Combination treatment

Abstract

To provide a method for treating cancer in a patient.SOLUTION: The methods comprise administering to the patients chemotherapeutic agents, immunomodulators, and antisense compounds targeted to STAT3.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present disclosure provides methods of treating cancer in a patient, comprising administering to the patient a chemotherapeutic agent, an immunomodulatory agent, and an antisense compound that targets STAT3. Also provided herein are compositions and kits for carrying out the methods provided herein. [Background technology]

[0002] Chemotherapy-immunotherapy ("chemo-IO") combinations are being explored as potentially powerful cancer treatment tools. For example, the combination of antisense compounds targeting the master immune regulator STAT3 with immunotherapeutic immunomodulators, such as immune checkpoint inhibitors, is described in U.S. Patent Application Publication No. 2009 / 022999. Immune responses mediated by immune checkpoint inhibition can be enhanced by the immunogenic effects of cytotoxic agents, which can increase tumor antigens as a result of direct tumor cell death. Chemo-IO combination strategies can minimize direct T-cell death caused by chemotherapy, enhance antigen presentation, and promote T-cell activation. Challenges associated with developing chemo-IO combination treatments may include finding effective combinations of agents and determining effective dosages and schedules, as drug combinations will likely impact patients differently than simply achieving the additive effects of each drug alone. Furthermore, because many current chemotherapeutic agents have numerous adverse side effects, a further challenge in development is increasing efficacy while reducing side effects of the combination therapy compared to each agent alone. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] International Publication No. 2016 / 062722 Brochure Summary of the Invention [Means for solving the problem]

[0004] In some embodiments, the disclosure provides a method of treating cancer in a patient, comprising administering to the patient: (a) about 50 mg / m 2 ~about 70mg / m 2 (b) a chemotherapeutic agent; and (c) an antisense compound that targets STAT3.

[0005] In some embodiments, the immunomodulatory agent is an immune checkpoint inhibitor. In some embodiments, the immunomodulatory agent is selected from an anti-PD-L1 antibody or antigen-binding fragment thereof; an anti-PD1 antibody or antigen-binding fragment thereof; an anti-CTLA-4 antibody or antigen-binding fragment thereof; and an OX-40 agonist. In some embodiments, the immunomodulatory agent 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 immunomodulatory agent is an anti-PD-L1 antibody. In some embodiments, the anti-PD-L1 antibody is MEDI4736.

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

[0007] In some embodiments, the immunomodulatory agent 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. 2 ~about 65mg / m 2 In some embodiments, the method comprises administering 60 mg / m cisplatin. 2 of 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 a treatment cycle, the chemotherapeutic agent, the immunomodulatory agent, and the antisense compound targeting STAT3 are administered to the patient simultaneously. In some embodiments, in a treatment cycle, the chemotherapeutic agent is administered to the patient before the immunomodulatory agent and the antisense compound targeting STAT3. In some embodiments, in a treatment cycle, the chemotherapeutic agent and the immunomodulatory agent are administered to the patient before the antisense compound targeting STAT3.

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

[0014] In some embodiments, the treatment cycle is 1 week, 2 weeks, 3 weeks, or 4 weeks. In some embodiments, the method comprises 2 to 8 treatment cycles.

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

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

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

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

[0019] In some embodiments, the present disclosure provides a pharmaceutical composition comprising: (a) a chemotherapeutic agent; and (b) an immunomodulatory agent, wherein the chemotherapeutic agent and the immunomodulatory agent are in the pharmaceutical composition in a weight ratio of 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 immunomodulatory agent is selected from an anti-PD-L1 antibody or antigen-binding fragment thereof; an anti-PD1 antibody or antigen-binding fragment thereof; an anti-CTLA-4 antibody or antigen-binding fragment thereof; and an OX-40 agonist.

[0022] In some embodiments, the immunomodulatory agent 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 immunomodulatory agent is an anti-PD-L1 antibody. In some embodiments, the anti-PD-L1 antibody is MEDI4736.

[0024] In some embodiments, the chemotherapeutic agent and the immunomodulatory agent are in the pharmaceutical composition in a weight ratio of 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 that targets STAT3.

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

[0027] In some embodiments, the immunomodulatory agent 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 immunomodulatory agent is an anti-PD-L1 antibody. In some embodiments, the anti-PD-L1 antibody is MEDI4736.

