Combination therapy for cancer

Abstract

The present invention relates to combination therapy for cancer. The disclosure provides methods of treating cancer in a patient comprising administering to the patient a chemotherapeutic agent, an immunomodulator, and an antisense compound targeting STAT3. Also provided herein are compositions and kits for performing the methods provided herein. In preferred embodiments, the chemotherapeutic agent is cis-platinum, the antisense compound targeting STAT3 is AZD9150, and the immunomodulator is MEDI4736.

Description

[0001] This application is a divisional application of Chinese patent application 202080067375.3 “Combination therapy for cancer” filed on September 29, 2020. Technical Field

[0002] The present disclosure provides methods of treating cancer in a patient comprising administering to the patient a chemotherapeutic agent, an immunomodulator, and an antisense compound targeted to STAT3. Also provided herein are compositions and kits for performing the methods provided herein. Background Art

[0003] Chemotherapy-immunotherapy ("chemo-IO") combinations are being explored as a potentially powerful tool for cancer treatment. Combinations of antisense compounds (e.g., antisense compounds targeting the master immunomodulator STAT3) and immunomodulators (e.g., immune checkpoint inhibitors) for immunotherapy are described in WO 2016 / 062722. Immune responses mediated by immune checkpoint inhibition can be enhanced by the immunogenic effects of cytotoxic agents, which are a result of direct tumor cell killing and can increase tumor antigens. Chemo-IO combination strategies can minimize direct T cell killing of chemotherapy, enhance antigen presentation, and promote T cell activation. Challenges associated with developing chemo-IO combination therapies may include finding an effective combination of agents and determining an effective dosing amount and schedule, because the effect of a drug combination on a patient may be different from the additive effect of providing only each drug alone. In addition, many current chemotherapeutic agents have many adverse side effects, so another challenge in development is to reduce the side effects of the combination therapy while increasing effectiveness compared to each drug alone. Summary of the invention

[0004] In some embodiments, the present disclosure provides a method of treating cancer in a patient, the method comprising administering to the patient: (a) about 50 mg / m 2 Up to about 70 mg / m 2 (b) chemotherapeutic agents; (b) immunomodulatory agents; and (c) antisense compounds targeting STAT3.

[0005] In some embodiments, the immunomodulator is an immune checkpoint inhibitor. In some embodiments, the immunomodulator is selected from an anti-PD-L1 antibody or an antigen-binding fragment thereof; an anti-PD1 antibody or an antigen-binding fragment thereof; an anti-CTLA-4 antibody or an antigen-binding fragment thereof; and an OX-40 agonist. In some embodiments, the immunomodulator is selected from MEDI4736, MPDL3280A, 2.7A4, AMP-714, MDX-1105, nivolumab, pembrolizumab, pidilizumab, BMS936559, MPDL3280A, tremelimumab, ipilimumab, and OX40L FP. In some embodiments, the immunomodulator is an anti-PD-L1 antibody. In some embodiments, the anti-PD-L1 antibody is MEDI4736.

[0006] In some embodiments, the antisense compound targeting STAT3 does not inhibit STAT1, STAT4 or STAT6. In some embodiments, the antisense compound targeting STAT3 is an antisense oligonucleotide. In some embodiments, the antisense compound targeting STAT3 is AZD9150.

[0007] In some embodiments, the immunomodulator is MEDI4736 or an antigen-binding fragment thereof and the antisense compound targeting STAT3 is AZD9150.

[0008] In some embodiments, the method comprises administering about 1 mg / kg to about 20 mg / kg of MEDI4736 or an antigen binding fragment thereof. In some embodiments, the method comprises administering about 200 mg to about 400 mg of AZD9150.

[0009] In some embodiments, the chemotherapeutic agent administered to the patient is cisplatin. In some embodiments, the method comprises administering about 55 mg / m 2 Up to about 65 mg / m 2 In some embodiments, the method comprises administering 60 mg / m 2 Cisplatin.

[0010] In some embodiments, the cancer is selected from breast cancer, renal cancer, lung cancer, pancreatic cancer, colorectal cancer, hepatocellular carcinoma (HCC), head and neck cancer, and lymphoma. In some embodiments, the lung cancer is non-small cell lung cancer (NSCLC). In some embodiments, the head and neck cancer is head and neck squamous cell carcinoma (HNSCC). In some embodiments, the lymphoma is diffuse large B cell carcinoma (DLBCL).

[0011] In some embodiments, the patient has a PD-L1 positive cancer. In some embodiments, the patient comprises cancer cells that express PD-L1.

[0012] In some embodiments, in one treatment cycle, a chemotherapeutic agent, an immunomodulator, and an antisense compound targeting STAT3 are administered to the patient simultaneously. In some embodiments, in one treatment cycle, a chemotherapeutic agent is administered to the patient, followed by an immunomodulator and an antisense compound targeting STAT3. In some embodiments, in one treatment cycle, a chemotherapeutic agent and an immunomodulator are administered to the patient, followed by an antisense compound targeting STAT3.

[0013] In some embodiments, in one treatment cycle, the patient is administered a chemotherapeutic agent at a lower dose than the immunomodulator and the antisense compound targeting STAT3. In some embodiments, in one treatment cycle, the patient is administered about 1 dose of the chemotherapeutic agent, about 2 to about 5 doses of the immunomodulator, and about 5 to about 20 doses of the antisense compound targeting STAT3.

[0014] In some embodiments, the treatment cycle is one week, two weeks, three weeks, or four weeks. In some embodiments, the method comprises two to eight treatment cycles.

[0015] In some embodiments, the method results in an increase in CD11b+ / Ly6C+ dendritic cells compared to administration of the immunomodulator alone, administration of the antisense compound targeted to STAT3 alone, or administration of the chemotherapeutic agent alone.

[0016] In some embodiments, the method results in an increase in progression-free survival and / or overall survival compared to administration of the immunomodulator alone, administration of an antisense compound targeted to STAT3 alone, or administration of a chemotherapeutic agent alone.

[0017] In some embodiments, the present disclosure provides a method of treating cancer in a patient, the method comprising administering to the patient: (a) about 50 mg / m2 to about 60 mg / m 2 Cisplatin; (b) about 1 mg / kg to about 20 mg / kg MEDI4736; and (c) about 200 mg to about 400 mg AZD9150.

[0018] In some embodiments, the method comprises administering about 60 mg / m 2 Cisplatin, about 10 mg / kg MEDI4736, and about 300 mg AZD9150.

[0019] In some embodiments, the present disclosure provides a pharmaceutical composition comprising: (a) a chemotherapeutic agent; and (b) an immunomodulatory agent, wherein the weight ratio of the chemotherapeutic agent and the immunomodulatory agent in the pharmaceutical composition is about 1:1 to about 1:4.

[0020] In some embodiments, the chemotherapeutic agent is cisplatin. In some embodiments, the immunomodulatory agent is an immune checkpoint inhibitor.

[0021] In some embodiments, the immunomodulator is selected from an anti-PD-L1 antibody or an antigen-binding fragment thereof; an anti-PD1 antibody or an antigen-binding fragment thereof; an anti-CTLA-4 antibody or an antigen-binding fragment thereof; and an OX-40 agonist.

[0022] In some embodiments, the immunomodulator is selected from MEDI4736, MPDL3280A, 2.7A4, AMP-714, MDX-1105, nivolumab, pembrolizumab, pidilizumab, BMS936559, MPDL3280A, tremelimumab, ipilimumab, and OX40L FP.

[0023] In some embodiments, the immunomodulator is an anti-PD-L1 antibody. In some embodiments, the anti-PD-L1 antibody is MEDI4736.

[0024] In some embodiments, the weight ratio of the chemotherapeutic agent to the immunomodulator in the pharmaceutical composition is about 1:2.

[0025] In some embodiments, the present disclosure provides a kit for treating cancer, comprising: (a) a chemotherapeutic agent; (b) an immunomodulatory agent; and (c) an antisense compound targeting STAT3.

[0026] In some embodiments, the chemotherapeutic agent is cisplatin. In some embodiments, the immunomodulator is an immune checkpoint inhibitor. In some embodiments, the immunomodulator is selected from an anti-PD-L1 antibody or an antigen-binding fragment thereof; an anti-PD1 antibody or an antigen-binding fragment thereof; an anti-CTLA-4 antibody or an antigen-binding fragment thereof; and an OX-40 agonist.

[0027] In some embodiments, the immunomodulator is selected from MEDI4736, MPDL3280A, 2.7A4, AMP-714, MDX-1105, nivolumab, pembrolizumab, pidilizumab, BMS936559, MPDL3280A, tremelimumab, ipilimumab, and OX40L FP.

[0028] In some embodiments, the immunomodulator is an anti-PD-L1 antibody. In some embodiments, the anti-PD-L1 antibody is MEDI4736.

[0029] In some embodiments, the antisense compound targeting STAT3 does not inhibit STAT1, STAT4 or STAT6. In some embodiments, the antisense compound targeting STAT3 is an antisense oligonucleotide. In some embodiments, the antisense compound targeting STAT3 is AZD9150.

[0030] In some embodiments, the chemotherapeutic agent is cisplatin, the immunomodulator is MEDI4736, and the antisense compound targeting STAT3 is AZD9150.

[0031] The present invention relates to the following technical solutions:

[0032] 1. A method of treating cancer in a patient, the method comprising administering to the patient:

[0033] a) About 50 mg / m 2 Up to about 70 mg / m 2 chemotherapeutic agents;

[0034] b) immunomodulators; and

[0035] c) Antisense compounds targeting STAT3.

[0036] 2. The method of Scheme 1, wherein the immunomodulator is an immune checkpoint inhibitor.

[0037] 3. The method of scheme 1 or 2, wherein the immunomodulator is selected from anti-PD-L1 antibody or an antigen-binding fragment thereof; anti-PD1 antibody or an antigen-binding fragment thereof; anti-CTLA-4 antibody or an antigen-binding fragment thereof; and OX-40 agonist.

