATLSLSPGERATLSCRASQSISSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGS GSGTDFTLTISSLEPEDFAVYYCQQRSNWPLTFGQGTNLEIK SEQ ID NO:5 Heavy Chain CDR1 Amino Acid Sequence; Anti-LAG-3 mAb (BMS-986016) DYYWN SEQ ID NO:6 Heavy Chain CDR2 Amino Acid Sequence; Anti-LAG-3 mAb (BMS-986016) EINHRGSTNSNPSLKS SEQ ID NO:7 Heavy Chain CDR3 Amino Acid Sequence; Anti-LAG-3 mAb (BMS-986016) GYSDYEYNWFDP SEQ ID NO:8 Light Chain CDR1 Amino Acid Sequence; Anti-LAG-3 mAb (BMS-986016) RASQSISSYLA SEQ ID NO:9 Light Chain CDR2 Amino Acid Sequence; Anti-LAG-3 mAb (BMS-986016) DASNRATSEQ ID NO:10 Light Chain CDR3 Amino Acid Sequence; Anti-LAG-3 mAb (BMS-986016) QQRSNWPLT SEQ ID NO:11 Heavy Chain Amino Acid Sequence; Anti-PD-1 mAb (BMS-936558) QVQLVESGGGVVQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEWVAVIWYDGSKRYYADSVK GRFTISRDNSKNTLFLQMNSLRAEDTAVYYCATNDDYWGQGTLVTVSSASTKGPSVFPLAPCSRS TSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYT CNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS QEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSI EKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPV LDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO:12 Light Chain Amino Acid Sequence; Anti-PD-1 mAb (BMS-936558) EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGS GSGTDFTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTA SVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACE VTHQGLSSPVTKSFNRGEC SEQ ID NO:13 Heavy Chain Variable Region (VH) Amino Acid Sequence; Anti-PD-1 mAb (BMS-936558) QVQLVESGGGVVQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEWVAVIWYDGSKRYYADSVK GRFTISRDNSKNTLFLQMNSLRAEDTAVYYCATNDDYWGQGTLVTVSS SEQ ID NO:14 Light Chain Variable Region (VL) Amino Acid Sequence; Anti-PD-1 mAb (BMS- 936558) EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGS GSGTDFTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIK SEQ ID NO:15 Heavy Chain CDR1 Amino Acid Sequence; Anti-PD-1 mAb (BMS-936558) NSGMH SEQ ID NO:16 Heavy Chain CDR2 Amino Acid Sequence; Anti-PD-1 mAb (BMS-936558) VIWYDGSKRYYADSVKG SEQ ID NO:17 Heavy Chain CDR3 Amino Acid Sequence; Anti-PD-1 mAb (BMS-936558) NDDY SEQ ID NO:18 Light Chain CDR1 Amino Acid Sequence; Anti-PD-1 mAb (BMS-936558) RASQSVSSYLASEQ ID NO:19 Light Chain CDR2 Amino Acid Sequence; Anti-PD-1 mAb (BMS-936558) DASNRAT SEQ ID NO:20 Light Chain CDR3 Amino Acid Sequence; Anti-PD-1 mAb (BMS-936558) QQSSNWPRT SEQ ID NO:21 Heavy Chain Amino Acid Sequence; Anti-LAG-3 mAb (BMS-986016) without terminal lysine QVQLQQWGAGLLKPSETLSLTCAVYGGSFSDYYWNWIRQPPGKGLEWIGEINHRGSTNSNPSLKS RVTLSLDTSKNQFSLKLRSVTAADTAVYYCAFGYSDYEYNWFDPWGQGTLVTVSSASTKGPSVFP LAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSS LGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVT CVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSN KGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENN YKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG SEQ ID NO:22 Lymphocyte Activation Gene 3 Protein Amino Acid Sequence (Homo Sapiens, NP_002277) MWEAQFLGLLFLQPLWVAPVKPLQPGAEVPVVWAQEGAPAQLPCSPTIPLQDLSLLRRAGVTWQH QPDSGPPAAAPGHPLAPGPHPAAPSSWGPRPRRYTVLSVGPGGLRSGRLPLQPRVQLDERGRQRG DFSLWLRPARRADAGEYRAAVHLRDRALSCRLRLRLGQASMTASPPGSLRASDWVILNCSFSRPD RPASVHWFRNRGQGRVPVRESPHHHLAESFLFLPQVSPMDSGPWGCILTYRDGFNVSIMYNLTVL GLEPPTPLTVYAGAGSRVGLPCRLPAGVGTRSFLTAKWTPPGGGPDLLVTGDNGDFTLRLEDVSQ AQAGTYTCHIHLQEQQLNATVTLAIITVTPKSFGSPGSLGKLLCEVTPVSGQERFVWSSLDTPSQ RSFSGPWLEAQEAQLLSQPWQCQLYQGERLLGAAVYFTELSSPGAQRSGRAPGALPAGHLLLFLI LGVLSLLLLVTGAFGFHLWRRQWRPRRFSALEQGIHPPQAQSKIEELEQEPEPEPEPEPEPEPEP EPEQL SEQ ID NO:23 Heavy Chain Amino Acid Sequence; Anti-LAG-3 mAb (REGN3767) QVQLVESGGGVVQPGRSLRLSCVASGFTFSSYGMHWVRQAPGKGLEWVAIIWYDGSNKYY ADSVKGRFTISRDNSKNTQYLQMNSLRAEDTAVYYCASVATSGDFDYYGMDVWGQGTTVT VSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL QSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPPVAGP SVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNS TYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEM TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQ EGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO:24 Light Chain Amino Acid Sequence; Anti-LAG-3 mAb (REGN3767) EIVLTQSPATLSLSPGERTTLSCRASQRISTYLAWYQQKPGQAPRLLIYDASKRATGIPA RFSGSGSGTGFTLTISSLEPEDFAVYYCQQRSNWPLTFGGGTKVEIKRTVAAPSVFIFPP SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECSEQ ID NO:25 Heavy Chain Variable Region (VH) Amino Acid Sequence; Anti-LAG-3 mAb (REGN3767) QVQLVESGGGVVQPGRSLRLSCVASGFTFSSYGMHWVRQAPGKGLEWVAIIWYDGSNKYY ADSVKGRFTISRDNSKNTQYLQMNSLRAEDTAVYYCASVATSGDFDYYGMDVWGQGTTVT VSS