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

[0030] In some embodiments, the chemotherapeutic agent is cisplatin, the immunomodulatory agent is MEDI4736, and the antisense compound targeting STAT3 is AZD9150. [Brief explanation of the drawings]

[0031] [Figure 1] Figures 1A-1C relate to Example 1. Figure 1A shows a graph of combined low-dose (5 mg / kg) cisplatin treatment in MC-38 OVA mice. Figure 1B shows the results of individual mice tested. Figure 1C shows cisplatin exposure in mice at various time points after administration. [Figure 2]Figures 2A-2M relate to Example 2. Figures 2A-2D show the results of treatment of MC-38 OVA mice 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 simultaneous cisplatin and anti-PD-L1 antibody 7 days after tumor implantation (Figure 2D). Figure 2E shows the body weights of mice measured at various time points after tumor implantation and treatment. Figures 2F–2M show the results of treatment of MC-OVA mice with: PBS control (Figure 2F); control antisense oligonucleotide (Figure 2G); cisplatin alone 7 days after tumor inoculation (Figure 2H); simultaneous cisplatin and anti-PD-L1 antibody 7 days after tumor inoculation (Figure 2I); simultaneous STAT3 ASO and anti-PD-L1 antibody 7 days after tumor inoculation (Figure 2I); STAT3 ASO 3 days after inoculation and anti-PD-L1 antibody 7 days after tumor inoculation (Figure 2J); cisplatin 3 days after tumor inoculation, simultaneous STAT3 ASO and anti-PD-L1 antibody 7 days after tumor inoculation (Figure 2K); STAT3 ASO 3 days after tumor inoculation, simultaneous cisplatin and anti-PD-L1 antibody 7 days after tumor inoculation (Figure 2L); and simultaneous cisplatin and anti-PD-L1 antibody 7 days after tumor inoculation (Figure 2M). [Figure 3] Figure 3A shows the effectiveness of various treatments for tumor-implanted MC38-OVA mice described in embodiments herein. Figure 3A shows the average of the results from Figures 2A-2D and 2F-2M. Figure 3B shows the body weights of mice measured at various time points after tumor implantation and treatment. [Figure 4] Figure 4A shows the results of mean tumor growth in MC38 mice after treatment with vehicle, STAT3 ASO, anti-PD-L1 antibody, and STAT3 ASO and anti-PD-L1 antibody. Figure 4B shows the individual results averaged and presented in Figure 4A. Figure 4C shows the results of mean tumor growth in MC38 mice after treatment with control antibody, anti-PD-L1 antibody, STAT3 ASO alone, or the combination of anti-PD-L1 antibody and STAT3 ASO. Figure 4D shows the individual results averaged and presented in Figure 4D. DETAILED DESCRIPTION OF THE INVENTION

[0032] The present disclosure relates to methods of treating cancer in a patient.

[0033] In some embodiments, the nucleic acid molecules described herein, such as antisense oligonucleotides, can hybridize to a sequence of interest, such as a DNA sequence or an RNA sequence. A nucleic acid molecule is "hybridizable" or "hybridized" to another nucleic acid molecule, such as cDNA, genomic DNA, or RNA, if the single-stranded form of the nucleic acid molecule can anneal to the other nucleic acid molecule under appropriate conditions of temperature and solution ionic strength. 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.

[0034] Hybridization and washing conditions are known and are exemplified in Sambrook et al., Molecular Cloning: A Laboratory Manual, Second Edition, Cold Spring Harbor Laboratory Press, Cold Spring Harbor (1989), particularly Chapter 11 and Table 11.1 therein. Temperature and ionic strength conditions determine the "stringency" of hybridization. The stringency of hybridization conditions can be selected to achieve the selective formation or maintenance of a desired hybridization product of two complementary nucleic acid polynucleotides in the presence of other potentially cross-reactive or interfering polynucleotides. Stringent conditions are sequence-dependent; typically, longer complementary sequences will specifically hybridize at higher temperatures than shorter complementary sequences. Stringent hybridization conditions are usually determined by the thermal melting point (T) for a particular polynucleotide at a defined ionic strength, concentration of chemical denaturant, pH, and concentration of hybridization partner. m) (i.e., the temperature at which 50% of the sequence hybridizes to a substantially complementary sequence). Typically, a nucleotide sequence containing a higher percentage of G and C bases will hybridize under more stringent conditions than a nucleotide sequence containing a lower percentage of G and C bases. Typically, stringency can be increased by raising the temperature, increasing the pH, decreasing the ionic strength, and / or increasing the concentration of chemical nucleic acid denaturants (e.g., 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 of greater than about 20° C., 30° C., 40° C., 60° C., or 80° C.; and a chemical denaturing agent concentration of greater than about 10%, 20%, 30%, 40%, or 50%. Because many factors can affect hybridization stringency, the combination of parameters may be more important than the absolute value of any parameter alone.

[0035] For example, T of 55°C m Exemplary low stringency hybridization conditions, corresponding to a higher T of about 55°C to about 65°C, include 5x sodium citrate buffered saline (SSC), 0.1% SDS, 0.25% milk, and no formamide; or 30% formamide, 5x SSC, and 0.5% SDS. m Exemplary moderate stringency hybridization conditions include 40% formamide and 5x or 6x SCC. The highest T above 65°C mExemplary high stringency hybridization conditions corresponding to the above conditions include 50% formamide and 5x or 6x SCC. Further exemplary hybridization conditions include a buffer solution (e.g., a phosphate, Tris, or HEPES buffer solution having approximately 20 mM to 200 mM of buffer components) at a pH of approximately 6.5 to 8.5, an ionic strength of approximately 20 mM to 200 mM, and a temperature of approximately 15°C to 40°C. For example, the buffer may contain a salt at a concentration of approximately 10 mM to 1 M, approximately 20 mM to 500 mM, approximately 30 mM to 100 mM, approximately 40 mM to 80 mM, or approximately 50 mM. Exemplary salts include NaCl, KCl, (NH4)2SO4, Na2SO4, and CH3COONH4.