[0038] 4. The method of any one of schemes 1 to 3, wherein the immunomodulator is selected from MEDI4736, MPDL3280A, 2.7A4, AMP-714, MDX-1105, nivolumab, pembrolizumab, pidilizumab, BMS936559, MPDL3280A, tremelimumab, ipilimumab and OX40L FP.

[0039] 5. The method of any one of schemes 1 to 3, wherein the immunomodulator is an anti-PD-L1 antibody.

[0040] 6. The method of Scheme 5, wherein the anti-PD-L1 antibody is MEDI4736.

[0041] 7. The method of any one of Schemes 1 to 6, wherein the antisense compound targeting STAT3 does not inhibit STAT1, STAT4 or STAT6.

[0042] 8. The method of any one of Schemes 1 to 7, wherein the antisense compound targeting STAT3 is an antisense oligonucleotide.

[0043] 9. The method of any one of Schemes 1 to 8, wherein the antisense compound targeting STAT3 is AZD9150.

[0044] 10. The method of any one of schemes 1 to 9, wherein the immunomodulator is MEDI4736 or an antigen-binding fragment thereof, and the antisense compound targeting STAT3 is AZD9150.

[0045] 11. The method of claim 10, comprising administering about 1 mg / kg to about 20 mg / kg of MEDI4736 or an antigen-binding fragment thereof.

[0046] 12. The method of claim 10, comprising administering about 200 mg to about 400 mg of AZD9150.

[0047] 13. The method of any one of Schemes 1 to 12, wherein the chemotherapeutic agent administered to the patient is cisplatin.

[0048] 14. The method of claim 13, comprising administering about 55 mg / m 2 Up to about 65 mg / m 2 Cisplatin.

[0049] 15. The method of scheme 14, comprising administering 60 mg / m 2 Cisplatin.

[0050] 16. The method of any one of schemes 1 to 15, wherein the cancer is selected from breast cancer, renal cancer, lung cancer, pancreatic cancer, colorectal cancer, hepatocellular carcinoma (HCC), head and neck cancer, and lymphoma.

[0051] 17. The method of Scheme 16, wherein the lung cancer is non-small cell lung cancer (NSCLC).

[0052] 18. The method of scheme 17, wherein the head and neck cancer is head and neck squamous cell carcinoma (HNSCC).

[0053] 19. The method of Scheme 18, wherein the lymphoma is diffuse large B-cell carcinoma (DLBCL).

[0054] 20. The method of any one of Schemes 1 to 19, wherein the patient has PD-L1 positive cancer.

[0055] 21. The method of Scheme 20, wherein the patient comprises cancer cells expressing PD-L1.

[0056] 22. The method of any one of schemes 1 to 21, wherein the chemotherapeutic agent, the immunomodulator, and the antisense compound targeting STAT3 are administered to the patient simultaneously in one treatment cycle.

[0057] 23. The method of any one of schemes 1 to 21, wherein in one treatment cycle, the chemotherapeutic agent is administered to the patient, followed by the immunomodulator and the antisense compound targeting STAT3.

[0058] 24. The method of any one of schemes 1 to 21, wherein in one treatment cycle, the chemotherapeutic agent and the immunomodulator are administered to the patient, followed by administration of the antisense compound targeting STAT3.

[0059] 25. The method of any one of schemes 1 to 21, wherein in one treatment cycle, the patient is administered a lower dose of the chemotherapeutic agent than the immunomodulator and the antisense compound targeted to STAT3.

[0060] 26. The method of claim 25, wherein in one treatment cycle, about 1 dose of the chemotherapeutic agent, about 2 to about 5 doses of the immunomodulator, and about 5 to about 20 doses of the antisense compound targeting STAT3 are administered to the patient.

[0061] 27. The method of any one of schemes 22 to 26, wherein the treatment cycle is one week, two weeks, three weeks, or four weeks.

[0062] 28. The method of any one of schemes 22 to 27, wherein the method comprises two to eight treatment cycles.

[0063] 29. The method of any one of schemes 1 to 28, wherein the method results in an increase in CD11b+ / Ly6C+ dendritic cells compared to administration of the immunomodulator alone, administration of the antisense compound targeted to STAT3 alone, or administration of the chemotherapeutic agent alone.

[0064] 30. The method of any one of schemes 1 to 28, wherein the method results in an increase in progression-free survival and / or overall survival compared to administration of the immunomodulator alone, administration of the antisense compound targeted to STAT3 alone, or administration of the chemotherapeutic agent alone.

[0065] 31. A method of treating cancer in a patient, the method comprising administering to the patient:

[0066] a) About 50 mg / m 2 About 60 mg / m 2 Cisplatin;

[0067] b) about 1 mg / kg to about 20 mg / kg MEDI4736; and

[0068] c) from about 200 mg to about 400 mg AZD9150.

[0069] 32. The method of claim 31, comprising administering about 60 mg / m 2 Cisplatin, about 10 mg / kg MEDI4736, and about 300 mg AZD9150.

[0070] 33. A pharmaceutical composition comprising:

[0071] a) chemotherapeutic agents; and

[0072] b) immunomodulators,

[0073] The weight ratio of the chemotherapeutic agent to the immunomodulator in the pharmaceutical composition is about 1:1 to about 1:4.

[0074] 34. The pharmaceutical composition of Scheme 33, wherein the chemotherapeutic agent is cisplatin.

[0075] 35. A pharmaceutical composition as described in Scheme 33 or 34, wherein the immunomodulator is an immune checkpoint inhibitor.

[0076] 36. The pharmaceutical composition of any one of schemes 33 to 35, wherein the immunomodulator is selected from an anti-PD-L1 antibody or an antigen-binding fragment thereof; an anti-PD1 antibody or an antigen-binding fragment thereof; an anti-CTLA-4 antibody or an antigen-binding fragment thereof; and an OX-40 agonist.

[0077] 37. The pharmaceutical composition of any one of schemes 33 to 36, wherein the immunomodulator is selected from MEDI4736, MPDL3280A, 2.7A4, AMP-714, MDX-1105, nivolumab, pembrolizumab, pidilizumab, BMS936559, MPDL3280A, tremelimumab, ipilimumab and OX40L FP.

[0078] 38. The pharmaceutical composition of any one of schemes 33 to 36, wherein the immunomodulator is an anti-PD-L1 antibody.

[0079] 39. The pharmaceutical composition of Scheme 38, wherein the anti-PD-L1 antibody is MEDI4736.

[0080] 40. The pharmaceutical composition of any one of schemes 33 to 39, wherein the weight ratio of the chemotherapeutic agent and the immunomodulator in the pharmaceutical composition is about 1:2.

[0081] 41. A kit for treating cancer, comprising:

[0082] a) chemotherapeutic agents;

[0083] b) immunomodulators; and

[0084] c) Antisense compounds targeting STAT3.

[0085] 42. A kit as described in Scheme 41, wherein the chemotherapeutic agent is cisplatin.

[0086] 43. A kit as described in Scheme 41 or 42, wherein the immunomodulator is an immune checkpoint inhibitor.

[0087] 44. The kit of any one of schemes 41 to 43, wherein the immunomodulator is selected from an anti-PD-L1 antibody or an antigen-binding fragment thereof; an anti-PD1 antibody or an antigen-binding fragment thereof; an anti-CTLA-4 antibody or an antigen-binding fragment thereof; and an OX-40 agonist.

[0088] 45. The kit of any one of schemes 41 to 44, wherein the immunomodulator is selected from MEDI4736, MPDL3280A, 2.7A4, AMP-714, MDX-1105, nivolumab, pembrolizumab, pidilizumab, BMS936559, MPDL3280A, tremelimumab, ipilimumab and OX40L FP.

[0089] 46. ​​The kit of any one of schemes 41 to 44, wherein the immunomodulator is an anti-PD-L1 antibody.

[0090] 47. The kit of claim 46, wherein the anti-PD-L1 antibody is MEDI4736.

[0091] 48. A kit as described in any of Schemes 41 to 47, wherein the antisense compound targeting STAT3 does not inhibit STAT1, STAT4 or STAT6.

[0092] 49. A kit as described in any one of Schemes 41 to 48, wherein the antisense compound targeting STAT3 is an antisense oligonucleotide.

[0093] 50. A kit as described in any one of Schemes 41 to 49, wherein the antisense compound targeting STAT3 is AZD9150.

[0094] 51. A kit as described in any of Schemes 41 to 50, wherein the chemotherapeutic agent is cisplatin, the immunomodulator is MEDI4736, and the antisense compound targeting STAT3 is AZD9150. BRIEF DESCRIPTION OF THE DRAWINGS

[0095] Figures 1A-1C Involving instance 1. Figure 1A Combination graphs showing low dose (5 mg / kg) cisplatin treatment in MC-38OVA mice. Figure 1BResults for each individual mouse tested are shown. Figure 1C Cisplatin exposure in mice at various time points after dosing is shown.

[0096] Figures 2A-2M Involving instance 2. Figures 2A-2D Results are shown for MC-38OVA mice treated with: PBS control ( Figure 2A ); cisplatin alone (7 days after tumor implantation) ( Figure 2B ); cisplatin (3 days after tumor implantation) and anti-PD-L1 antibody (7 days after tumor implantation) ( Figure 2C ); and cisplatin and anti-PD-L1 antibody (simultaneously 7 days after tumor implantation) ( Figure 2D ). Figure 2E Shown are the body weights of mice measured at various time points after tumor implantation and treatment. Figure 2F-2M Results are shown for MC-OVA mice treated with: PBS control ( Figure 2F ); control antisense oligonucleotide ( Figure 2G ); cisplatin alone (7 days after tumor implantation) ( Figure 2H ); cisplatin and anti-PD-L1 antibody (simultaneously 7 days after tumor implantation) ( Fig.2I ); STAT3 ASO and anti-PD-L1 antibody (simultaneously 7 days after tumor implantation) ( Fig.2I ); STAT3 ASO (3 days after implantation) and anti-PD-L1 antibody (7 days after tumor implantation) ( Figure 2J ); cisplatin (3 days after tumor implantation), STAT3 ASO and anti-PD-L1 antibody (simultaneously 7 days after tumor implantation) ( Figure 2K ); STAT3 ASO (3 days after tumor implantation), cisplatin and anti-PD-L1 antibody (simultaneously 7 days after tumor implantation) ( Figure 2L ); and cisplatin, anti-PD-L1 antibody (simultaneously 7 days after tumor implantation) ( Figure 2M ).