SEQ ID NO:26 Light Chain Variable Region (VL) Amino Acid Sequence; Anti-LAG-3 mAb (REGN3767) EIVLTQSPATLSLSPGERTTLSCRASQRISTYLAWYQQKPGQAPRLLIYDASKRATGIPA RFSGSGSGTGFTLTISSLEPEDFAVYYCQQRSNWPLTFGGGTKVEIK SEQ ID NO:27 Heavy Chain CDR1 Amino Acid Sequence; Anti-LAG-3 mAb (REGN3767) GFTFSSYG SEQ ID NO:28 Heavy Chain CDR2 Amino Acid Sequence; Anti-LAG-3 mAb (REGN3767) IWYDGSNK SEQ ID NO:29 Heavy Chain CDR3 Amino Acid Sequence; Anti-LAG-3 mAb (REGN3767) ASVATSGDFDYYGMDV SEQ ID NO:30 Light Chain CDR1 Amino Acid Sequence; Anti-LAG-3 mAb (REGN3767) QRISTY Light Chain CDR2 Amino Acid Sequence; Anti-LAG-3 mAb (REGN3767) DAS SEQ ID NO:31 Light Chain CDR3 Amino Acid Sequence; Anti-LAG-3 mAb (REGN3767) QQRSNWPLT SEQ ID NO:32 Heavy Chain Amino Acid Sequence; Anti-PD-1 mAb (REGN2810) EVQLLESGGVLVQPGGSLRLSCAASGFTFSNFGMTWVRQAPGKGLEWVSGISGGGRDTYF ADSVKGRFTISRDNSKNTLYLQMNSLKGEDTAVYYCVKWGNIYFDYWGQGTLVTVSSAST KGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY SLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLF PPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVV SVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQV SLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVF SCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO:33 Light Chain Amino Acid Sequence; Anti-PD-1 mAb (REGN2810) DIQMTQSPSSLSASVGDSITITCRASLSINTFLNWYQQKPGKAPNLLIYAASSLHGGVPSRFSGSGSGTDFTLTIRTLQPEDFATYYCQQSSNTPFTFGPGTVVDFRRTVAAPSVFIFPP SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO:34 Heavy Chain Variable Region (VH) Amino Acid Sequence; Anti-PD-1 mAb (REGN2810) EVQLLESGGVLVQPGGSLRLSCAASGFTFSNFGMTWVRQAPGKGLEWVSGISGGGRDTYF ADSVKGRFTISRDNSKNTLYLQMNSLKGEDTAVYYCVKWGNIYFDYWGQGTLVTVSS SEQ ID NO:35 Light Chain Variable Region (VL) Amino Acid Sequence; Anti-PD-1 mAb (REGN2810) DIQMTQSPSSLSASVGDSITITCRASLSINTFLNWYQQKPGKAPNLLIYAASSLHGGVPS RFSGSGSGTDFTLTIRTLQPEDFATYYCQQSSNTPFTFGPGTVVDFR SEQ ID NO:36 Heavy Chain CDR1 Amino Acid Sequence; Anti-PD-1 mAb (REGN2810) GFTFSNFG SEQ ID NO:37 Heavy Chain CDR2 Amino Acid Sequence; Anti-PD-1 mAb (REGN2810) ISGGGRDT SEQ ID NO:38 Heavy Chain CDR3 Amino Acid Sequence; Anti-PD-1 mAb (REGN2810) VKWGNIYFDY SEQ ID NO:39 Light Chain CDR1 Amino Acid Sequence; Anti-PD-1 mAb (REGN2810) LSINTF Light Chain CDR2 Amino Acid Sequence; Anti-PD-1 mAb (REGN2810) AAS SEQ ID NO:40 Light Chain CDR3 Amino Acid Sequence; Anti-PD-1 mAb (REGN2810) QQSSNTPFT SEQ ID NO:41 Heavy Chain Amino Acid Sequence; Anti-LAG-3 mAb (LAG525) QVQLVQSGAEVKKPGASVKVSCKASGFTLTNYGMNWVRQARGQRLEWIGWINTDTGEPTY ADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARNPPYYYGTNNAEAMDYWGQGTT VTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA VLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFL GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQ FNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQ EEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKS RWQEGNVFSCSVMHEALHNHYTQKSLSLSLGSEQ ID NO:42 Heavy Chain Amino Acid Sequence; Anti-LAG-3 mAb (LAG525) QVQLVQSGAEVKKPGASVKVSCKASGFTLTNYGMNWVRQAPGQGLEWMGWINTDTGEPTY ADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARNPPYYYGTNNAEAMDYWGQGTT VTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA VLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFL GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQ FNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQ EEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKS RWQEGNVFSCSVMHEALHNHYTQKSLSLSLG SEQ ID NO:43 Light Chain Amino Acid Sequence; Anti-LAG-3 mAb (LAG525) DIQMTQSPSSLSASVGDRVTITCSSSQDISNYLNWYLQKPGQSPQLLIYYTSTLHLGVPS RFSGSGSGTEFTLTISSLQPDDFATYYCQQYYNLPWTFGQGTKVEIKRTVAAPSVFIFPP SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO:44 Light Chain Amino Acid Sequence; Anti-LAG-3 mAb (LAG525) DIQMTQSPSSLSASVGDRVTITCSSSQDISNYLNWYQQKPGKAPKLLIYYTSTLHLGIPP RFSGSGYGTDFTLTINNIESEDAAYYFCQQYYNLPWTFGQGTKVEIKRTVAAPSVFIFPP SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO:45 Heavy Chain Variable Region (VH) Amino Acid Sequence; Anti-LAG-3 mAb (LAG525) QVQLVQSGAEVKKPGASVKVSCKASGFTLTNYGMNWVRQARGQRLEWIGWINTDTGEPTY ADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARNPPYYYGTNNAEAMDYWGQGTT VTVSS SEQ ID NO:46 Heavy Chain Variable Region (VH) Amino Acid Sequence; Anti-LAG-3 mAb (LAG525) QVQLVQSGAEVKKPGASVKVSCKASGFTLTNYGMNWVRQAPGQGLEWMGWINTDTGEPTY ADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARNPPYYYGTNNAEAMDYWGQGTT VTVSS SEQ ID NO:47 Light Chain Variable Region (VL) Amino Acid Sequence; Anti-LAG-3 mAb (LAG525) DIQMTQSPSSLSASVGDRVTITCSSSQDISNYLNWYLQKPGQSPQLLIYYTSTLHLGVPS RFSGSGSGTEF...