[0036] The term "complementary" is used to describe the relationship of nucleotide bases and / or polynucleotides that are capable of hybridizing to one another, e.g., 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, when the two nucleotide sequences are aligned in reverse orientation. Nucleobase matches or complementary nucleobases described herein 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 need not have nucleobase complementarity at every nucleoside and may contain one or more nucleobase mismatches. Thus, the present disclosure also includes isolated polynucleotides complementary to the sequences disclosed or used herein, as well as substantially similar nucleic acid sequences thereof. The degree to which two polynucleotides have matching nucleobases can be expressed in terms of "percent complementarity" or "percent complementary." In some embodiments, a 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%, at least 99%, or 100% complementarity with a polynucleotide provided herein. In embodiments where two polynucleotides are "fully complementary" or "100% complementary," the polynucleotides have a nucleobase match at every nucleoside without any nucleobase mismatches.

[0037] Unless specifically modified by the term "intact," as in "intact antibody," the term "antibody," as used herein, also includes antibody fragments, e.g., Fab, F(ab')2, Fv, scFv, Fd, dAb, and other antibody fragments, that retain antigen-binding function, e.g., the ability to bind to an antigen, such as CTLA-4, PD1, or PD-L1. Typically, such fragments include the antigen-binding domain.

[0038] The term "mAb" refers to a monoclonal antibody. Antibodies of the present disclosure may include, but are not limited to, whole natural antibodies; bispecific antibodies; chimeric antibodies; Fab, Fab', single-chain V-region fragments (scFv); fusion polypeptides; and unconventional antibodies.

[0039] 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 or amino acid sequences. In the context of polynucleotides, "sequence similarity" refers to nucleic acid sequences in which changes in one or more nucleotide bases result in the 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 that do not substantially affect the functional properties of the resulting transcript, such as the deletion or insertion of one or more nucleotide bases. Thus, it is understood that the present disclosure encompasses more than specific exemplary sequences. Methods for making nucleotide base substitutions are known, as are methods for determining retention of biological activity of the encoded polypeptide.

[0040] Moreover, one of skill in the art will recognize 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 of the present disclosure are 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% identical to the polynucleotides disclosed herein.

[0041] Sequence similarity can be determined by sequence alignment using methods known in the art, such as BLAST, MUSCLE, Clustal (including ClustalW and ClustalX), and T-Coffee (including variants such as M-Coffee, R-Coffee, and Expresso).

[0042] In some embodiments, only specific portions of two or more polynucleotide or polypeptide sequences are aligned to determine sequence identity. In some embodiments, only specific domains of two or more sequences are aligned to determine sequence similarity. The comparison window can be a segment of at least 10 to over 1000 residues, at least 20 to about 1000 residues, or at least 50 to 500 residues, over which sequences can be aligned and compared. Alignment methods for determining sequence identity are well known and can be performed using publicly available databases, such as BLAST. For example, in some embodiments, the "percent identity" of two nucleotide sequences is determined using the algorithm of Karlin and Altschul, Proc Nat Acad Sci USA 87:2264-2268 (1990), modified as in Karlin and Altschul, Proc Nat Acad Sci USA 90:5873-5877 (1993). Such an algorithm is incorporated into BLAST programs, for example, the 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 a program, for example, the XBLAST program, score=50, wordlength=3, to obtain amino acid sequences homologous to the protein molecules of the present disclosure. When gaps exist between the two sequences, Gapped BLAST can be used as described in Altschul et al., Nucleic Acids Res 25(17):3389-3402 (1997). When using BLAST and Gapped BLAST programs, the default parameters of the respective programs (e.g., XBLAST and NBLAST) can be used.

[0043] In some embodiments, a 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%, at least 99%, or 100% sequence identity to a reference polypeptide or polynucleotide (or a fragment of a reference polypeptide or polynucleotide) provided herein. In some embodiments, a 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 a fragment of a reference polypeptide or nucleic acid molecule) provided herein.

[0044] As used herein, "dose" refers to a specified amount of a pharmaceutical agent provided in a single administration or over a specified period of time. In some embodiments, a dose can be administered by 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 accommodated by a single injection, and therefore, the desired dose can be achieved using two or more injections. In some embodiments, a pharmaceutical agent is administered by infusion over an extended period of time, or continuously. A dose may be determined as the amount of pharmaceutical agent per hour, day, week, or month.