[0097] Figure 3A The efficacy of different treatments given to MC38-OVA mice implanted with tumors as described in the Examples herein is shown. Figure 3A Shows Figures 2A-2D and the average of the results in 2F-2M. Figure 3B Shown are the body weights of mice measured at various time points after tumor implantation and treatment.

[0098] Figure 4A Shown are mean tumor growth results after treatment of MC38 mice with vehicle, STAT3 ASO, anti-PD-L1 antibody, and STAT3 ASO and anti-PD-L1 antibody. Figure 4BShows Figure 4A The average individual results are shown in . Figure 4C Shown are the mean tumor growth results after treatment of MC38 mice with a control antibody, anti-PD-L1 antibody, STAT3 ASO alone, or a combination of anti-PD-L1 antibody and STAT3 ASO. Figure 4D Shows Figure 4D The average individual results are shown in . DETAILED DESCRIPTION

[0099] The present disclosure relates to methods of treating cancer in a patient.

[0100] In some embodiments, nucleic acid molecules (such as antisense oligonucleotides described herein) can hybridize with a target sequence (e.g., a DNA sequence or an RNA sequence). When a nucleic acid molecule in a single-stranded form can anneal to another nucleic acid molecule under suitable temperature and solution ionic strength conditions, the nucleic acid molecule is "hybridizable" or "hybridized" with the other nucleic acid molecule (such as cDNA, genomic DNA or RNA). In some embodiments, complementary nucleic acid molecules include, but are not limited to, antisense compounds and nucleic acid targets. In some embodiments, complementary nucleic acid molecules include, but are not limited to, polynucleotides and target nucleic acids.

[0101] Hybridization and washing conditions are known and are described in Sambrook et al., Molecular Cloning: A Laboratory Manual, 2nd ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor (1989), particularly in Chapter 11 and Table 11.1 thereof. Temperature and ionic strength conditions determine the "stringency" of hybridization. The stringency of hybridization conditions can be selected to provide selective formation or maintenance of a desired hybridization product of two complementary nucleic acid polynucleotides in the presence of other potential cross-reacting or interfering polynucleotides. Stringent conditions are sequence-dependent; typically, longer complementary sequences specifically hybridize at higher temperatures than shorter complementary sequences. Typically, stringent hybridization conditions are higher than the thermal melting point (T) of a specific polynucleotide at a determined ionic strength, chemical denaturant concentration, pH, and hybridization partner concentration. mIn some embodiments, the stringency of a hybridization reaction is about 5°C to about 10°C lower than the stringency of a hybridization reaction (i.e., the temperature at which 50% of the sequence hybridizes to a substantially complementary sequence). In general, nucleotide sequences having a higher percentage of G and C bases hybridize under more stringent conditions than nucleotide sequences having a lower percentage of G and C bases. In general, stringency can be increased by increasing the temperature, increasing the pH, decreasing the ionic strength, and / or increasing the concentration of chemical nucleic acid denaturants such as formamide, dimethylformamide, dimethyl sulfoxide, ethylene glycol, propylene glycol, and ethylene carbonate. Stringent hybridization conditions typically include a salt concentration or ionic strength of less than about 1 M, 500 mM, 200 mM, 100 mM, or 50 mM; a hybridization temperature greater than about 20°C, 30°C, 40°C, 60°C, or 80°C; and a chemical denaturant concentration greater than about 10%, 20%, 30%, 40%, or 50%. Because many factors can affect the stringency of hybridization, combinations of parameters may be more significant than the absolute value of any individual parameter.

[0102] Exemplary low stringency hybridization conditions (eg, corresponding to a T of 55°C) m ) includes 5X saline-sodium citrate buffer (SSC), 0.1% SDS, 0.25% milk, and no formamide; or 30% formamide, 5X SSC, and 0.5% SDS. Exemplary moderate stringency hybridization conditions (corresponding to a higher T of about 55°C to about 65°C) m ) include 40% formamide and 5X or 6X SCC. Exemplary high stringency hybridization conditions (corresponding to a maximum T above 65°C) m ) include 50% formamide and 5X or 6X SCC. Additional exemplary hybridization conditions include a buffer solution (e.g., phosphate, Tris, or HEPES buffer solution, having a buffer component of about 20 mM to 200 mM) at a pH of about 6.5 to 8.5 and having an ionic strength of about 20 mM to 200 mM, at a temperature of about 15° C. to 40° C. For example, the buffer may include a salt concentration of about 10 mM to about 1 M, about 20 mM to about 500 mM, about 30 mM to about 100 mM, about 40 mM to about 80 mM, or about 50 mM. Exemplary salts include NaCl, KCl, (NH 4 ) 2 SO 4 、Na 2 SO 4 , and CH 3 COONH 4 .

[0103] The term "complementary" is used to describe the relationship between nucleotide bases and / or polynucleotides that are capable of hybridizing to each other, for example, when the two nucleotide sequences are aligned in opposite directions, the nucleotide sequence of such a polynucleotide or one or more regions thereof matches the nucleotide sequence of another polynucleotide or one or more regions thereof. As described herein, nucleobase matching or complementary nucleobases include the following pairs: adenine (A) and thymine (T), adenine (A) and uracil (U), cytosine (C) and guanine (G), and 5-methylcytosine ( m C) and guanine (G). Complementary polynucleotides and / or nucleic acids do not need to have nucleobase complementarity at each nucleoside, and may include one or more nucleobase mismatches. Therefore, the disclosure also includes isolated polynucleotides complementary to sequences disclosed or used herein and those substantially similar nucleic acid sequences. The degree to which two polynucleotides have matching nucleobases can be represented from the "complementarity percentage" or "complementarity percentage". In certain embodiments, polynucleotides have 70%, at least 70%, 75%, at least 75%, 80%, at least 80%, 85%, at least 85%, 90%, at least 90%, 95%, at least 95%, 97%, at least 97%, 98%, at least 98%, 99%, or at least 99% or 100% complementarity with polynucleotides provided herein. In embodiments where two polynucleotides are "fully complementary" or "100% complementary", such polynucleotides have nucleobase matches at each nucleoside without any nucleobase mismatches.

[0104] Unless otherwise modified by the term "complete", as in "intact antibody", the term "antibody" as used herein also includes antibody fragments such as Fab, F(ab')2, Fv, scFv, Fd, dAb, and other antibody fragments that retain antigen binding function (e.g., the ability to bind to antigens such as CTLA-4, PD1, or PD-L1). Typically, such fragments will contain an antigen binding domain.

[0105] The term "mAb" refers to a monoclonal antibody. The antibodies disclosed herein may include, but are not limited to, all-natural antibodies; bispecific antibodies; chimeric antibodies; Fab, Fab', single-chain V region fragment (scFv); fusion polypeptides; and unconventional antibodies.

[0106] As used herein, the terms "sequence similarity" or "% similarity" and "sequence identity" or "% identity" refer to the degree of identity or correspondence between nucleic acid sequences or amino acid sequences. In the context of polynucleotides, "sequence similarity" can refer to nucleic acid sequences in which changes in one or more nucleotide bases result in substitution of one or more amino acids, but do not affect the functional properties of the protein encoded by the polynucleotide. "Sequence similarity" can also refer to modifications of polynucleotides, such as deletions or insertions of one or more nucleotide bases that do not substantially affect the functional properties of the resulting transcript. Therefore, it should be understood that the present disclosure does not only cover specific exemplary sequences. Methods for making nucleotide base substitutions and methods for determining retention of biological activity of encoded polypeptides are known.

[0107] In addition, the skilled artisan recognizes that similar polynucleotides encompassed by the present disclosure are also defined by their ability to hybridize under stringent conditions to the sequences exemplified herein. Similar polynucleotides disclosed herein have about 70%, at least about 70%, about 75%, at least about 75%, about 80%, at least about 80%, about 85%, at least about 85%, about 90%, at least about 90%, about 95%, at least about 95%, about 99%, at least about 99% or about 100% identity to the polynucleotides disclosed herein.

[0108] Sequence similarity can be determined by sequence alignment using methods known in the art, such as, for example, BLAST, MUSCLE, Clustal (including ClustalW and ClustalX), and T-Coffee (including variants such as, for example, M-Coffee, R-Coffee and Expresso).

[0109] In some embodiments, only specific portions of two or more polynucleotides or polypeptide sequences are compared to determine sequence identity. In some embodiments, only specific domains of two or more sequences are compared to determine sequence similarity. The comparison window can be a segment of at least 10 to more than 1000 residues, at least 20 to about 1000 residues, or at least 50 to 500 residues, in which these sequences can be compared and compared. Alignment methods for determining sequence identity are well known, and publicly available databases (such as BLAST) can be used for comparison. For example, in some embodiments, the algorithm of Karlin and Altschul, Proc Nat Acad Sci USA [Proceedings of the National Academy of Sciences of the United States] 87: 2264-2268 (1990) is used, and the "percentage identity" of two nucleotide sequences is determined as improved by Karlin and Altschul, Proc Nat Acad Sci USA [Proceedings of the National Academy of Sciences of the United States] 90: 5873-5877 (1993). Such algorithms are incorporated into BLAST programs, such as BLAST+ or NBLAST and XBLAST programs described in Altschul et al., J Mol Biol, 215:403-410 (1990). BLAST protein searches can be performed using programs such as the XBLAST program (score = 50, word length = 3) to obtain amino acid sequences homologous to the protein molecules of the present disclosure. In the case where there is a gap between the two sequences, a gap BLAST such as described in Altschul et al., Nucleic Acids Res, 25 (17): 3389-3402 (1997) can be used. When utilizing BLAST programs and gap BLAST programs, the default parameters of the respective programs (e.g., XBLAST and NBLAST) can be used.