Claims

WHAT IS CLAIMED IS:

1. A method of treating a tumor in a human subject in need thereof, the method comprising administering to the subject an immunotherapy comprising a lymphocyte activation gene- 3 (LAG-3) antagonist, wherein a sample of the subject’s tumor is fibrinogen-like protein 1 (FGL-1) positive.

2. A method of treating tumors in a population of human subjects in need thereof, the method comprising administering to each subject in the population an immunotherapy comprising a LAG-3 antagonist, wherein a sample of each subject’s tumor in the population is FGL-1 positive.

3. The method of claim 1 or 2, further comprising determining the level of FGL-1 expression in the sample prior to administering the immunotherapy.

4. A method of selecting a tumor in a human subject for an immunotherapy comprising a LAG-3 antagonist, comprising: (a) determining the level of FGL-1 expression in a sample of the subject’s tumor; and (b) administering the immunotherapy to the subject if the sample is FGL-1 positive.

5. A method of selecting tumors in a population of human subjects for an immunotherapy comprising a LAG-3 antagonist, comprising: (a) determining the level of FGL-1 expression in a sample of each subject’s tumor in the population; and (b) administering the immunotherapy to the subject if the sample is FGL-1 positive.

6. A method of selecting a human subject afflicted with a tumor for an immunotherapy comprising a LAG-3 antagonist, comprising: (a) determining the level of FGL-1 expression in a sample of the subject’s tumor; and (b) administering the immunotherapy to the subject if the sample is FGL-1 positive.

7. A method of selecting a population of human subjects afflicted with tumors for an immunotherapy comprising a LAG-3 antagonist, comprising:(a) determining the level of FGL-1 expression in a sample of a tumor from a human subject, wherein the subject is a member of the population selected for the immunotherapy if the sample is FGL-1 positive; and (b) administering the immunotherapy to each subject in the population.

8. The method of any one of claims 1-7, wherein at least about 1% of tumor cells in the sample express FGL-1.

9. The method of any one of claims 1-8, wherein less than about 95%, less than about 90%, less than about 85%, less than about 80%, less than about 75%, less than about 70%, less than about 65%, less than about 60%, less than about 55%, less than about 50%, less than about 45%, less than about 40%, less than about 35%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, or less than about 5% of tumor cells in the sample express FGL-1.

10. The method of any one of claims 1-7, wherein about 1% to about 100%, about 1% to about 95%, about 1% to about 90%, about 1% to about 85%, about 1% to about 80%, about 1% to about 75%, about 1% to about 70%, about 1% to about 65%, about 1% to about 60%, about 1% to about 55%, about 1% to about 50%, about 1% to about 45%, about 1% to about 40%, about 1% to about 35%, about 1% to about 30%, about 1% to about 25%, about 1% to about 20%, about 1% to about 15%, about 1% to about 10%, or about 1% to about 5% of tumor cells in the sample express FGL-1.

11. The method of any one of claims 1-10, wherein FGL-1 expression has been determined from an immunohistochemistry assay.

12. The method of any one of claims 1-11, wherein the sample comprises a histoscore (H- score) of about 1 to about 300 according to the formula: (1 × percentage of tumor cells in the sample with weak FGL-1 expression) + (2 × percentage of tumor cells in the sample with moderate FGL-1 expression) + (3 × percentage of tumor cells in the sample with strong FGL-1 expression).

13. The method of any one of claims 1-12, wherein the sample is LAG-3 positive.

14. The method of claim 13, further comprising determining the level of LAG-3 expression in the sample prior to administering the immunotherapy.

15. The method of any one of claims 1-14, wherein the sample is programmed death ligand-1 (PD-L1) negative.

16. The method of claim 15, further comprising determining the level of PD-L1 expression in the sample prior to administering the immunotherapy.

17. A method of treating a tumor in a human subject in need thereof, the method comprising administering to the subject an immunotherapy comprising a lymphocyte activation gene- 3 (LAG-3) antagonist, wherein a sample of the subject’s plasma or serum is FGL-1 positive.

18. A method of treating tumors in a population of human subjects in need thereof, the method comprising administering to each subject in the population an immunotherapy comprising a LAG-3 antagonist, wherein a sample of each subject’s plasma or serum in the population is FGL-1 positive.

19. The method of claim 17 or 18, further comprising determining the level of FGL-1 expression in the sample prior to administering the immunotherapy.

20. A method of selecting a tumor in a human subject for an immunotherapy comprising a LAG-3 antagonist, comprising: (a) determining the level of FGL-1 expression in a sample of the subject’s plasma or serum; and (b) administering the immunotherapy to the subject if the sample is FGL-1 positive.

21. A method of selecting tumors in a population of human subjects for an immunotherapy comprising a LAG-3 antagonist, comprising: (a) determining the level of FGL-1 expression in a sample of each subject’s plasma or serum in the population; and (b) administering the immunotherapy to the subject if the sample is FGL-1 positive.

22. A method of selecting a human subject afflicted with a tumor for an immunotherapy comprising a LAG-3 antagonist, comprising: (a) determining the level of FGL-1 expression in a sample of the subject’s plasma or serum; and (b) administering the immunotherapy to the subject if the sample is FGL-1 positive.

23. A method of selecting a population of human subjects afflicted with tumors for an immunotherapy comprising a LAG-3 antagonist, comprising: (a) determining the level of FGL-1 expression in a sample of plasma or serum from a human subject, wherein the subject is a member of the population selected for the immunotherapy if the sample is FGL-1 positive; and (b) administering the immunotherapy to each subject in the population.

24. The method of any one of claims 1-23, wherein the tumor comprises a hepatocellular carcinoma, colorectal cancer, gastric cancer, small-cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), squamous NSCLC, non-squamous NSCLC, solid cancer with liver metastatic disease, cervical cancer, breast cancer, triple-negative breast cancer, pancreatic cancer, urothelial cancer, prostate cancer, hormone refractory prostate adenocarcinoma, hematological cancer, squamous cell carcinoma, glioma, gastrointestinal cancer, renal cancer, clear cell carcinoma, ovarian cancer, liver cancer, endometrial cancer, kidney cancer, renal cell carcinoma (RCC), thyroid cancer, neuroblastoma, glioblastoma, glioblastoma multiforme, stomach cancer, bladder cancer, hepatoma, colon cancer, head and neck cancer, gastroesophageal cancer, germ cell tumor, pediatric sarcoma, sinonasal natural killer T-cell lymphoma, melanoma, bone cancer, skin cancer, uterine cancer, cancer of the anal region, testicular cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, rectal cancer, solid tumor of childhood, cancer of the ureter, carcinoma of the renal pelvis, neoplasm of the central nervous system (CNS), primary CNS lymphoma, spinal axis tumor, brain cancer, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid cancer, environmentally-induced cancer, virus- related cancer or cancer of viral origin, or any combination thereof.

25. The method of any one of claims 1-24, wherein the tumor is recurrent or refractory.

26. The method of any one of claims 1-25, wherein the tumor is unresectable, advanced, and / or metastatic.

27. The method of any one of claims 1-26, wherein the tumor is a malignant tumor.

28. The method of any one of claims 19-27, wherein the tumor comprises a hepatocellular carcinoma, and the sample comprises an H-score of less than about 250.