[0045] As used herein, "parenteral administration" means administration by injection (e.g., bolus injection) or infusion. Parenteral administration includes subcutaneous (SC), intravenous (IV), intramuscular (IM), intraarterial (IA), intraperitoneal (IP), or intracranial (IC), e.g., intrathecal or intraventricular administration.

[0046] In some embodiments, the disclosure provides a method of treating cancer in a patient, comprising administering to the patient: (a) about 50 mg / m 2 ~about 70mg / m 2 (b) a chemotherapeutic agent; and (c) an antisense compound that targets STAT3.

[0047] As used herein, the term "chemotherapeutic agent" refers to a compound that nonspecifically reduces or inhibits the growth and / or survival of cancer cells or cells that are likely to become cancerous and produce tumorigenic progeny. Such compounds are often directed against intracellular processes essential for cell growth or division and are therefore particularly effective against cancerous cells, which generally grow and divide rapidly.

[0048] Non-limiting examples of chemotherapeutic agents include: oxazaphosphorines, such as cyclophosphamide and ifosfamide; nitrogen mustards, such as busulfan, chlorambucil, and melphalan; hydrazines, such as temozolomide; platinum-based agents, such as cisplatin, carboplatin, and oxaliplatin; topoisomerase I inhibitors, such as irinotecan and topotecan; topoisomerase II inhibitors, such as etoposide, teniposide, and anthracyclines, such as doxorubicin, daunorubicin, and idarubicin; vinca alkaloids, such as vincristine and vinblastine; taxanes, such as docetaxel and paclitaxel; and folic acid substitutes. Antigen antagonists include 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, and 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.

[0049] 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 and non-small cell lung cancer, breast cancer, cervical cancer, gastric cancer, prostate cancer, Hodgkin's and non-Hodgkin's lymphoma, neuroblastoma, sarcoma, multiple myeloma, melanoma, and mesothelioma. A typical clinical dosage of cisplatin is about 100 mg / m 2which can be administered once or over several doses in a treatment cycle. Common side effects associated with cisplatin can include nausea and vomiting leading to weight loss; low blood counts; nephrotoxicity; ototoxicity; low blood levels of magnesium, calcium, and potassium; peripheral neuropathy; loss of appetite and taste changes; and hair loss.

[0050] Lowering the dosage of cisplatin can advantageously mitigate the side effects associated with cisplatin. In some embodiments, the method comprises administering cisplatin at a dose of 60 mg / m 2 In some embodiments, the method comprises administering less than about 50 mg / m cisplatin to the patient. 2 ~about 70mg / m 2 In some embodiments, the method comprises administering to the patient about 50 mg / m cisplatin. 2 ~about 65mg / m 2 In some embodiments, the method comprises administering to the patient about 50 mg / m cisplatin. 2 ~about 60mg / m 2 In some embodiments, the method comprises administering to the patient about 55 mg / m cisplatin. 2 ~about 60mg / m 2 In some embodiments, the method comprises administering to the patient about 50 mg / m cisplatin. 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 , approximately 62 mg / m 2 , about 63mg / m 2 , about 64mg / m 2 , about 65mg / m 2 , about 66mg / m 2 , about 67mg / m2 , about 68mg / m 2 , about 69mg / m 2 , or about 70 mg / m 2 In some embodiments, administering cisplatin in combination with an immunomodulatory agent and an antisense compound targeting STAT3 allows the cisplatin to be administered at a dose that reduces side effects compared to administering cisplatin alone.

[0051] 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, two doses, three doses, four doses, five doses, six doses, seven doses, eight doses, nine doses, ten doses, or more than ten doses. In some aspects, cisplatin is administered via intraperitoneal administration (IP).

[0052] As used herein, the term "immunomodulator" refers to an agent that enhances an immune response (e.g., an anti-tumor immune response). The immunomodulator can be an antibody or antigen-binding fragment thereof, a protein, a peptide, a small molecule, or a combination thereof. In some embodiments, the immunomodulator is an immune checkpoint inhibitor. As used herein, "immune checkpoint inhibitor" refers to an agent that inhibits a protein or peptide (i.e., an immune checkpoint agent) that blocks the immune system, for example, from attacking cancer cells. In some embodiments, an immune checkpoint agent that blocks the immune system prevents the generation and / or activation of T cells. In some embodiments, the immune checkpoint agent is cytotoxic T-cell-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 dampens the immune response in healthy individuals to prevent an overreaction of the immune system. In some embodiments, cancer cells hijack the normal PD-L1 / PD1 immune checkpoint mechanism by overexpressing PD-L1, a ligand that binds to PD1 on effector CD8 T cells, thereby preventing T cells from mounting an immune response against cancer cells and / or tumors. PD-L1 is frequently expressed in a wide range of cancers. Tumor PD-L1 overexpression correlates with poor prognosis in some cancers (see, e.g., Hamid et al., Expert Opin. Biol. Ther. 13(6):847-861, 2013).