[0110] In some embodiments, the polypeptide or polynucleotide has 70%, at least 70%, 75%, at least 75%, 80%, at least 80%, 85%, at least 85%, 90%, at least 90%, 95%, at least 95%, 97%, at least 97%, 98%, at least 98%, 99%, or at least 99%, or 100% sequence identity to a reference polypeptide or polynucleotide (or fragment of a reference polypeptide or polynucleotide) provided herein. In some embodiments, the polypeptide or polynucleotide has about 70%, at least about 70%, about 75%, at least about 75%, about 80%, at least about 80%, about 85%, at least about 85%, about 90%, at least about 90%, about 95%, at least about 95%, about 97%, at least about 97%, about 98%, at least about 98%, about 99%, at least about 99%, or about 100% sequence identity to a reference polypeptide or polynucleotide (or fragment of a reference polypeptide or nucleic acid molecule) provided herein.

[0111] As used herein, "dose" means a specified amount of a medicament provided in a single administration or within a specified period. In some embodiments, a dose can be administered in one, two or more boluses, tablets or injections. For example, in embodiments where subcutaneous administration is desired, the desired dose requires a volume that is not easily provided by a single injection, and therefore, two or more injections may be used to achieve the desired dose. In some embodiments, the medicament is administered over an extended period or continuously by infusion. The dose may be specified as the amount of the medicament per hour, per day, per week or per month.

[0112] As used herein, "parenteral administration" means administration by injection (e.g., bolus injection) or infusion. Parenteral administration includes subcutaneous administration (SC), intravenous administration (IV), intramuscular administration (IM), intraarterial administration (IA), intraperitoneal administration (IP), or intracranial administration (IC), such as intrathecal or intracerebroventricular administration.

[0113] In some embodiments, the present disclosure provides a method of treating cancer in a patient, the method comprising administering to the patient: (a) about 50 mg / m 2 Up to about 70 mg / m 2 (b) chemotherapeutic agents; (b) immunomodulatory agents; and (c) antisense compounds targeting STAT3.

[0114] As used herein, the term "chemotherapeutic agent" refers to a chemical compound that non-specifically reduces or inhibits the growth, proliferation and / or survival of cancer cells or cells that may become cancerous and thereby produce tumorigenic offspring. Such chemical compounds are generally directed against intracellular processes that are essential for cell growth or division and are therefore particularly effective against cancer cells, which typically grow and divide rapidly.

[0115] Non-limiting examples of chemotherapeutic agents include: oxazaphosphorines, such as, for example, cyclophosphamide and ifosfamide; nitrogen mustards, such as, for example, busulfan, chlorambucil, and melphalan; hydrazines, such as, for example, temozolomide; platinum-based agents, such as cisplatin, carboplatin, and oxaliplatin; topoisomerase I inhibitors, such as, for example, irinotecan and topotecan; topoisomerase II inhibitors, such as, for example, etoposide, teniposide, and anthracyclines, such as, for example, doxorubicin, daunorubicin, and idarubicin; vinca alkaloids, such as, for example, vincristine and vinblastine; taxanes, such as, for example, docetaxel and paclitaxel; anti-leukopenia agents, such as sedative agents, and sedative agents. Acids, such as methotrexate and pemetrexed; pyrimidine antagonists, such as cytarabine, 5-fluorouracil, gemcitabine, and capecitabine; purine analogs, such as 6-mercaptopurine, azathioprine, and cladribine; purine antagonists, such as fludarabine; ribonuclease reductase inhibitors, such as hydroxyurea; antibiotics, such as bleomycin, actinomycin D, and mitomycin; enzymes, such as L-asparaginase; proteasome inhibitors, such as bortezomib; tyrosine kinase inhibitors, such as imatinib, erlotinib, afatinib; and growth factor inhibitors, such as gefitinib, cetuximab, and bevacizumab. In some embodiments, the chemotherapeutic agent administered to the patient is a platinum-based agent. In some embodiments, the chemotherapeutic agent is cisplatin.

[0116] In general, cisplatin can be used to treat testicular cancer (e.g., metastatic testicular cancer), ovarian cancer (e.g., metastatic ovarian cancer), bladder cancer (e.g., advanced bladder cancer), head and neck cancer, esophageal cancer, small cell lung cancer and non-small cell lung cancer, breast cancer, cervical cancer, gastric cancer, prostate cancer, Hodgkin's lymphoma and non-Hodgkin's lymphoma, neuroblastoma, sarcoma, multiple myeloma, melanoma, and mesothelioma. The typical clinical dose of cisplatin is about 100 mg / m 2 , which may be administered once or in several divided doses during a treatment cycle. Common side effects associated with cisplatin may include nausea and vomiting, leading to weight loss; low blood cell counts; nephrotoxicity; ototoxicity; low blood levels of magnesium, calcium, and potassium; peripheral neuropathy; loss of appetite and taste changes; and hair loss.

[0117] Reducing the dose of cisplatin can advantageously reduce the side effects associated with cisplatin. In some embodiments, the method comprises administering to the patient less than 60 mg / m 2 In some embodiments, the method comprises administering to the patient about 50 mg / m 2 Up to about 70 mg / m 2 In some embodiments, the method comprises administering to the patient about 50 mg / m 2 Up to about 65 mg / m 2In some embodiments, the method comprises administering to the patient about 50 mg / m 2 About 60 mg / m 2 In some embodiments, the method comprises administering to the patient about 55 mg / m 2 About 60 mg / m 2 In some embodiments, the method comprises administering to the patient about 50 mg / m 2 , about 51mg / m 2 , about 52mg / m 2 , about 53mg / m 2 , about 54mg / m 2 , about 55mg / m 2 , about 56mg / m 2 , about 57mg / m 2 , about 58mg / m 2 , about 59mg / m 2 , about 60mg / m 2 , about 61mg / m 2 , about 62mg / m 2 , about 63mg / m 2 , about 64mg / m 2 , about 65mg / m 2 , about 66mg / m 2 , about 67mg / m 2 , about 68mg / m 2 , about 69mg / m 2 , or about 70 mg / m 2 Cisplatin. In some embodiments, administering cisplatin in combination with an immunomodulator and an antisense compound targeted to STAT3 allows for administration of cisplatin at a dose that reduces side effects compared to administration of cisplatin alone.

[0118] In some embodiments, cisplatin is administered to a patient in a single dose. In some embodiments, cisplatin is administered to a patient in multiple doses, for example, in 2 doses, 3 doses, 4 doses, 5 doses, 6 doses, 7 doses, 8 doses, 9 doses, 10 doses, or more than 10 doses. In some embodiments, cisplatin is administered via intraperitoneal administration (IP).

[0119] As used herein, "immunomodulator" refers to an agent that enhances an immune response (e.g., an anti-tumor immune response). An immunomodulator can be an antibody or an antigen-binding fragment thereof, a protein, a peptide, a small molecule, or a combination thereof. In some embodiments, an immunomodulator is an immune checkpoint inhibitor. As used herein, "immune checkpoint inhibitor" refers to an agent (i.e., an immune checkpoint agent) that inhibits blocking the immune system, such as a protein or peptide that attacks cancer cells. In some embodiments, immune checkpoint agents that block the immune system prevent the generation and / or activation of T cells. In some embodiments, immune checkpoint agents are cytotoxic T lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD1), or programmed death ligand 1 (PD-L1). PD-L1 and PD1 form a cell surface-bound ligand-receptor pair that, in healthy individuals, suppresses immune responses to prevent overreaction of the immune system. In some embodiments, cancer cells hijack normal PD-L1 / PD1 immune checkpoint mechanisms by overexpressing the ligand PD-L1 (which binds to PD1 on effector CD8T cells), thereby preventing T cells from establishing an immune response to cancer cells and / or tumors. PD-L1 is expressed at high frequencies in a wide range of cancers. Tumor PD-L1 overexpression is associated with poor prognosis in a variety of cancers (see, e.g., Hamid et al., Expert Opin Biol Ther 13(6):847-861, 2013).

[0120] In some embodiments, the immune checkpoint inhibitor inhibits the CTLA-4 pathway or the PD-L1 / PD1 pathway. In some embodiments, the immune checkpoint inhibitor is an antibody. In some embodiments, the immune checkpoint inhibitor comprises an antibody that inhibits CTLA-4, PD1, or PD-L1. Immunomodulators, immune checkpoint inhibitors, and examples thereof are provided, for example, in WO 2016 / 062722.

[0121] In some embodiments, the immune checkpoint inhibitor is an anti-PD-L1 antibody or a derivative or antigen-binding fragment thereof. In some embodiments, the anti-PD-L1 antibody or a derivative or antigen-binding fragment thereof selectively binds to a PD-L1 protein or a fragment thereof. Examples of anti-PD-L1 antibodies and derivatives and fragments thereof are described in, for example, WO 01 / 14556, WO 2007 / 005874, WO2009 / 089149, WO 2011 / 066389, WO 2012 / 145493; US 8,217,149, US 8,779,108, US2012 / 0039906, US2013 / 0034559, US2014 / 0044738, and US2014 / 0356353. In some embodiments, the anti-PD-L1 antibody is MEDI4736 (durvalumab), MDPL3280A, 2.7A4, AMP-814, MDX-1105, or atezolizumab (BMS-936559).

[0122] In some embodiments, the anti-PD-L1 antibody is MEDI4736. In some embodiments, the anti-PD-L1 antibody comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to any one of SEQ ID NO: 3-10. MEDI4736 is an anti-PD-L1 antibody that is selective for PD-L1 polypeptides and blocks the binding of PD-L1 to PD-1 and CD80 receptors. MEDI4736 can relieve PD-L1-mediated inhibition of human T-cell activation in vitro, and can further inhibit tumor growth in a xenograft model via a T-cell-dependent mechanism. MEDI4736 is further described in, for example, US 8,779,108. The fragment crystallizable (Fc) domain of MEDI4736 contains a triple mutation in the constant domain of the IgG1 heavy chain, which reduces binding to complement component C1q and Fcγ receptors responsible for mediating antibody-dependent cell-mediated cytotoxicity (ADCC).