29. The method of any one of claims 19-28, wherein the tumor comprises a hepatocellular carcinoma, and the sample comprises an H-score of less than about 140.

30. The method of any one of claims 19-27, wherein the tumor comprises a NSCLC, and the sample comprises an H-score of less than or equal to about 10.

31. The method of any one of claims 19-27, wherein the tumor comprises a NSCLC, and the sample comprises an H-score of greater than about 45.

32. The method of claim 30 or 31, wherein the NSCLC comprises non-squamous NSCLC.

33. The method of any one of claims 19-32, wherein the H-score is a manual calculation.

34. The method of any one of claims 19-32, wherein the H-score is an automated calculation by image analysis software.

35. The method of any one of claims 1-34, wherein the immunotherapy further comprises a programmed death-1 (PD-1) pathway inhibitor.

36. The method of any one of claims 1-35, wherein the LAG-3 antagonist comprises an anti- LAG-3 antibody.

37. The method of claim 36, wherein the anti-LAG-3 antibody comprises a full-length antibody.

38. The method of claim 36 or 37, wherein the anti-LAG-3 antibody comprises a monoclonal, human, humanized, chimeric, or multispecific antibody.

39. The method of claim 38, wherein the multispecific antibody comprises a dual-affinity re- targeting antibody, a dual variable domain immunoglobulin, or a bispecific antibody.

40. The method of claim 36, wherein the anti-LAG-3 antibody comprises a F(ab')2 fragment, a Fab' fragment, a Fab fragment, a Fv fragment, a scFv fragment, a dsFv fragment, a dAb fragment, or a single chain binding polypeptide.

41. The method of any one of claims 36-40, wherein the anti-LAG-3 antibody comprises BMS- 986016 (relatlimab), IMP731 (H5L7BW), MK4280 (28G-10, favezelimab), REGN3767 (fianlimab), GSK2831781, humanized BAP050, IMP-701 (LAG525, ieramilimab), aLAG3(0414), aLAG3(0416), Sym022, TSR-033, TSR-075, XmAb841 (XmAb22841), MGD013 (tebotelimab), BI754111, FS118, P 13B02-30, AVA-017, 25F7, AGEN1746, RO7247669, INCAGN02385, IBI-110, EMB-02, IBI-323, LBL-007, ABL501, or an antigen binding portion thereof.

42. The method of any one of claims 36-41, wherein the anti-LAG-3 antibody comprises CDR1, CDR2 and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID NO:3, and CDR1, CDR2 and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID NO:

4.

43. The method of any one of claims 36-42, wherein the anti-LAG-3 antibody comprises: (a) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO:5; (b) a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO:6; (c) a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO:7; (d) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO:8;(e) a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO:9; and (f) a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO:

10.

44. The method of any one of claims 36-43, wherein the anti-LAG-3 antibody comprises heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs:3 and 4, respectively.

45. The method of any one of claims 36-39 or 41-44, wherein the anti-LAG-3 antibody comprises heavy and light chains comprising the sequences set forth in SEQ ID NOs:1 and 2, respectively.

46. The method of any one of claims 36-39 or 41-44, wherein the anti-LAG-3 antibody comprises heavy and light chains comprising the sequences set forth in SEQ ID NOs:21 and 2, respectively.

47. The method of any one of claims 1-35, wherein the LAG-3 antagonist comprises a soluble LAG-3 polypeptide.

48. The method of claim 47, wherein the soluble LAG-3 polypeptide is a fusion polypeptide.

49. The method of claim 47 or 48, wherein the soluble LAG-3 polypeptide comprises a ligand binding fragment of the LAG-3 extracellular domain.

50. The method of claim 49, wherein the ligand binding fragment of the LAG-3 extracellular domain comprises an amino acid sequence with at least about 90%, at least about 95%, at least about 98%, at least about 99%, or about 100% sequence identity to SEQ ID NO:

22.

51. The method of any one of claims 47-50, wherein the soluble LAG-3 polypeptide further comprises a half-life extending moiety.

52. The method of claim 51, wherein the half-life extending moiety comprises an immunoglobulin constant region or a portion thereof, an immunoglobulin-bindingpolypeptide, an immunoglobulin G (IgG), albumin-binding polypeptide (ABP), a PASylation moiety, a HESylation moiety, XTEN, a PEGylation moiety, an Fc region, or any combination thereof.

53. The method of any one of claims 47-52, wherein the soluble LAG-3 polypeptide comprises IMP321 (eftilagimod alpha).

54. The method of any one of claims 1-53, wherein the LAG-3 antagonist is formulated for parenteral administration.

55. The method of any one of claims 1-54, wherein the LAG-3 antagonist is formulated for intravenous, intraperitoneal, intramuscular, intrathecal, or subcutaneous administration.

56. The method of any one of claims 1-55, wherein the LAG-3 antagonist is administered at a flat dose.

57. The method of any one of claims 1-56, wherein the LAG-3 antagonist is administered at a dose of from at least about 0.25 mg to about 2000 mg, about 0.25 mg to about 1600 mg, about 0.25 mg to about 1200 mg, about 0.25 mg to about 800 mg, about 0.25 mg to about 400 mg, about 0.25 mg to about 100 mg, about 0.25 mg to about 50 mg, about 0.25 mg to about 40 mg, about 0.25 mg to about 30 mg, about 0.25 mg to about 20 mg, about 20 mg to about 2000 mg, about 20 mg to about 1600 mg, about 20 mg to about 1200 mg, about 20 mg to about 800 mg, about 20 mg to about 400 mg, about 20 mg to about 100 mg, about 100 mg to about 2000 mg, about 100 mg to about 1800 mg, about 100 mg to about 1600 mg, about 100 mg to about 1400 mg, about 100 mg to about 1200 mg, about 100 mg to about 1000 mg, about 100 mg to about 800 mg, about 100 mg to about 600 mg, about 100 mg to about 400 mg, about 400 mg to about 2000 mg, about 400 mg to about 1800 mg, about 400 mg to about 1600 mg, about 400 mg to about 1400 mg, about 400 mg to about 1200 mg, or about 400 mg to about 1000 mg.