[0053] 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. Immunomodulatory agents, immune checkpoint inhibitors, and examples thereof, are described, for example, in WO 2016 / 062722.

[0054] 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 the 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, WO 2009 / 089149, WO 2011 / 066389, WO 2012 / 145493; U.S. Patent No. 8,217,149; U.S. Patent No. 8,779,108; U.S. Patent Application Publication No. 2012 / 0039906; U.S. Patent Application Publication No. 2013 / 0034559; U.S. Patent Application Publication No. 2014 / 0044738; and U.S. Patent Application Publication No. 2014 / 0356353. In some embodiments, the anti-PD-L1 antibody is MEDI4736 (durvalumab), MDPL3280A, 2.7A4, AMP-814, MDX-1105, or atezolizumab (BMS-936559).

[0055] In some embodiments, the anti-PD-L1 antibody is MEDI4736. In some embodiments, the anti-PD-L1 antibody comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to any of SEQ ID NOs: 3-10. MEDI4736 is an anti-PD-L1 antibody that is selective for PD-L1 polypeptide and blocks PD-L1 binding to the PD-1 receptor and CD80 receptor. MEDI4736 can attenuate PD-L1-mediated suppression of human T cell activation in vitro and can further inhibit tumor growth in xenograft models via a T cell-dependent mechanism. MEDI4736 is further described, for example, in U.S. Patent No. 8,779,108. The fragment crystallizable (Fc) domain of MEDI4736 contains a triple mutation within the constant domain of the IgG1 heavy chain, which reduces binding to complement component C1q and Fcγ receptors, which are responsible for mediating antibody-dependent cell-mediated cytotoxicity (ADCC).

[0056] In some embodiments, MEDI4736 or an antigen-binding fragment thereof 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 an antigen-binding fragment thereof used comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 3 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 4. In some embodiments, MEDI4736 or an antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the Kabat-defined CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 5-7, and the light chain variable region comprises the Kabat-defined CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 8-10. One of skill in the art would be able to readily identify CDR definitions based on the Chothia definition, Abm definition, or other definitions known to those of skill in the art. In some embodiments, MEDI4736 or an antigen-binding fragment thereof comprises the heavy chain variable CDR sequences and the light chain variable CDR sequences of the 2.14H90PT antibody described in WO 2011 / 066389.

[0057] 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-PD-1 antibody is nivolumab, pembrolizumab, pidilizumab, or MPDL3280A.

[0058] In some embodiments, the immune checkpoint inhibitor is an anti-CTLA-4 antibody or a derivative or antigen-binding fragment thereof. In embodiments, the anti-CTLA-4 antibody selectively binds to the CTLA-4 protein or a fragment thereof. Examples of anti-CTLA-4 antibodies and derivatives and fragments thereof are described in, for example, U.S. Patent Nos. 6,682,736; 7,109,003; 7,123,281; 7,411,057; 7,807,797; 7,824,679; 8,143,379; 8,491,895; and U.S. Patent Application Publication No. 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 at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to any of SEQ ID NOs: 13-20.

[0059] In some embodiments, the immunomodulatory agent is an OX40 agonist. OX40 is a tumor necrosis factor receptor (TNFR) found primarily on activated CD4+ and CD8+ T cells, regulatory T cells (Tregs), and natural killer (NK) cells. Signaling through OX40 on activated CD4+ and CD8+ T cells enhances cytokine production, releases granzymes and perforin, and expands effector and memory T cell pools. OX40 signaling on Treg cells also inhibits Treg proliferation, shuts down Treg induction, and blocks Treg suppressive function. See, e.g., Paterson et al., Mol Immunol 24:1281-1290, 1987; Mallet et al., EMBO J 9:1063-1068, 1990; and Calderhead et al., J Immunol 151:5261-5271, 1993. OX40 is also known in the art as CD134, ACT-4, and ACT-35. Examples of OX40 agonists are described, for example, in WO 2013 / 119202; WO 2013 / 130102; U.S. Pat. No. 5,821,332; U.S. Pat. No. 6,312,700; U.S. Pat. No. 6,156,878; U.S. Pat. No. 7,504,101; U.S. Pat. No. 7,622,444; and U.S. Pat. No. 7,959,925.

[0060] 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 by Weinberg et al., J Immunother 29:575-585, 2006. In some embodiments, the OX40 agonist is a humanized OX40 antibody described by Morris et al., Mol Immunol 44(12):3112-3121, 2007. In some embodiments, the OX40 agonist comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to any 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 at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to any of SEQ ID NOs: 32, 34, or 36.