[0123] In some embodiments, MEDI4736 or its antigen-binding fragment comprises a heavy chain and a light chain or a heavy chain variable region and a light chain variable region. In some embodiments, MEDI4736 or its antigen-binding fragment for use comprises a light chain variable region and a heavy chain variable region, the light chain variable region comprises an amino acid sequence of SEQ ID NO: 3, and the heavy chain variable region comprises an amino acid sequence of SEQ ID NO: 4. In some embodiments, MEDI4736 or its antigen-binding fragment comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a CDR1, CDR2 and CDR3 sequence defined by Kabat of SEQ ID NO: 5-7, and wherein the light chain variable region comprises a CDR1, CDR2 and CDR3 sequence defined by Kabat of SEQ ID NO: 8-10. One of ordinary skill in the art will be able to easily identify Chothia's, Abm's or other CDR definitions known to one of ordinary skill in the art. In some embodiments, MEDI4736 or an antigen-binding fragment thereof comprises the variable heavy chain and variable light chain CDR sequences of the 2.14H90PT antibody as described in WO2011 / 066389.

[0124] In some embodiments, the immune checkpoint inhibitor is an anti-PD-1 antibody or a derivative or antigen-binding fragment thereof. In some embodiments, the anti-PD-1 antibody selectively binds to the PD-1 protein or a fragment thereof. In some embodiments, the anti-PD1 antibody is nivolumab, pembrolizumab, pidilizumab, or MPDL3280A.

[0125] In some embodiments, the immune checkpoint inhibitor is an anti-CTLA-4 antibody or a derivative or antigen-binding fragment thereof. In an embodiment, the anti-CTLA-4 antibody selectively binds to the CTLA-4 protein or a fragment thereof. Examples of anti-CTLA-4 antibodies and their derivatives and fragments are described in, for example, US 6,682,736, US 7,109,003, US 7,123,281, US 7,411,057, US 7,807,797, US 7,824,679, US 8,143,379, US 8,491,895, and US 2007 / 0243184. In some embodiments, the anti-CTLA-4 antibody is tremelimumab or ipilimumab. In some embodiments, the anti-CTLA-4 antibody comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to any one of SEQ ID NO: 13-20.

[0126] In some embodiments, the immunomodulator is an OX40 agonist. OX40 is a tumor necrosis factor receptor (TNFR) mainly present in activated CD4+ and CD8+ T cells, regulatory T cells (Treg) and natural killer (NK) cells. Signaling by OX40 on activated CD4+ and CD8+ T cells leads to enhanced cytokine production, granzyme and perforin release, and expansion of effector and memory T cell pools. In addition, OX40 signaling on Treg cells inhibits the expansion of Treg, stops the induction of Treg and blocks Treg suppression function. See, for example, Paterson et al., Mol Immunol [Molecular Immunology] 24: 1281-1290, 1987; Mallet et al., EMBO J. [Journal of the European Molecular Biology Association] 9: 1063-1068, 1990; and Calderhead et al., J Immunol [Journal of Immunology] 151: 5261-5271, 1993. OX40 is also known in the art as CD134, ACT-4, and ACT-35. Examples of OX40 agonists are described in, for example, WO 2013 / 119202, WO 2013 / 130102, US 5,821,332, US 6,312,700, US 6,156,878, US 7,504,101, US 7,622,444, and US 7,959,925.

[0127] In some embodiments, the OX40 agonist is a ligand that specifically binds to the OX40 receptor. In some embodiments, the OX40 agonist increases the biological activity of the OX40 receptor. In some embodiments, the biological activity of the OX40 receptor is increased by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 100% or more. In some embodiments, the OX40 agonist is an anti-OX40 antibody. In some embodiments, the OX40 agonist is 9B12, or an antigen-binding fragment or derivative thereof, as described in Weinberg et al., J Immunother [Journal of Immunotherapy] 29: 575-585, 2006. In some embodiments, the OX40 agonist is a humanized OX40 antibody, as described by Morris et al., Mol Immunol [Molecular Immunology] 44 (12): 3112-3121, 2007. In some embodiments, the OX40 agonist comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to any one of SEQ ID NOs: 23, 25, or 26. In some embodiments, the OX40 agonist is an OX40 ligand fusion protein (OX40L FP). In some embodiments, the OX40L FP increases and / or enhances tumor-specific T cell immunity. In some embodiments, the OX40L FP comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to any one of SEQ ID NOs: 32, 34, or 36.

[0128] In some embodiments, about 0.1 mg / kg to about 20 mg / kg of immunomodulator is administered to the patient. In some embodiments, about 1 mg / kg to about 20 mg / kg of immunomodulator is administered to the patient. In some embodiments, about 5 mg / kg to about 15 mg / kg of immunomodulator is administered to the patient. In some embodiments, about 8 mg / kg to about 12 mg / kg of immunomodulator is administered to the patient. In some embodiments, about 10 mg / kg of immunomodulator is administered to the patient. In some embodiments, about 0.1mg / kg, about 0.5mg / kg, about 1mg / kg, about 2mg / kg, about 3mg / kg, about 4mg / kg, about 5mg / kg, about 6mg / kg, about 7mg / kg, about 8mg / kg, about 9mg / kg, about 10mg / kg, about 11mg / kg, about 12mg / kg, about 13mg / kg, about 14mg / kg, about 15mg / kg, about 16mg / kg, about 17mg / kg, about 18mg / kg, about 19mg / kg, or about 20mg / kg immunomodulator is administered to the patient. In some embodiments, immunomodulator is administered to the patient in a single dose. In some embodiments, immunomodulator is administered to the patient in multiple doses, for example, in 2 doses, 3 doses, 4 doses, 5 doses, 6 doses, 7 doses, 8 doses, 9 doses, 10 doses, or more than 10 doses. One skilled in the art will appreciate that the specific amounts and quantities of immunomodulator in each dose may be adjusted based on a variety of factors including, for example, the particular immunomodulator to be administered and the patient's age, disease progression, and / or interactions with the patient's other medications.

[0129] In some embodiments, the immunomodulator is MEDI4736. In some embodiments, the method includes administering a chemotherapeutic agent, about 0.1 mg / kg to about 20 mg / kg MEDI4736, and an antisense compound targeting STAT3 to the patient. In some embodiments, the method includes administering a chemotherapeutic agent, about 1 mg / kg to about 20 mg / kg MEDI4736, and an antisense compound targeting STAT3 to the patient. In some embodiments, the method includes administering a chemotherapeutic agent, about 3 mg / kg MEDI4736, and an antisense compound targeting STAT3 to the patient. In some embodiments, the method includes administering a chemotherapeutic agent, about 10 mg / kg MEDI4736, and an antisense compound targeting STAT3 to the patient. In some embodiments, the method includes administering a chemotherapeutic agent, about 20 mg / kg MEDI4736, and an antisense compound targeting STAT3 to the patient. In some embodiments, an immunomodulator is administered intraperitoneally. In some embodiments, both chemotherapeutic agents and immunomodulators are administered intraperitoneally. In some embodiments, chemotherapeutic agents and immunomodulators are co-administered intraperitoneally (i.e., in the same dosage form) chemotherapeutic agents and immunomodulators. In some embodiments, the chemotherapeutic agent and the immunomodulatory agent are administered separately (ie, each agent is in separate dosage forms) intraperitoneally.

[0130] As used herein, the term "antisense compound" means an oligomeric compound that can hybridize to a target nucleic acid, for example, by hydrogen bonding. Examples of antisense compounds include single-stranded and double-stranded compounds, such as antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), short hairpin RNAs (shRNAs), small nucleolar RNAs (snoRNAs), microRNAs (miRNAs), and partial duplexes (meroduplexes, mdRNAs), and satellite repeats.

[0131] "Antisense oligonucleotide" or "ASO" refers to a polynucleotide comprising a sequence complementary to a target nucleic acid or a region or segment thereof. In some embodiments, the ASO can specifically hybridize to a target nucleic acid or a region or segment thereof. In some embodiments, the ASO can affect RNA processing and / or regulate protein expression. In general, an ASO is a single-stranded oligonucleotide that binds to a single-stranded RNA to inactivate the RNA. In some embodiments, the ASO binds to the messenger RNA (mRNA) of a gene, thereby inactivating the gene. In some embodiments, the ASO binds to the transcription start site, translation start site, 5' non-translated sequence, 3' non-translated sequence, coding sequence, pre-mRNA sequence, mRNA splicing site, and / or intron / exon junction of the mRNA encoding the gene, thereby inactivating the gene. In some embodiments, the ASO comprises DNA, RNA, or a combination thereof. ASOs are further described in, for example, Goodchild, Methods Mol Biol 764: 1-15, 2011; Smith et al., Ann Rev Pharmacol Toxicol. 59: 605-630, 2019; and Stein et al., Mol Ther 25(5): 1069-1075, 2017.

[0132] As described herein, signal transducer and activator of transcription 3 (STAT3) is a known immunosuppressive transcription factor and master regulator that promotes tumorigenesis. In some embodiments, the antisense compound targeting STAT3 is an oligomeric compound that can specifically hybridize with a STAT3 target nucleic acid. In some embodiments, the antisense compound targeting STAT3 inhibits the transcription and / or translation of STAT3. Antisense compounds and antisense oligonucleotides (e.g., antisense compounds and antisense oligonucleotides targeting STAT3) are provided in, for example, WO 2016 / 062722.