58. The method of any one of claims 1-57, wherein the LAG-3 antagonist is administered at a dose of about 0.25 mg, about 0.5 mg, about 0.75 mg, about 1 mg, about 1.25 mg, about 1.5 mg, about 1.75 mg, about 2 mg, about 2.25 mg, about 2.5 mg, about 2.75 mg, about 3 mg,about 3.25 mg, about 3.5 mg, about 3.75 mg, about 4 mg, about 4.25 mg, about 4.5 mg, about 4.75 mg, about 5 mg, about 5.25 mg, about 5.5 mg, about 5.75 mg, about 6 mg, about 6.25 mg, about 6.5 mg, about 6.75 mg, about 7 mg, about 7.25 mg, about 7.5 mg, about 7.75 mg, about 8 mg, about 8.25 mg, about 8.5 mg, about 8.75 mg, about 9 mg, about 9.25 mg, about 9.5 mg, about 9.75 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, about 800 mg, about 810 mg, about 820 mg, about 830 mg, about 840 mg, about 850 mg, about 860 mg, about 870 mg, about 880 mg, about 890 mg, about 900 mg, about 910 mg, about 920 mg, about 930 mg, about 940 mg, about 950 mg, about 960 mg, about 970 mg, about 980 mg, about 990 mg, about 1000 mg, about 1040 mg, about 1080 mg, about 1100 mg, about 1140 mg, about 1180 mg, about 1200 mg, about 1240 mg, about 1280 mg, about 1300 mg, about 1340 mg, about 1380 mg, about 1400 mg, about 1440 mg, about 1480 mg, about 1500 mg, about 1540 mg, about 1580 mg, about 1600 mg, about 1640 mg, about 1680 mg, about 1700 mg, about 1740 mg, about 1780 mg, about 1800 mg, about 1840 mg, about 1880 mg, about 1900 mg, about 1940 mg, about 1980 mg, or about 2000 mg.

59. The method of any one of claims 1-55, wherein the LAG-3 antagonist is administered at a weight-based dose.

60. The method of any one of claims 1-55 or 59, wherein the LAG-3 antagonist is administered at a dose of from about 0.003 mg / kg to about 25 mg / kg, about 0.003 mg / kg to about 20mg / kg, about 0.003 mg / kg to about 15 mg / kg, about 0.003 mg / kg to about 10 mg / kg, about 0.003 mg / kg to about 5 mg / kg, about 0.003 mg / kg to about 1 mg / kg, about 0.003 mg / kg to about 0.9 mg / kg, about 0.003 mg / kg to about 0.8 mg / kg, about 0.003 mg / kg to about 0.7 mg / kg, about 0.003 mg / kg to about 0.6 mg / kg, about 0.003 mg / kg to about 0.5 mg / kg, about 0.003 mg / kg to about 0.4 mg / kg, about 0.003 mg / kg to about 0.3 mg / kg, about 0.003 mg / kg to about 0.2 mg / kg, about 0.003 mg / kg to about 0.1 mg / kg, about 0.1 mg / kg to about 25 mg / kg, about 0.1 mg / kg to about 20 mg / kg, about 0.1 mg / kg to about 15 mg / kg, about 0.1 mg / kg to about 10 mg / kg, about 0.1 mg / kg to about 5 mg / kg, about 0.1 mg / kg to about 1 mg / kg, about 1 mg / kg to about 25 mg / kg, about 1 mg / kg to about 20 mg / kg, about 1 mg / kg to about 15 mg / kg, about 1 mg / kg to about 10 mg / kg, about 1 mg / kg to about 5 mg / kg, about 5 mg / kg to about 25 mg / kg, about 5 mg / kg to about 20 mg / kg, about 5 mg / kg to about 15 mg / kg, about 5 mg / kg to about 10 mg / kg, about 10 mg / kg to about 25 mg / kg, about 10 mg / kg to about 20 mg / kg, about 10 mg / kg to about 15 mg / kg, about 15 mg / kg to about 25 mg / kg, about 15 mg / kg to about 20 mg / kg, or about 20 mg / kg to about 25 mg / kg.

61. The method of any one of claims 1-55, 59, or 60, wherein the LAG-3 antagonist is administered at a dose of about 0.003 mg / kg, about 0.004 mg / kg, about 0.005 mg / kg, about 0.006 mg / kg, about 0.007 mg / kg, about 0.008 mg / kg, about 0.009 mg / kg, about 0.01 mg / kg, about 0.02 mg / kg, about 0.03 mg / kg, about 0.04 mg / kg, about 0.05 mg / kg, about 0.06 mg / kg, about 0.07 mg / kg, about 0.08 mg / kg, about 0.09 mg / kg, about 0.1 mg / kg, about 0.2 mg / kg, about 0.3 mg / kg, about 0.4 mg / kg, about 0.5 mg / kg, about 0.6 mg / kg, about 0.7 mg / kg, about 0.8 mg / kg, about 0.9 mg / kg, about 1.0 mg / kg, about 2.0 mg / kg, about 3.0 mg / kg, about 4.0 mg / kg, about 5.0 mg / kg, about 6.0 mg / kg, about 7.0 mg / kg, about 8.0 mg / kg, about 9.0 mg / kg, about 10.0 mg / kg, about 11.0 mg / kg, about 12.0 mg / kg, about 13.0 mg / kg, about 14.0 mg / kg, about 15.0 mg / kg, about 16.0 mg / kg, about 17.0 mg / kg, about 18.0 mg / kg, about 19.0 mg / kg, about 20.0 mg / kg, about 21.0 mg / kg, about 22.0 mg / kg, about 23.0 mg / kg, about 24.0 mg / kg, or about 25.0 mg / kg.

62. The method of any one of claims 56-61, wherein the dose is administered once about every one week, once about every two weeks, once about every three weeks, once about every four weeks, once about every five weeks, once about every six weeks, once about every seven weeks, once about every eight weeks, once about every nine weeks, once about every ten weeks, once about every eleven weeks, or once about every twelve weeks.

63. The method of any one of claims 35-62, wherein the PD-1 pathway inhibitor comprises an anti-PD-1 antibody and / or an anti-PD-L1 antibody.

64. The method of any one of claims 35-63, wherein the PD-1 pathway inhibitor comprises an anti-PD-1 antibody.

65. The method of claim 63 or 64, wherein the anti-PD-1 antibody comprises a full-length antibody.

66. The method of any one of claims 63-65, wherein the anti-PD-1 antibody comprises a monoclonal, human, humanized, chimeric, or multispecific antibody.

67. The method of claim 66, wherein the multispecific antibody comprises a dual-affinity re- targeting antibody, a dual variable domain immunoglobulin, or a bispecific antibody.

68. The method of claim 63 or 64, wherein the anti-PD-1 antibody comprises a F(ab')2 fragment, a Fab' fragment, a Fab fragment, a Fv fragment, a scFv fragment, a dsFv fragment, a dAb fragment, or a single chain binding polypeptide.