[0061] In some embodiments, about 0.1 mg / kg to about 20 mg / kg of an immunomodulatory agent is administered to a patient. In some embodiments, about 1 mg / kg to about 20 mg / kg of an immunomodulatory agent is administered to a patient. In some embodiments, about 5 mg / kg to about 15 mg / kg of an immunomodulatory agent is administered to a patient. In some embodiments, about 8 mg / kg to about 12 mg / kg of an immunomodulatory agent is administered to a patient. In some embodiments, about 10 mg / kg of an immunomodulatory agent is administered to a patient. In some embodiments, about 0.1 mg / kg, about 0.5 mg / kg, about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, or about 20 mg / kg of an immunomodulatory agent is administered to a patient. In some embodiments, the immunomodulatory agent is administered to a patient in a single dose. In some embodiments, the immunomodulatory agent is administered to a patient in multiple doses, for example, two doses, three doses, four doses, five doses, six doses, seven doses, eight doses, nine doses, ten doses, or more than ten doses. One of skill in the art will understand that the specific number of doses of immunomodulatory agent, and each dose, may be adjusted based on a variety of factors, including, for example, the particular immunomodulatory agent to be administered, the patient's age, the progression of the disease, and / or interactions with the patient's other medications.

[0062] In some embodiments, the immunomodulatory agent is MEDI4736. In some embodiments, the method comprises administering to the patient a chemotherapeutic agent, about 0.1 mg / kg to about 20 mg / kg of MEDI4736, and an antisense compound targeted to STAT3. In some embodiments, the method comprises administering to the patient a chemotherapeutic agent, about 1 mg / kg to about 20 mg / kg of MEDI4736, and an antisense compound targeted to STAT3. In some embodiments, the method comprises administering to the patient a chemotherapeutic agent, about 3 mg / kg of MEDI4736, and an antisense compound targeted to STAT3. In some embodiments, the method comprises administering to the patient a chemotherapeutic agent, about 10 mg / kg of MEDI4736, and an antisense compound targeted to STAT3. In some embodiments, the method comprises administering to the patient a chemotherapeutic agent, about 20 mg / kg of MEDI4736, and an antisense compound targeted to STAT3. In some embodiments, the immunomodulatory agent is administered intraperitoneally. In some embodiments, the chemotherapeutic agent and the immunomodulatory agent are both administered intraperitoneally. In some embodiments, the chemotherapeutic agent and the immunomodulatory agent are co-administered intraperitoneally (i.e., in the same dosage form). In some embodiments, the chemotherapeutic agent and the immunomodulatory agent are administered separately intraperitoneally (i.e., each agent is in a separate dosage form).

[0063] The term "antisense compound" as used herein refers to an oligomeric compound that can undergo hybridization to target nucleic acid, for example, via hydrogen bonding. Examples of antisense compounds include single-stranded and double-stranded compounds, such as antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), small hairpin RNAs (shRNAs), small nucleolar RNAs (snoRNAs), microRNAs (miRNAs), meroduplexes (mdRNAs), and satellite repeat sequences.

[0064] "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, an ASO is capable of specifically hybridizing to a target nucleic acid or a region or segment thereof. In some embodiments, an ASO can affect RNA processing and / or modulate protein expression. Generally, an ASO is a single-stranded oligonucleotide that binds to and inactivates single-stranded RNA. In some embodiments, an ASO inactivates a gene by binding to the messenger RNA (mRNA) for that gene. In some embodiments, an ASO inactivates a gene by binding to the transcription start site, translation start site, 5' untranslated sequence, 3' untranslated sequence, coding sequence, pre-mRNA sequence, mRNA splice site, and / or intron / exon junction of the mRNA encoding the gene. In some embodiments, the ASO can be 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.

[0065] As described herein, signal transducer and activator of transcription 3 (STAT3) is a transcription factor and master regulator of immunosuppression known to promote tumorigenesis. In some embodiments, antisense compounds targeting STAT3 are oligomeric compounds capable of specifically hybridizing to STAT3 target nucleic acids. In some embodiments, antisense compounds targeting STAT3 inhibit the transcription and / or translation of STAT3. For example, antisense compounds and antisense oligonucleotides targeting STAT3 are described, for example, in WO 2016 / 062722.

[0066] While STAT3 regulates immune suppression and is involved in tumorigenesis, other members of the STAT family, which may be similar in structure and / or sequence to STAT3, perform distinct functions. For example, STAT1 enhances inflammation and innate and adaptive immunity, triggering anti-proliferative and pro-apoptotic responses, mostly in tumor cells. STAT4 mediates anti-tumor T cell proliferation. H STAT3 has been shown to be important in the IL-1 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 4(4):324-331, 2002; Yu et al., Nat Rev Cancer 9(11):798-809, 2009; and Kamran et al., Biomed Res Int 2013:421-821, 2013. In some embodiments, antisense compounds targeting STAT3 do not hybridize to STAT1, STAT4, or STAT6. In some embodiments, antisense compounds targeting STAT3 do not inhibit STAT1, STAT4, or STAT6.

[0067] In some embodiments, STAT3 target nucleic acid includes any nucleic acid encoding STAT3. In some embodiments, STAT3 target nucleic acid includes DNA sequence encoding STAT3, RNA sequence transcribed from DNA encoding STAT3 (including genomic DNA including introns and exons), and 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; WO 2014 / 070868; WO 2008 / 109494 and US Patent Application Publication No. 2010 / 0298409. In some embodiments, the antisense compound targeting STAT3 is an antisense oligonucleotide. 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).

