Methods of treating cancer with a lymphotoxin beta receptor agonist

Abstract

This disclosure relates to methods of treating cancer by administering a lymphotoxin beta receptor (LTBR) agonist, such as in combination with adoptive cell therapy (ACT). The combination of LTBR agonist and ACT demonstrates unexpected synergistic anti-tumor efficacy in inducing potent and durable tumor control in subjects with cancer.

Description

This disclosure relates to methods for treating cancer by administering lymphotoxin beta receptor (LTBR) agonists, for example, in combination with adoptive cell therapy (ACT). The combination of LTBR agonists and ACT has demonstrated unexpected synergistic antitumor efficacy in inducing potent and durable tumor control in subjects with cancer. Abstract

Claims

We claim:

1. A method for treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a lymphotoxin beta receptor (LTBR) agonist in combination with a therapeutically effective amount of an adoptive cell therapy (ACT), wherein administration of the combination leads to increased efficacy and duration of anti-tumor response, as compared to a subject treated with the ACT as monotherapy.

2. A method for increasing the efficacy of adoptive cell therapy (ACT), comprising:(a) selecting a subject with cancer; and(b) administering to the subject a therapeutically effective amount of an ACT in combination with a therapeutically effective amount of a lymphotoxin beta receptor (LTBR) agonist, wherein administration of the combination leads to increased efficacy and duration of anti-tumor response, as compared to a subject treated with the ACT as monotherapy.

3. The method of claim 1 or 2, wherein the LTBR agonist is an antibody or antigen-binding fragment thereof that binds specifically to LTBR.

4. The method of any one of claims 1-3, wherein the ACT comprises an immune cell selected from a T cell, a tumor-infiltrating lymphocyte, and a natural killer (NK) cell.

5. The method of claim 4, wherein the immune cell comprises a modified T cell receptor (TCR) against a tumor-associated antigen (TAA), or a chimeric antigen receptor (CAR) against a TAA.

6. The method of claim 5, wherein the TAA is selected from AFP, ALK, BAGE proteins, BCMA, BIRC5 (survivin), BIRC7, [3-catenin, brc-abl, BRCA1, BORIS, CA9, carbonic anhydrase IX, caspase-8, CALR, CCR5, CD19, CD20 (MS4A1), CD22, CD30, CD40, CDK4, CEA, CTLA4, cyclin-B1 , CYP1 B1 , EGFR, EGFRvlll, ErbB2 / Her2, ErbB3, ErbB4, ETV6-AML, EpCAM, EphA2, Fra-1 , FOLR1 , GAGE proteins, GD2, GD3, GloboH, glypican-3, GM3, gp100, Her2, HLA / B-raf, HLA / k-ras, HLA / MAGE-A3, hTERT, LMP2, MAGE proteins (e.g., MAGE-1 , -2, -3, -4, -6, and - 12), MART-1, mesothelin, ML-IAP, Muc1 , Muc2, Muc3, Muc4, Muc5, Muc16 (CA-125), MUM1 , NA17, NY-BR1 , NY-BR62, NY-BR85, NY-ESO1 , 0X40, p15, p53, PAP, PAX3, PAX5, PCTA-1, PLAC1 , PRLR, PRAME, PSMA (F0LH1), RAGE proteins, Ras, RGS5, Rho, SART-1 , SART-3,STEAP1 , STEAP2, TAG-72, TGF- , TMPRSS2, Thompson-nouvelle antigen (Tn), TRP-1 , TRP- 2, tyrosinase, and uroplakin-3.

7. The method of any one of claims 1-6, further comprising administering an additional therapeutic agent or therapy to the subject.

8. The method of claim 7, wherein the additional therapeutic agent or therapy is selected from radiation, surgery, a checkpoint inhibitor, a chemotherapeutic agent, a cancer vaccine, a vascular endothelial growth factor (VEGF) antagonist, an angiopoietin-2 (Ang2) inhibitor, a transforming growth factor beta (TGF ) inhibitor, an epidermal growth factor receptor (EGFR) inhibitor, an antibody to a tumor-specific antigen, Bacillus Calmette-Guerin vaccine, granulocyte-macrophage colony-stimulating factor (GM-CSF), a cytotoxin, an interleukin 6 receptor (IL-6R) inhibitor, an interleukin 4 receptor (IL-4R) inhibitor, an IL-10 inhibitor, IL-2, IL-7, IL-12, IL-21, IL-15, an antibody-drug conjugate, an anti-inflammatory drug, and combinations thereof.