69. The method of any one of claims 63-68, wherein the anti-PD-1 antibody comprises nivolumab, pembrolizumab, PDR001 (spartalizumab), MEDI-0680, TSR-042, cemiplimab, JS001, PF-06801591, BGB-A317, BI 754091, INCSHR1210, GLS-010, AM- 001, STI-1110, AGEN2034, MGA012, BCD-100, IBI308, SSI-361, or an antigen binding portion thereof.

70. The method of any one of claims 63-69, wherein the anti-PD-1 antibody comprises CDR1, CDR2 and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID NO:13, and CDR1, CDR2 and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID NO:

14.

71. The method of any one of claims 63-70, wherein the anti-PD-1 antibody comprises: (a) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO:15;(b) a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO:16; (c) a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO:17; (d) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO:18; (e) a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO:19; and (f) a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO:

20.

72. The method of any one of claims 63-71, wherein the anti-PD-1 antibody comprises heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs:13 and 14, respectively.

73. The method of any one of claims 63-67 or 69-72, wherein the anti-PD-1 antibody comprises heavy and light chains comprising the sequences as set forth in SEQ ID NOs:11 and 12, respectively.

74. The method of any one of claims 35-62, wherein the PD-1 pathway inhibitor comprises a soluble PD-L2 polypeptide.

75. The method of claim 74, wherein the soluble PD-L2 polypeptide is a fusion polypeptide.

76. The method of claim 74 or 75, wherein the soluble PD-L2 polypeptide comprises a ligand binding fragment of the PD-L2 extracellular domain.

77. The method of any one of claims 74-76, wherein the soluble PD-L2 polypeptide further comprises a half-life extending moiety.

78. The method of claim 77, wherein the half-life extending moiety comprises an immunoglobulin constant region or a portion thereof, an immunoglobulin-binding polypeptide, an immunoglobulin G (IgG), albumin-binding polypeptide (ABP), aPASylation moiety, a HESylation moiety, XTEN, a PEGylation moiety, an Fc region, or any combination thereof.

79. The method of any one of claims 74-78, wherein the soluble PD-L2 polypeptide comprises AMP-224.

80. The method of any one of claims 35-63, wherein the PD-1 pathway inhibitor comprises an anti-PD-L1 antibody.

81. The method of claim 63 or 80, wherein the anti-PD-L1 antibody comprises a full-length antibody.

82. The method of any one of claims 63, 80, or 81, wherein the anti-PD-L1 antibody comprises a monoclonal, human, humanized, chimeric, or multispecific antibody.

83. The method of claim 82, wherein the multispecific antibody comprises a dual-affinity re- targeting antibody, a dual variable domain immunoglobulin, or a bispecific antibody.

84. The method of claim 63 or 80, wherein the anti-PD-L1 antibody comprises a F(ab')2 fragment, a Fab' fragment, a Fab fragment, a Fv fragment, a scFv fragment, a dsFv fragment, a dAb fragment, or a single chain binding polypeptide.

85. The method of any one of claims 63 or 80-84, wherein the anti-PD-L1 antibody comprises BMS-936559, atezolizumab, durvalumab, avelumab, STI-1014, CX-072, KN035, LY3300054, BGB-A333, ICO 36, FAZ053, CK-301, or an antigen binding portion thereof.

86. The method of any one of claims 35-62, wherein the PD-1 pathway inhibitor comprises BMS-986189.

87. The method of any one of claims 35-86, wherein the PD-1 pathway inhibitor is formulated for parenteral administration.

88. The method of any one of claims 35-87, wherein the PD-1 pathway inhibitor is formulated for intravenous, intraperitoneal, intramuscular, intrathecal, or subcutaneous administration.

89. The method of any one of claims 35-88, wherein the PD-1 pathway inhibitor is administered at a flat dose.

90. The method of any one of claims 35-89, wherein the PD-1 pathway inhibitor is administered at a dose of from at least about 0.25 mg to about 2000 mg, about 0.25 mg to about 1600 mg, about 0.25 mg to about 1200 mg, about 0.25 mg to about 800 mg, about 0.25 mg to about 400 mg, about 0.25 mg to about 100 mg, about 0.25 mg to about 50 mg, about 0.25 mg to about 40 mg, about 0.25 mg to about 30 mg, about 0.25 mg to about 20 mg, about 20 mg to about 2000 mg, about 20 mg to about 1600 mg, about 20 mg to about 1200 mg, about 20 mg to about 800 mg, about 20 mg to about 400 mg, about 20 mg to about 100 mg, about 100 mg to about 2000 mg, about 100 mg to about 1800 mg, about 100 mg to about 1600 mg, about 100 mg to about 1400 mg, about 100 mg to about 1200 mg, about 100 mg to about 1000 mg, about 100 mg to about 800 mg, about 100 mg to about 600 mg, about 100 mg to about 400 mg, about 400 mg to about 2000 mg, about 400 mg to about 1800 mg, about 400 mg to about 1600 mg, about 400 mg to about 1400 mg, about 400 mg to about 1200 mg, or about 400 mg to about 1000 mg.

91. The method of any one of claims 35-90, wherein the PD-1 pathway inhibitor is administered at a dose of about 0.25 mg, about 0.5 mg, about 0.75 mg, about 1 mg, about 1.25 mg, about 1.5 mg, about 1.75 mg, about 2 mg, about 2.25 mg, about 2.5 mg, about 2.75 mg, about 3 mg, about 3.25 mg, about 3.5 mg, about 3.75 mg, about 4 mg, about 4.25 mg, about 4.5 mg, about 4.75 mg, about 5 mg, about 5.25 mg, about 5.5 mg, about 5.75 mg, about 6 mg, about 6.25 mg, about 6.5 mg, about 6.75 mg, about 7 mg, about 7.25 mg, about 7.5 mg, about 7.75 mg, about 8 mg, about 8.25 mg, about 8.5 mg, about 8.75 mg, about 9 mg, about 9.25 mg, about 9.5 mg, about 9.75 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg,about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, about 800 mg, about 810 mg, about 820 mg, about 830 mg, about 840 mg, about 850 mg, about 860 mg, about 870 mg, about 880 mg, about 890 mg, about 900 mg, about 910 mg, about 920 mg, about 930 mg, about 940 mg, about 950 mg, about 960 mg, about 970 mg, about 980 mg, about 990 mg, about 1000 mg, about 1040 mg, about 1080 mg, about 1100 mg, about 1140 mg, about 1180 mg, about 1200 mg, about 1240 mg, about 1280 mg, about 1300 mg, about 1340 mg, about 1380 mg, about 1400 mg, about 1440 mg, about 1480 mg, about 1500 mg, about 1540 mg, about 1580 mg, about 1600 mg, about 1640 mg, about 1680 mg, about 1700 mg, about 1740 mg, about 1780 mg, about 1800 mg, about 1840 mg, about 1880 mg, about 1900 mg, about 1940 mg, about 1980 mg, or about 2000 mg.