[0068] In some embodiments, the antisense compound targeted to STAT3 is AZD9150. The nucleotide sequence of AZD9150 is provided in SEQ ID NO: 2. In some embodiments, the antisense compound targeted to STAT3 comprises a nucleotide sequence at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO:2.

[0069] In some embodiments, about 100 mg to about 500 mg of an antisense compound targeting STAT3 is administered to a patient. In some embodiments, about 200 mg to about 400 mg of an antisense compound targeting STAT3 is administered to a 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 an antisense compound targeting STAT3 is administered to a patient. In some embodiments, the antisense compound targeting STAT3 is administered to a patient in a single dose. In some embodiments, the antisense compound targeting STAT3 is administered to the patient in multiple doses, for example, two doses, three doses, four doses, five doses, six doses, seven doses, eight doses, nine doses, ten doses, or more than ten doses. Those skilled in the art will appreciate that, in a manner similar to the immunomodulatory agents described herein, the specific number of doses of the antisense compound targeting STAT3, and each dose, may be adjusted based on various factors, including, for example, the specific antisense compound to be administered, the patient's age, disease progression, and / or interactions with other medications in 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 immunomodulatory agent, as described herein, are administered intraperitoneally.

[0070] In some embodiments, the antisense compound targeting STAT3 is AZD9150. In some embodiments, the method comprises administering to the patient a chemotherapeutic agent, an immunomodulatory agent, and about 100 mg to about 500 mg of AZD9150. In some embodiments, the method comprises administering to the patient a chemotherapeutic agent, an immunomodulatory agent, and about 200 mg to about 400 mg of AZD9150. In some embodiments, the method comprises administering to the patient a chemotherapeutic agent, an immunomodulatory agent, and about 300 mg of AZD9150.

[0071] In some embodiments, the chemotherapeutic agent is cisplatin, the immunomodulatory agent is MEDI4736, and the antisense compound targeting STAT3 is AZD9150. In some embodiments, the disclosure provides a method of treating cancer in a patient, comprising administering to the patient: (a) about 50 mg / m 2 ~about 60mg / m 2 (b) about 1 mg / kg to about 200 mg / kg of MEDI4736; and (c) about 200 mg to about 400 mg of AZD9150. In some embodiments, the method comprises administering about 60 mg / m 2 cisplatin, about 10 mg / kg MEDI4736, and about 300 mg AZD9150 to the patient. In some embodiments, the combined administration of a chemotherapeutic agent, an immunomodulatory agent, and an antisense compound targeting STAT3 described herein results in an additive and / or synergistic effect. As used herein, the term "synergistic effect" refers to a combination of therapies (e.g., a combination of cisplatin, MEDI4736 or an antigen-binding fragment thereof, and AZD9150 described herein) that is more effective than the additive effect of a single therapy.

[0072] A synergistic effect of a combination of therapies (e.g., the combination of cisplatin, MEDI4736 or an antigen-binding fragment thereof, and AZD9150 described herein) may allow for the use of lower dosages of one or more therapeutic agents and / or less frequent administration of the therapeutic agents to a patient with cancer. The ability to utilize lower dosages of therapeutic agents and / or administer the therapeutic agents less frequently reduces the toxicity associated with administering the therapeutic agents to a subject without reducing the effectiveness of the therapeutic agents in treating cancer. Synergy can also improve the effectiveness of the therapeutic agents in managing, treating, or ameliorating cancer. Synergy of a combination of therapeutic agents can avoid or reduce adverse or unwanted side effects associated with the use of either single therapy. A synergistic effect of a combination of therapeutic agents may also be manifested as a decrease in tumor mass (or tumor regression). A synergistic effect of a combination of therapeutic agents may also be manifested as a sustained decrease in tumor growth rate.

[0073] In some embodiments, the method comprises administering to a patient one or more treatment cycles of a chemotherapeutic agent, an immunomodulatory agent, and an antisense compound targeting STAT3. A "treatment cycle" in the context of cancer treatment refers to a period of treatment (e.g., administration of one or more agents) followed by a period of rest (no treatment), repeated on a regular schedule. For example, one treatment cycle may include one week of treatment followed by three weeks of rest. In some embodiments, a treatment cycle is from about one day to about three months. In some embodiments, a treatment cycle is from about five days to about one month. In some embodiments, a treatment cycle is from about one week to about three weeks. In some embodiments, a treatment cycle is from about one day, about three days, about one week, about ten days, about two weeks, about three weeks, about four weeks, about two months, about three months, or about 100 days. In some embodiments, the period of rest in a treatment cycle is from about one day to about one month. In some embodiments, the period of rest 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.