9. The method of claim 8, wherein the checkpoint inhibitor is selected from inhibitors of PD-1, PDL-1 , PDL-2, LAG-3, CTLA-4, TIM3, 2B4, A2aR, B7H1, B7H3, B7H4, BTLA, CD80, CD86, CD160, CD276, GAL9, HAVCR2, IDO1 , IDO2, KIR, LAIR1 , macrophage receptor with collageneous structure (MARCO), phosphatidylserine (PS), TIGHT, VISTA, and VTCN1.

10. The method of any one of claims 8-9, wherein the checkpoint inhibitor is an inhibitor of PD- 1 , PDL-1 , PDL-2, LAG-3, or CTLA-4.

11. The method of any one of claims 1-10, wherein the cancer is selected from adrenal gland cancer, anal cancer, autonomic ganglial cancer, biliary tract cancer, bladder cancer, blood cancer, bone cancer, brain cancer, breast cancer, cancer of the meninges, cervical cancer, colon cancer, colorectal cancer, endometrial cancer, eye cancer, esophageal cancer, fallopian tube cancer, gastric cancer, genital tract cancers, head and neck cancer, kidney cancer, large intestinal cancer, leukemia, liver cancer, lung cancer, lymphoma, myeloma, ovarian cancer, pancreatic cancer, penile cancer, peritoneal cancer, pituitary cancer, placental cancer, pleura cancer, prostate cancer, rectal cancer, renal cancer, salivary gland cancer, skin cancer, small intestinal cancer, squamous cell carcinoma, stomach cancer, testicular cancer, thymus cancer,thyroid cancer, upper aerodigestive cancers, urinary tract cancer, uterine cancer, vaginal cancer, and vulva cancer.

12. The method of any one of claims 1-11 , wherein the cancer expresses CXCL13, CCL19, CCL21 or LTa.

13. The method of any one of claims 1-12, wherein the cancer expresses LTa.

14. The method of any one of claims 1-13, wherein administration of the combination produces a therapeutic effect selected from one or more of: increased tumor-specific HEV formation, increased dendritic cell and T cell infiltration, enhanced T cell activation in tumor microenvironment, increased expression of TLS-related chemokines, delay in tumor growth, reduction in tumor cell number, tumor regression, increase in survival, partial response, and complete response.

15. The method of any one of claims 1-14, wherein the therapeutically effective amount of the LTBR agonist comprises 0.005 mg / kg to 10 mg / kg of the subject’s body weight.

16. The method of any one of claims 1-15, wherein the therapeutically effective amount of the ACT comprises 1x106or more immune cells.

17. The method of any one of claims 1-16, wherein the LTBR agonist and / or the ACT is administered in one or more doses to the subject.

18. The method of any one of claims 1-17, wherein the LTBR agonist and / or the ACT is administered intravascularly, subcutaneously, intraperitoneally, or intratumorally.

19. The method of any one of claims 1-18, wherein the LTBR agonist is administered before or after administration of the ACT.

20. The method of any one of claims 1-18, wherein the LTBR agonist is administered concurrently with administration of the ACT.

21. The method of any one of claims 1-20, wherein the LTBR agonist and the ACT are provided in separate compositions.

22. The method of any one of claims 1-18, wherein the LTBR agonist and the ACT are provided in a single composition.

23. A method for increasing tumor-specific HEV formation in a subject in need thereof, the method comprising:(a) selecting a subject with cancer; and(b) administering to the subject a therapeutically effective amount of an ACT in combination with a therapeutically effective amount of a lymphotoxin beta receptor (LTBR) agonist, wherein administration of the combination leads to increased tumor-specific HEV formation and increased efficacy and duration of anti-tumor response, as compared to a subject treated with the ACT as monotherapy.

24. A method for increasing expression of TLS-related chemokines in a subject in need thereof, the method comprising:(a) selecting a subject with cancer; and(b) administering to the subject a therapeutically effective amount of an ACT in combination with a therapeutically effective amount of a lymphotoxin beta receptor (LTBR) agonist, wherein administration of the combination leads to increased expression of TLS-related chemokines and increased efficacy and duration of anti-tumor response, as compared to a subject treated with the ACT as monotherapy.

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