[0133] Although STAT3 regulates immune suppression and participates in tumorigenesis, other members of the STAT family that may be similar to STAT3 in structure and / or sequence perform different functions. For example, STAT1 enhances inflammation and innate and adaptive immunity, triggering antiproliferative and proapoptotic responses in tumor cells in most cases. STAT4 has been shown to play a key role in anti-tumor T cell responses. H1 response, and STAT6 has been shown to play a role in interleukin 4-mediated growth inhibition and induction of apoptosis. See, for example, Gooch et al., Neoplasia [neoplasia] 4 (4): 324-331, 2002; Yu et al., Nat Rev Cancer [cancer nature review] 9 (11): 798-809, 2009; and Kamran et al., Biomed Res Int [International Biomedical Research] 2013: 421821, 2013. In some embodiments, the antisense compound targeting STAT3 does not hybridize with STAT1, STAT4 or STAT6. In some embodiments, the antisense compound targeting STAT3 does not inhibit STAT1, STAT4 or STAT6.

[0134] In certain embodiments, STAT3 target nucleic acid includes any nucleic acid encoding STAT3. In certain embodiments, STAT3 target nucleic acid includes a DNA sequence encoding STAT3, an RNA sequence transcribed from a DNA encoding STAT3 (including a genomic DNA comprising introns and exons), and an mRNA sequence encoding STAT3. Exemplary antisense compounds targeting STAT3, including antisense oligonucleotides, are described in, for example, WO 2000 / 061602, WO 2005 / 083124, WO 2012 / 135736, WO2014 / 070868, WO 2008 / 109494, and US2010 / 0298409. In certain embodiments, the antisense compounds targeting STAT3 are antisense oligonucleotides. In some embodiments, the antisense oligonucleotide comprises a nucleotide sequence that is at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or about 100% complementary to a portion or all of a nucleic acid encoding STAT3 (SEQ ID NO: 1). In some embodiments, the antisense oligonucleotide comprises a nucleotide sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or about 100% complementary to a portion or all of a nucleic acid encoding STAT3 (SEQ ID NO: 1).

[0135] In some embodiments, the antisense compound targeting STAT3 is AZD9150. The nucleotide sequence of AZD9150 is provided in SEQ ID NO: 2. In some embodiments, the antisense compound targeting STAT3 comprises a nucleotide sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 2.

[0136] In some embodiments, about 100 mg to about 500 mg of antisense compounds targeting STAT3 are administered to the patient. In some embodiments, about 200 mg to about 400 mg of antisense compounds targeting STAT3 are administered to the patient. In some embodiments, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, or about 500 mg of antisense compounds targeting STAT3 are administered to the patient. In some embodiments, antisense compounds targeting STAT3 are administered to the patient in a single dose. In some embodiments, antisense compounds targeting STAT3 are administered to the patient in multiple doses, for example, in 2 doses, 3 doses, 4 doses, 5 doses, 6 doses, 7 doses, 8 doses, 9 doses, 10 doses, or more than 10 doses. Those skilled in the art will appreciate that, in a manner similar to the immunomodulators described herein, the specific number of doses and amounts in each dose of the antisense compound targeting STAT3 can be adjusted based on a variety of factors (including, for example, the specific antisense compound to be administered and the age of the patient, disease progression, and / or interactions with other drugs of the patient). In some embodiments, the antisense compound targeting STAT3 is administered subcutaneously. In some embodiments, the antisense compound targeting STAT3 is administered subcutaneously, and the chemotherapeutic agent and immunomodulator are administered intraperitoneally as described herein.

[0137] In some embodiments, the antisense compound targeting STAT3 is AZD9150. In some embodiments, the method comprises administering to the patient a chemotherapeutic agent, an immunomodulator, and about 100 mg to about 500 mg of AZD9150. In some embodiments, the method comprises administering to the patient a chemotherapeutic agent, an immunomodulator, and about 200 mg to about 400 mg of AZD9150. In some embodiments, the method comprises administering to the patient a chemotherapeutic agent, an immunomodulator, and about 300 mg of AZD9150.

[0138] In some embodiments, the chemotherapeutic agent is cisplatin, the immunomodulator is MEDI4736, and the antisense compound targeting STAT3 is AZD9150. In some embodiments, the disclosure provides a method of treating cancer in a patient, the method comprising administering to the patient: (a) about 50 mg / m 2 About 60 mg / m 2Cisplatin; (b) about 1 mg / kg to about 200 mg / kg MEDI4736; and (c) about 200 mg to about 400 mg AZD9150. In some embodiments, the method comprises administering to the patient about 60 mg / kg 2 Cisplatin, about 10 mg / kg MEDI4736, and about 300 mg AZD9150. In some embodiments, administration of a combination of chemotherapeutic agents, immunomodulators, and antisense compounds targeting STAT3 as described herein results in an additive and / or synergistic effect. As used herein, the term "synergistic" refers to a combination therapy (e.g., a combination of cisplatin, MEDI4736, or an antigen-binding fragment thereof, and AZD9150 as described herein) that is more effective than the additive effects of a single therapy.

[0139] The synergistic effect of the combination therapy (e.g., a combination of cisplatin, MEDI4736, or an antigen-binding fragment thereof, and AZD9150 as described herein) can allow the use of lower doses of one or more therapeutic agents to cancer patients and / or the administration of the therapeutic agent to cancer patients at a lower frequency. The ability to utilize lower doses of therapeutic agents and / or to administer the therapy at a lower frequency reduces the toxicity associated with administering the therapy to a subject without reducing the efficacy of the therapy in the treatment of cancer. In addition, the synergistic effect can result in improved efficacy of the therapeutic agent in the management, treatment, or improvement of cancer. The synergistic effect of the combination of therapeutic agents can avoid or reduce adverse or unwanted side effects associated with the use of either monotherapy. The synergistic effect of the combination of therapeutic agents can also manifest itself as a reduction in tumor mass (or tumor regression). The synergistic effect of the combination of therapeutic agents can also manifest itself as a sustained reduction in tumor growth rate.

[0140] In some embodiments, the method includes administering chemotherapeutic agents, immunomodulators, and antisense compounds targeting STAT3 to the patient in one or more treatment cycles. In the context of cancer treatment, a "treatment cycle" refers to a treatment period (e.g., administration of one or more agents) repeated on a regular schedule, followed by a rest period (no treatment). For example, one week of treatment can be followed by a three-week rest period, which is a treatment cycle. In some embodiments, a treatment cycle is about 1 day to about 3 months. In some embodiments, a treatment cycle is about 5 days to about 1 month. In some embodiments, a treatment cycle is about 1 week to about 3 weeks. In some embodiments, a treatment cycle is about 1 day, about 3 days, about 1 week, about 10 days, about 2 weeks, about 3 weeks, about 4 weeks, about 2 months, about 3 months, or about 100 days. In some embodiments, the rest period in a treatment cycle is about 1 day to about 1 month. In some embodiments, the rest period in a treatment cycle is about 1 day, about 3 days, about 5 days, about 1 week, about 2 weeks, about 3 weeks, or about 4 weeks.

[0141] A "course of treatment" includes multiple treatment cycles, which can be repeated on a regular schedule or adjusted to a gradually decreasing schedule based on the disease progression of the monitored patient. For example, at the beginning of a course of treatment (e.g., when the patient is first diagnosed), the patient's treatment cycle may have a longer treatment period and / or a shorter rest period, and as the cancer gradually eases, the rest period is extended, thereby increasing the length of a treatment cycle. During the entire course of treatment, the technician can determine and adjust the treatment period and rest period in a treatment cycle, the number of treatment cycles, and the length of the course of treatment based on the patient's disease progression, treatment tolerance, and prognosis. In some embodiments, the method includes 1 to 10 treatment cycles. In some embodiments, the method includes 2 to 8 treatment cycles.

[0142] In a treatment cycle, one or more therapeutic agents (e.g., chemotherapeutic agents, immunomodulators and / or antisense compounds) can be administered simultaneously or at different times during the treatment cycle. In some embodiments, in a treatment cycle, chemotherapeutic agents, immunomodulators, and antisense compounds targeting STAT3 are administered to the patient simultaneously. In some embodiments, the chemotherapeutic agent is cisplatin, the immunomodulator is MEDI4736, and the antisense compound targeting STAT3 is AZD9150, as described herein.

[0143] In some embodiments, a chemotherapeutic agent is administered to a patient followed by administration of an immunomodulator and an antisense compound targeting STAT3. In some embodiments, a chemotherapeutic agent is administered to a patient about 12 hours, about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 10 days, or about 2 weeks prior to administration of an immunomodulator and an antisense compound targeting STAT3.

[0144] In some embodiments, after the administration of chemotherapeutic agents, immunomodulators and antisense compounds targeting STAT3 are administered simultaneously. In some embodiments, immunomodulators and antisense compounds targeting STAT3 are administered at different time points, for example, in any order (e.g., administration of immunomodulators, followed by administration of antisense compounds targeting STAT3, or administration of antisense compounds targeting STAT3, followed by administration of immunomodulators), each spaced about 10 minutes apart, about 30 minutes apart, 1 hour apart, about 2 hours apart, about 4 hours apart, about 8 hours apart, about 12 hours apart, about 1 day apart, about 2 days apart, about 3 days apart, about 4 days apart, about 5 days apart, about 6 days apart, about 1 week apart, about 10 days apart, or about 2 weeks apart. In some embodiments, chemotherapeutic agents are first administered, followed by immunomodulators, followed by administration of antisense compounds targeting STAT3. In some embodiments, chemotherapeutic agents are first administered, followed by administration of antisense compounds targeting STAT3, followed by administration of immunomodulators.

[0145] In some embodiments, chemotherapeutic agents and immunomodulators are administered to the patient, followed by administration of antisense compounds targeting STAT3. In some embodiments, chemotherapeutic agents and immunomodulators are administered simultaneously, followed by administration of antisense compounds targeting STAT3. In some embodiments, chemotherapeutic agents and immunomodulators are administered to the patient about 12 hours, about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 10 days, or about 2 weeks before administration of antisense compounds targeting STAT3. In some embodiments, chemotherapeutic agents and immunomodulators are administered at different time points, followed by administration of antisense compounds targeting STAT3, as described herein.