92. The method of any one of claims 35-88, wherein the PD-1 pathway inhibitor is administered at a weight-based dose.

93. The method of any one of claims 35-88 or 92, wherein the PD-1 pathway inhibitor is administered at a dose of from about 0.003 mg / kg to about 25 mg / kg, about 0.003 mg / kg to about 20 mg / kg, about 0.003 mg / kg to about 15 mg / kg, about 0.003 mg / kg to about 10 mg / kg, about 0.003 mg / kg to about 5 mg / kg, about 0.003 mg / kg to about 1 mg / kg, about 0.003 mg / kg to about 0.9 mg / kg, about 0.003 mg / kg to about 0.8 mg / kg, about 0.003 mg / kg to about 0.7 mg / kg, about 0.003 mg / kg to about 0.6 mg / kg, about 0.003 mg / kg to about 0.5 mg / kg, about 0.003 mg / kg to about 0.4 mg / kg, about 0.003 mg / kg to about 0.3 mg / kg, about 0.003 mg / kg to about 0.2 mg / kg, about 0.003 mg / kg to about 0.1 mg / kg, about 0.1 mg / kg to about 25 mg / kg, about 0.1 mg / kg to about 20 mg / kg, about 0.1 mg / kg to about 15 mg / kg, about 0.1 mg / kg to about 10 mg / kg, about 0.1 mg / kg to about 5 mg / kg, about 0.1 mg / kg to about 1 mg / kg, about 1 mg / kg to about 25 mg / kg, about 1 mg / kg to about 20 mg / kg, about 1 mg / kg to about 15 mg / kg, about 1 mg / kg to about 10 mg / kg, about 1 mg / kg to about 5 mg / kg, about 5 mg / kg to about 25 mg / kg, about 5 mg / kg to about 20 mg / kg, about 5 mg / kg to about 15 mg / kg, about 5 mg / kg to about 10 mg / kg, about 10 mg / kg to about 25 mg / kg,about 10 mg / kg to about 20 mg / kg, about 10 mg / kg to about 15 mg / kg, about 15 mg / kg to about 25 mg / kg, about 15 mg / kg to about 20 mg / kg, or about 20 mg / kg to about 25 mg / kg.

94. The method of any one of claims 35-88, 92, or 93, wherein the PD-1 pathway inhibitor is administered at a dose of about 0.003 mg / kg, about 0.004 mg / kg, about 0.005 mg / kg, about 0.006 mg / kg, about 0.007 mg / kg, about 0.008 mg / kg, about 0.009 mg / kg, about 0.01 mg / kg, about 0.02 mg / kg, about 0.03 mg / kg, about 0.04 mg / kg, about 0.05 mg / kg, about 0.06 mg / kg, about 0.07 mg / kg, about 0.08 mg / kg, about 0.09 mg / kg, about 0.1 mg / kg, about 0.2 mg / kg, about 0.3 mg / kg, about 0.4 mg / kg, about 0.5 mg / kg, about 0.6 mg / kg, about 0.7 mg / kg, about 0.8 mg / kg, about 0.9 mg / kg, about 1.0 mg / kg, about 2.0 mg / kg, about 3.0 mg / kg, about 4.0 mg / kg, about 5.0 mg / kg, about 6.0 mg / kg, about 7.0 mg / kg, about 8.0 mg / kg, about 9.0 mg / kg, about 10.0 mg / kg, about 11.0 mg / kg, about 12.0 mg / kg, about 13.0 mg / kg, about 14.0 mg / kg, about 15.0 mg / kg, about 16.0 mg / kg, about 17.0 mg / kg, about 18.0 mg / kg, about 19.0 mg / kg, about 20.0 mg / kg, about 21.0 mg / kg, about 22.0 mg / kg, about 23.0 mg / kg, about 24.0 mg / kg, or about 25.0 mg / kg.

95. The method of any one of claims 89-94, wherein the dose is administered once about every one week, once about every two weeks, once about every three weeks, once about every four weeks, once about every five weeks, once about every six weeks, once about every seven weeks, once about every eight weeks, once about every nine weeks, once about every ten weeks, once about every eleven weeks, or once about every twelve weeks.

96. The method of any one of claims 35-95, wherein the PD-1 pathway inhibitor is administered before the LAG-3 antagonist.

97. The method of any one of claims 35-95, wherein the LAG-3 antagonist is administered before the PD-1 pathway inhibitor.

98. The method of any one of claims 35-95, wherein the LAG-3 antagonist and the PD-1 pathway inhibitor are administered concurrently.

99. The method of any one of claims 35-98, wherein the LAG-3 antagonist and the PD-1 pathway inhibitor are formulated separately.

100. The method of any one of claims 35-95 or 98, wherein the LAG-3 antagonist and the PD- 1 pathway inhibitor are formulated together.

101. The method of any one of claims 1-100, wherein the method is a first line therapy.

102. The method of any one of claims 1-100, wherein the method is a second line therapy.

103. The method of any one of claims 1-100, wherein the method is a third line therapy.

104. The method of claim 102 or 103, wherein the subject has progressed on or is intolerant of a prior therapy.

105. The method of any one of claims 1-104, wherein the subject is naïve to prior systemic therapy.

106. The method of any one of claims 1-105, wherein the subject is naïve to prior immuno- oncology therapy, the subject is naïve to prior immuno-oncology for the malignant tumor, or the malignant tumor is naïve to prior immuno-oncology therapy.

107. The method of any one of claims 35-39, 41-46, 54-58, 62-67, 69-73, 87-91, or 95-106, wherein the LAG-3 antagonist comprises relatlimab intravenously administered between about 160 mg to about 480 mg once about every four weeks and the PD-1 pathway inhibitor comprises nivolumab intravenously administered between 240 mg to about 480 mg once about every four weeks.

108. The method of any one of claims 35-39, 41-46, 54-58, 62-67, 69-73, 87-91, or 95-106, wherein the LAG-3 antagonist comprises relatlimab intravenously administered at about 160 mg once about every four weeks and the PD-1 pathway inhibitor comprises nivolumab intravenously administered at about 480 mg once about every four weeks.

109. The method of any one of claims 35-39, 41-46, 54-58, 62-67, 69-73, 87-91, or 95-106, wherein the LAG-3 antagonist comprises relatlimab intravenously administered at about 360 mg once about every four weeks and the PD-1 pathway inhibitor comprises nivolumab intravenously administered at about 360 mg once about every four weeks.