[0146] In some embodiments, chemotherapeutic agents and antisense compounds targeting STAT3 are administered to the patient, followed by immunomodulators. In some embodiments, chemotherapeutic agents and antisense compounds targeting STAT3 are administered simultaneously, followed by immunomodulators. In some embodiments, chemotherapeutic agents and antisense compounds targeting STAT3 are administered to the patient about 12 hours, about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 10 days, or about 2 weeks before the administration of immunomodulators. In some embodiments, chemotherapeutic agents and antisense compounds targeting STAT3 are administered at different time points, followed by immunomodulators, as described herein.

[0147] In some embodiments, a treatment cycle includes administering one or more doses of a chemotherapeutic agent, an immunomodulator, and / or an antisense compound targeting STAT3. In some embodiments, in a treatment cycle, a chemotherapeutic agent is administered at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10 doses. In some embodiments, in a treatment cycle, an immunomodulator is administered at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more than 20 doses. In some embodiments, in a treatment cycle, an antisense compound targeting STAT3 is administered at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more than 20 doses. In embodiments where multiple doses are administered, multiple doses may be administered multiple times per day and / or multiple times per week. For example, multiple doses may be administered about 1, 2, 3, 4, 5, or more than 5 days per week, and / or about 1, 2, 3, 4, 5, or more than 5 days per week.

[0148] In embodiments where at least two agents (e.g., a chemotherapeutic agent and an immunomodulatory agent, a chemotherapeutic agent and an antisense compound targeted to STAT3, an immunomodulatory agent and an antisense compound targeted to STAT3, or all of the above) are administered simultaneously and at least one of the agents is administered in multiple doses, it is understood that at least one of the multiple doses of such agent or agents is administered simultaneously with another agent or class of agents.

[0149] In some embodiments, in one treatment cycle, the patient is administered a chemotherapeutic agent at a lower dose than the immunomodulator and the antisense compound targeting STAT3. In some embodiments, in one treatment cycle, the patient is administered about 1 dose of the chemotherapeutic agent, about 1 to about 10 doses of the immunomodulator, and about 1 to about 20 doses of the antisense compound targeting STAT3. In some embodiments, in one treatment cycle, the patient is administered about 1 dose of the chemotherapeutic agent, about 2 to about 5 doses of the immunomodulator, and about 5 to about 20 doses of the antisense compound targeting STAT3. In some embodiments, in one treatment cycle, the patient is administered about 1 dose of the chemotherapeutic agent, about 4 doses of the immunomodulator, and about 15 doses of the antisense compound targeting STAT3.

[0150] Non-limiting examples of a treatment cycle include: a single dose of about 50 mg / m 2 Up to about 70 mg / m 2 About 1 mg / kg to about 20 mg / kg of a chemotherapeutic agent, such as cisplatin; about 1 mg / kg to about 20 mg / kg of an immunomodulator, such as MEDI4736, administered twice a week for 2 weeks; and about 200 mg to about 400 mg of an antisense compound targeting STAT3, such as AZD9150, administered 5 times a week for 3 weeks. In some embodiments, the chemotherapeutic agent is administered, for example, about 12 hours to about 2 weeks before the administration of the immunomodulator and / or the antisense compound targeting STAT3, as described herein.

[0151] In some embodiments, compared to the method of administering only one or only two agents, the methods provided herein (e.g., administering all three of a chemotherapeutic agent, an immunomodulator, and an antisense compound targeting STAT3) advantageously minimize direct T cell killing of chemotherapy, enhance antigen presentation, and / or promote T cell activation, thereby providing patients with safer and more effective treatment. In some embodiments, compared to administering a single immunomodulator, administering a single antisense compound targeting STAT3, administering a single chemotherapeutic agent, or administering a combination of any two of these agents (e.g., a chemotherapeutic agent and an immunomodulator, and or a chemotherapeutic agent and an antisense compound targeting STAT3), the methods provided herein result in an increase in CD11b+ / Ly6C+ dendritic cells. In some embodiments, CD11b+ / Ly6C+ cells inhibit IL-17 production. In some embodiments, the increase in CD11b+ / Ly6C+ cells inhibits tumor growth.

[0152] In some embodiments, compared to the method of only applying one or only two of these three agents, the methods provided herein result in enhanced CD4 T cell functionality. In some embodiments, compared to the method of only applying one or only two of these three agents, the methods provided herein result in an increase of 1.1 times, 1.2 times, 1.3 times, 1.4 times, 1.5 times, 1.6 times, 1.7 times, 1.8 times, 1.9 times, 2 times, or more than 2 times in interferon-γ (IFNγ) levels in patients. In some embodiments, compared to the method of only applying one or only two of these three agents, the methods provided herein result in an increase of 1.1 times, 1.2 times, 1.3 times, 1.4 times, 1.5 times, 1.6 times, 1.7 times, 1.8 times, 1.9 times, 2 times, or more than 2 times in interleukin-2 (IL-2) levels in patients.

[0153] In some embodiments, compared with the method of only applying one or only two of these agents, the methods provided herein result in enhanced natural killer (NK) cell functionality. In some embodiments, compared with the method of only applying one or only two of these three agents, the methods provided herein result in an increase of 1.1 times, 1.2 times, 1.3 times, 1.4 times, 1.5 times, 1.6 times, 1.7 times, 1.8 times, 1.9 times, 2 times, or more than 2 times in the patient's granzyme B+ level. In some embodiments, compared with the method of only applying one or only two of these three agents, the methods provided herein result in an increase of 1 times, 1.3 times, 1.5 times, 1.8 times, 2 times, 2.3 times, 2.5 times, 2.8 times, 3 times, 3.3 times, 3.5 times, 3.8 times, 4 times, 4.3 times, 4.5 times, 4.8 times, 5 times, 10 times, or more than 10 times in the patient's tumor necrosis factor alpha (TNFα) level.

[0154] In some embodiments, the patient suffers from cancer. In some embodiments, the cancer is breast cancer, including triple negative breast cancer; ovarian cancer, including serous ovarian cancer; renal cancer; lung cancer, including non-small cell lung cancer (NSCLC); pancreatic cancer; colorectal cancer; hepatocellular carcinoma (HCC); head and neck cancer, including squamous cell carcinoma (HNSCC); or lymphoma, including diffuse large B cell carcinoma (DLBCL) and Hodgkin's lymphoma. In some embodiments, cancer is non-small cell lung cancer (NSCLC), squamous cell carcinoma, adenocarcinoma, large cell carcinoma, adenosquamous carcinoma or sarcomatoid carcinoma. In some embodiments, cancer is head and neck squamous cell carcinoma (HNSCC). In some embodiments, cancer is diffuse large B cell carcinoma (DLBCL).

[0155] In some embodiments, the patient has a PD-L1 positive cancer. "PD-L1 positive" cancer means that cells in a cancer sample exhibit immunohistochemical staining for PD-L1. Based on the immune status of the tumor type and / or tumor environment, the positive level with biological or clinical significance may vary. In some embodiments, the patient comprises cancer cells expressing PD-L1. In some embodiments, when immunochemical assessment is used, at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or more cells in the patient's tumor are PD-L1 positive.

[0156] In some embodiments, compared with the use of a separate immunomodulator, the use of a separate antisense compound targeting STAT3, or the use of a separate chemotherapeutic agent, the methods provided herein result in an increase in progression-free survival and / or overall survival. As used herein, "progression-free survival" means the length of time during and after the treatment of a disease (such as cancer) during which the patient survives with the disease but the disease does not worsen. Progression-free survival can usually be determined by a skilled technician as, for example, the average value from a clinical trial of an appropriate scale. As used herein, "overall survival" means the length of time from the treatment of a disease (such as cancer) during which the patient diagnosed with the disease still survives. Overall survival can usually be determined as the average value from a clinical trial of an appropriate scale.

[0157] In some embodiments, the methods provided herein reduce and / or inhibit cancer tumor growth. The reduction in tumor growth can be measured, for example, by comparing the growth of the patient's tumor at baseline, for expected tumor growth, for expected tumor growth based on a large patient population, or for the tumor growth of a control population.

[0158] In some embodiments, tumor response is measured to determine the efficacy of treatment (e.g., methods provided herein). In some embodiments, tumor response is measured using immune-related response criteria (irRc), for example, as described in Wolchok et al., Cancer Therapy [cancer therapy] 15 (23): 7412-7420, 2009. In some embodiments, solid tumor response evaluation criteria (RECIST) are used to measure tumor response, for example, as described in Eisenhauer et al., Eur J Cancer [European Journal of Cancer] 45: 288-247, 2009. In some embodiments, at or after the 4th week, for example, at the 7th week, the 10th week, the 13th week, the 20th week, the 25th week, the 30th week, the 35th week, the 40th week, the 41st week, the 45th week, the 50th week, or the 52nd week, tumor response can be detected.

[0159] In certain embodiments, the patient achieves disease control (DC).Disease control can be complete response (CR), partial response (PR) or stable disease (SD). "Complete response" (CR) refers to the disappearance of all lesions (whether measurable or unmeasurable), and there are no new lesions.Confirmation can be obtained using repeated continuous assessments of no less than four weeks since the first record date.New unmeasurable lesions are excluded from CR. "Partial response" (PR) refers to that tumor load is reduced by more than 30% relative to baseline.Confirmation can be obtained using continuous repeated assessments of at least 4 weeks since the first record date. "Stable disease" (SD) indicates that a reduction in tumor load less than about 30% relative to baseline cannot be established, and an increase of 20% or more compared to the lowest point cannot be established.

[0160] In some embodiments, the present disclosure provides a pharmaceutical composition comprising: (a) a chemotherapeutic agent; and (b) an immunomodulator, wherein the weight ratio of the chemotherapeutic agent and the immunomodulator in the pharmaceutical composition is about 1:1 to about 1:4. In some embodiments, the weight ratio of the chemotherapeutic agent and the immunomodulator in the pharmaceutical composition is about 1:2. Chemotherapeutic agents and immunomodulators are described herein. In some embodiments, the chemotherapeutic agent is cisplatin. In some embodiments, the immunomodulator is MEDI4736 or a derivative or antigen binding fragment thereof. In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient, such as a tension modifier, a preservative, a solubilizer, a complexing agent, a dispersant, a buffer, or a combination thereof. In some embodiments, the pharmaceutical composition is suitable for administration to a patient. In some embodiments, the pharmaceutical composition is suitable for intraperitoneal administration to a patient.

[0161] In some embodiments, the disclosure further provides a first pharmaceutical composition as described herein, comprising: (a) a chemotherapeutic agent; and (b) an immunomodulator, wherein the weight ratio of the chemotherapeutic agent and the immunomodulator in the pharmaceutical composition is about 1:1 to about 1:4; and a second pharmaceutical composition comprising an antisense compound targeting STAT3. Antisense compounds targeting STAT3 are described herein. In some embodiments, the second pharmaceutical composition further comprises a pharmaceutically acceptable excipient, for example, as described herein. In some embodiments, the second pharmaceutical composition is suitable for subcutaneous administration to a patient. In some embodiments, the chemotherapeutic agent is cisplatin. In some embodiments, the immunomodulator is MEDI4736 or a derivative or antigen-binding fragment thereof. In some embodiments, the antisense compound targeting STAT3 is AZD9150. In some embodiments, the first and second pharmaceutical compositions are provided to patients in need of treatment. In some embodiments, the patient suffers from cancer. Different types of cancer are described herein.

[0162] In some embodiments, the disclosure further provides a kit for treating cancer, comprising: (a) a chemotherapeutic agent; (b) an immunomodulator; and (c) an antisense compound targeting STAT3. Chemotherapeutic agents, immunomodulators, and antisense compounds targeting STAT3 are described herein. In some embodiments, the chemotherapeutic agent is cisplatin. In some embodiments, the immunomodulator is MEDI4736 or a derivative or antigen binding fragment thereof. In some embodiments, the antisense compound targeting STAT3 is AZD9150.

[0163] In some embodiments, the kit includes a sterile container containing one or more therapeutic compositions; such containers can be boxes, ampoules, bottles, vials, tubes, bags, pouches, blister packs, or other suitable container forms known in the art. Such containers can be made of plastic, glass, laminated paper, metal foil, or other materials suitable for containing drugs.

[0164] In some embodiments, the kit further includes instructions for administering a chemotherapeutic agent (e.g., cisplatin), an immunomodulator (e.g., MEDI4736), and an antisense compound targeting STAT3 (e.g., AZD9150) to a subject with cancer. In some embodiments, the instructions include at least one of the following: a description of one or more therapeutic agents; a dosage schedule and administration for treating or preventing cancer or its symptoms; precautions; warning information; indications; contraindications; overdose information; adverse reactions; animal pharmacology; clinical studies; and / or references. These instructions can be printed directly on the container (when present), or applied to the container as a label, or as a separate page, brochure, card, or folder provided in the container or provided with the container.

[0165] All references cited herein, including patents, patent applications, articles, textbooks, etc. and references cited therein (to the same extent as if they had not already been cited), are hereby incorporated by reference in their entirety.

[0166] Examples

[0167] Example 1. Identification of Low-Dose Cisplatin Treatment

[0168] Low-dose cisplatin treatment (5 mg / kg, equivalent to approximately 60 mg / m 2 human dose) of antitumor activity. Figures 1A-1C The results in indicate that this dose produced maximal tumor growth inhibition.

[0169] Example 2. Antitumor activity of therapeutic combinations

[0170] The efficacy of different combinations and dosing schedules of cisplatin, anti-PD-L1 antibody, and STAT3 antisense oligonucleotide (ASO) were tested in the MC-38OVA mouse model, and the activity of cross-primed dendritic cells from tumor-draining lymph nodes was also evaluated in a co-culture assay using OTI / OTII T cells. The therapeutic combinations tested are shown in Table 1.

[0171] Table 1

[0172]

[0173]

[0174] Figures 2A-2D The results in 2F-2M show tumor growth after administration of the agents according to Table 1. The combination of cisplatin and anti-PD-L1 antibody ( Figure 2C and 2D ) had similar antitumor efficacy and compared with the PBS control ( Figure 2A ) or cisplatin alone ( Figure 2B ) has been improved compared to the Figure 2F-2M It was further shown that compared with PBS control or control ASO ( Figure 2F ), cisplatin alone ( Figure 2G ), and anti-PD-L1 antibodies ( Figure 2H ) or STAT3 ASO ( Fig.2I ) in combination with cisplatin, or with STAT3 ASO ( Fig.2I and 2J ) compared with the combination of cisplatin, anti-PD-L1 antibody, and STAT3 ASO ( Figure 2K-2M ) had the best performance in driving tumor regression. Figure 2E Shows the use Figures 2A-2D Body weights of mice treated with the indicated reagents.

[0175] Figure 3A Shows Figure 2A-2B A combined graph of the results in Figure 4. The "triple combination" of all three tested (i.e., the combination of cisplatin, anti-PD-L1 antibody, and STAT3 ASO) resulted in tumor stasis and greater anti-tumor efficacy compared to the combination of only two of these three agents. Figure 3B Combined graphs of weight changes associated with each treatment are shown.

[0176] Figures 4A-4D Additional data from experiments testing anti-PD-L1 antibodies and STAT3 ASOs, either alone or in combination, are shown in . Figure 4B Shown are tumor growth after treatment of MC38 mice with vehicle, STAT3 ASO, anti-PD-L1 antibody, and STAT3 ASO and anti-PD-L1 antibody. Figure 4A Shows Figure 4B The combination of data in . Figure 4D Shown is tumor growth after treatment of MC38 mice with a control antibody, anti-PD-L1 antibody, STAT3 ASO alone, or a combination of anti-PD-L1 antibody and STAT3 ASO. Figure 4C Shows Figure 4D The combination of data in .

[0177] Mice treated with the triple combination (i.e., a combination of cisplatin, anti-PD-L1 antibody, and STAT3 ASO) showed a 20% response rate, while all other treatment groups had a complete response of 0. Flow cytometry studies of mice treated with the triple combination showed enhanced CD4 T cell functionality (IFNγ increased 1.6x, p<0.001, and IL-2 increased 1.2x, p=0.001) and enhanced NK functionality (Granzyme B+ increased 1.3x, p<0.01; TNFα increased 4.3x, p<0.001).

[0178] sequence

[0179] SEQ ID NO: 1 corresponds to the nucleotide sequence of a nucleic acid encoding STAT3 as described in the Examples herein.

[0180] SEQ ID NO: 2 corresponds to the nucleotide sequence of AZD9150 which is an antisense compound targeted to STAT3 as described in the Examples herein.

[0181] SEQ ID NOs: 3-10 correspond to the amino acid sequence of MEDI4736, which is an anti-PD-L1 antibody as described in the Examples herein. SEQ ID NO: 3 corresponds to the amino acid sequence of the light chain variable region of MEDI4736. SEQ ID NO: 4 corresponds to the amino acid sequence of the heavy chain variable region of MEDI4736. SEQ ID NOs: 5-10 correspond to the CDRs of MEDI4736.

[0182] SEQ ID NO: 11 corresponds to the nucleotide sequence of a mouse STAT3 antisense oligonucleotide as described in the Examples herein.

[0183] SEQ ID NO: 12 corresponds to the nucleotide sequence of a control antisense oligonucleotide as described in the Examples herein.

[0184] SEQ ID NOs: 13-20 correspond to the amino acid sequence of tremelimumab, an anti-CTLA-4 antibody as described in the Examples herein.

[0185] SEQ ID NO:21 corresponds to the amino acid sequence of the CTLA-4 protein as described in the Examples herein.

[0186] SEQ ID NO:22 corresponds to the amino acid sequence of the OX40 protein as described in the Examples herein.

[0187] SEQ ID NOs: 23-38 correspond to the amino acid sequences or nucleotide sequences of OX40 agonists as described in the Examples herein.

[0188] All references cited herein, including patents, patent applications, articles, textbooks, etc. and references cited therein (to the same extent as if they had not already been cited), are hereby incorporated by reference in their entirety.

Claims

1. A method of treating cancer in a patient, the method comprising administering to the patient: a) About 50 mg / m 2 About 70 mg / m 2 chemotherapeutic agents; b) immunomodulators; and c) Antisense compounds targeting STAT3.

2. The method of claim 1, wherein the immunomodulator is an immune checkpoint inhibitor.

3. The method of claim 1 or 2, wherein the immunomodulator is selected from an anti-PD-L1 antibody or an antigen-binding fragment thereof; an anti-PD1 antibody or an antigen-binding fragment thereof; an anti-CTLA-4 antibody or an antigen-binding fragment thereof; and an OX-40 agonist.

4. The method of any one of claims 1 to 3, wherein the immunomodulator is selected from MEDI4736, MPDL3280A, 2.7A4, AMP-714, MDX-1105, nivolumab, pembrolizumab, pidilizumab, BMS936559, MPDL3280A, tremelimumab, ipilimumab, and OX40L FP.

5. The method of any one of claims 1 to 3, wherein the immunomodulator is an anti-PD-L1 antibody.

6. The method of claim 5, wherein the anti-PD-L1 antibody is MEDI4736.

7. The method of any one of claims 1 to 6, wherein the antisense compound targeted to STAT3 does not inhibit STAT1, STAT4 or STAT6.

8. The method of any one of claims 1 to 7, wherein the antisense compound targeted to STAT3 is an antisense oligonucleotide.

9. The method of any one of claims 1 to 8, wherein the antisense compound targeting STAT3 is AZD9150.

10. The method of any one of claims 1 to 9, wherein the immunomodulator is MEDI4736 or an antigen-binding fragment thereof, and the antisense compound targeting STAT3 is AZD9150.

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