110. The method of any one of claims 35-39, 41-46, 54-58, 62-67, 69-73, 87-91, or 95-106, wherein the LAG-3 antagonist comprises relatlimab intravenously administered at about 480 mg once about every four weeks and the PD-1 pathway inhibitor comprises nivolumab intravenously administered at about 480 mg once about every four weeks.

111. The method of any one of claims 35-39, 41-46, 54-58, 62-67, 69-73, 87-91, or 95-106, wherein the LAG-3 antagonist comprises relatlimab subcutaneously administered at about 320 mg once about every four weeks and the PD-1 pathway inhibitor comprises nivolumab subcutaneously administered at about 960 mg once about every four weeks.

112. The method of any one of claims 35-39, 41-46, 54-58, 62-67, 69-73, 87-91, or 95-106, wherein the LAG-3 antagonist comprises relatlimab subcutaneously administered at about 960 mg once about every four weeks and the PD-1 pathway inhibitor comprises nivolumab subcutaneously administered at about 960 mg once about every four weeks.

113. A method of treating a tumor in a human subject in need thereof comprising intravenously administering to the subject relatlimab at about 480 mg once about every four weeks and nivolumab at about 480 mg once about every four weeks, wherein the subject’s tumor is identified as having a histoscore (H-score) of less than about 250 according to the formula: (1 × percentage of tumor cells in the sample with weak FGL-1 expression) + (2 × percentage of tumor cells in the sample with moderate FGL-1 expression) + (3 × percentage of tumor cells in the sample with strong FGL-1 expression).

114. The method of claim 113, wherein the tumor comprises a hepatocellular carcinoma.

115. The method of claim 113 or 114, wherein the H-score is less than about 140.

116. A method of treating a tumor in a human subject in need thereof comprising intravenously administering to the subject relatlimab at about 360 mg once about every four weeks and nivolumab at about 360 mg once about every four weeks, wherein the subject’s tumor is identified as having an H-score of less than or equal to about 10 according to the formula: (1 × percentage of tumor cells in the sample with weak FGL-1 expression) + (2 ×percentage of tumor cells in the sample with moderate FGL-1 expression) + (3 × percentage of tumor cells in the sample with strong FGL-1 expression).

117. A method of treating a tumor in a human subject in need thereof comprising intravenously administering to the subject relatlimab at about 360 mg once about every four weeks and nivolumab at about 360 mg once about every four weeks, wherein the subject’s tumor is identified as having an H-score of greater than about 45 according to the formula: (1 × percentage of tumor cells in the sample with weak FGL-1 expression) + (2 × percentage of tumor cells in the sample with moderate FGL-1 expression) + (3 × percentage of tumor cells in the sample with strong FGL-1 expression).

118. A method of treating a tumor in a human subject in need thereof comprising intravenously administering to the subject relatlimab at about 360 mg once about every four weeks and nivolumab at about 360 mg once about every four weeks, wherein a sample of the subject’s plasma or serum comprises less than about 360 ng / mL of soluble FGL-1.

119. The method of any one of claims 116-118, wherein the tumor comprises a non-small cell lung cancer.

120. The method of any one of claims 116-119, wherein the non-small lung cancer comprises non-squamous non-small cell lung cancer.

121. The method of any one of claims 1-120, further comprising administering to the subject an additional therapeutic agent.

122. The method of claim 121, wherein the additional therapeutic agent comprises an anti-cancer agent.

123. The method of claim 122, wherein the anti-cancer agent comprises a tyrosine kinase inhibitor, an anti-angiogenesis agent, a checkpoint inhibitor, a checkpoint stimulator, a chemotherapeutic agent, an immunotherapeutic agent, a platinum agent, an alkylating agent, a taxane, a nucleoside analog, an antimetabolite, a topoisomerase inhibitor, an anthracycline, a vinca alkaloid, or any combination thereof.

124. The method of claim 123, wherein the checkpoint inhibitor comprises a cytotoxic T- lymphocyte-associated protein 4 (CTLA-4) inhibitor, a T cell immunoglobulin and ITIM domain (TIGIT) inhibitor, a T cell immunoglobulin and mucin-domain containing-3 (TIM- 3) inhibitor, a TIM-1 inhibitor, a TIM-4 inhibitor, a B7-H3 inhibitor, a B7-H4 inhibitor, a B and T cell lymphocyte attenuator (BTLA) inhibitor, a V-domain Ig suppressor of T cell activation (VISTA) inhibitor, an indoleamine 2,3-dioxygenase (IDO) inhibitor, a nicotinamide adenine dinucleotide phosphate oxidase isoform 2 (NOX2) inhibitor, a killer- cell immunoglobulin-like receptor (KIR) inhibitor, an adenosine A2a receptor (A2aR) inhibitor, a transforming growth factor beta (TGF-β) inhibitor, a phosphoinositide 3-kinase (PI3K) inhibitor, a CD47 inhibitor, a CD48 inhibitor, a CD73 inhibitor, a CD113 inhibitor, a sialic acid-binding immunoglobulin-like lectin-7 (SIGLEC-7) inhibitor, a SIGLEC-9 inhibitor, a SIGLEC-15 inhibitor, a glucocorticoid-induced TNFR-related protein (GITR) inhibitor, a galectin-1 inhibitor, a galectin-9 inhibitor, a carcinoembryonic antigen-related cell adhesion molecule-1 (CEACAM-1) inhibitor, a G protein-coupled receptor 56 (GPR56) inhibitor, a glycoprotein A repetitions predominant (GARP) inhibitor, a 2B4 inhibitor, a programmed death-1 homolog (PD1H) inhibitor, a leukocyte-associated immunoglobulin-like receptor 1 (LAIR1) inhibitor, or any combination thereof.

125. The method of claim 123 or 124, wherein the checkpoint inhibitor comprises a CTLA-4 inhibitor.

126. The method of claim 125, wherein the CTLA-4 inhibitor comprises an anti-CTLA-4 antibody.

127. The method of claim 126, wherein the anti-CTLA-4 antibody comprises a full-length antibody.

128. The method of claim 126 or 127 wherein the anti-CTLA-4 antibody comprises a monoclonal, human, humanized, chimeric, or multispecific antibody.

129. The method of claim 128, wherein the multispecific antibody comprises a dual-affinity re- targeting antibody, a dual variable domain immunoglobulin, or a bispecific antibody.

130. The method of claim 126, wherein the anti-CTLA-4 antibody comprises a F(ab')2fragment, a Fab' fragment, a Fab fragment, a Fv fragment, a scFv fragment, a dsFv fragment, a dAb fragment, or a single chain binding polypeptide.

131. The method of any one of claims 126-130, wherein the anti-CTLA-4 antibody comprises ipilimumab, tremelimumab, MK-1308, AGEN-1884, or an antigen binding portion thereof.

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