[0074] A "treatment course" includes multiple treatment cycles, which may be repeated on a regular schedule or adjusted as a tapering schedule as the patient's disease progression is monitored. For example, a patient's treatment cycle may have longer treatment periods and / or shorter rest periods at the beginning of the treatment course (e.g., when the patient is first diagnosed), and the length of a treatment cycle may be increased by lengthening the rest periods as the cancer enters remission. The duration of treatment and rest in a treatment cycle, the number of treatment cycles, and the length of the treatment course can be determined and adjusted throughout the treatment course by one skilled in the art 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.

[0075] In a treatment cycle, one or more therapeutic agents (e.g., a chemotherapeutic agent, an immunomodulatory agent, and / or an antisense compound) can be administered simultaneously or at different times during the treatment cycle. In some embodiments, a chemotherapeutic agent, an immunomodulatory agent, and an antisense compound targeting STAT3 are administered to a patient simultaneously in a treatment cycle. In some embodiments, as described herein, the chemotherapeutic agent is cisplatin, the immunomodulatory agent is MEDI4736, and the antisense compound targeting STAT3 is AZD9150.

[0076] In some embodiments, the chemotherapeutic agent is administered to the patient before the immunomodulatory agent and the antisense compound targeting STAT3, hi some embodiments, the chemotherapeutic agent is 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 immunomodulatory agent and the antisense compound targeting STAT3.

[0077] In some embodiments, after the administration of a chemotherapeutic agent, the immunomodulator and the antisense compound targeting STAT3 are administered simultaneously. In some embodiments, the immunomodulator and the antisense compound targeting STAT3 are administered in either order (e.g., the immunomodulator followed by the antisense compound targeting STAT3, or the antisense compound targeting STAT3 followed by the immunomodulator), at different times from each other, for example, about 10 minutes apart, about 30 minutes apart, about 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, the chemotherapeutic agent is administered first, followed by the immunomodulator, followed by the antisense compound targeting STAT3. In some embodiments, the chemotherapeutic agent is administered first, followed by an antisense compound targeting STAT3, followed by an immunomodulatory agent.

[0078] In some embodiments, the chemotherapeutic agent and immunomodulatory agent are administered to the patient before the antisense compound targeted to STAT3. In some embodiments, the chemotherapeutic agent and immunomodulatory agent are administered simultaneously before the administration of the antisense compound targeted to STAT3. In some embodiments, the chemotherapeutic agent and immunomodulatory agent 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 antisense compound targeted to STAT3. In some embodiments, the chemotherapeutic agent and immunomodulatory agent are administered at different times before the administration of the antisense compound targeted to STAT3, as described herein.

[0079] In some embodiments, the chemotherapeutic agent and the antisense compound targeting STAT3 are administered to the patient before the immunomodulatory agent. In some embodiments, the chemotherapeutic agent and the antisense compound targeting STAT3 are administered simultaneously, before the administration of the immunomodulatory agent. In some embodiments, the chemotherapeutic agent and the antisense compound 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 immunomodulatory agent. In some embodiments, the chemotherapeutic agent and the antisense compound targeting STAT3 are administered at different times before the administration of the immunomodulatory agent, as described herein.

[0080] In some embodiments, a treatment cycle comprises administering one or more doses of a chemotherapeutic agent, an immunomodulatory agent, and / or an antisense compound targeting STAT3. In some embodiments, the chemotherapeutic agent is administered 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10 doses in a treatment cycle. In some embodiments, the immunomodulatory agent is administered 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 a treatment cycle. In some embodiments, the antisense compound targeting STAT3 is administered 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 a treatment cycle. In embodiments in which multiple doses are administered, the multiple doses may be administered multiple times per day and / or multiple times per week, for example, multiple doses may be administered on about 1, 2, 3, 4, 5, or more than 5 days per week and / or on about 1, 2, 3, 4, 5, or more than 5 days per week.

[0081] In embodiments in which at least two agents (e.g., a chemotherapeutic agent and an immunomodulatory agent, a chemotherapeutic agent and an antisense compound targeting STAT3, an immunomodulatory agent and an antisense compound targeting STAT3, or all of the foregoing) are administered simultaneously and at least one of the agents is administered in multiple doses, it should be understood that at least one of the multiple doses of such agent is administered simultaneously with the other agent.

[0082] In some embodiments, a patient is administered a smaller dose of a chemotherapeutic agent than the immunostimulant and the antisense compound targeting STAT3 in a treatment cycle. In some embodiments, a patient is administered about 1 dose of a chemotherapeutic agent, about 1 to about 10 doses of an immunomodulatory agent, and about 1 to about 20 doses of an antisense compound targeting STAT3 in a treatment cycle. In some embodiments, a patient is administered about 1 dose of a chemotherapeutic agent, about 2 to about 5 doses of an immunomodulatory agent, and about 5 to about 20 doses of an antisense compound targeting STAT3 in a treatment cycle. In some embodiments, a patient is administered about 1 dose of a chemotherapeutic agent, about 4 doses of an immunomodulatory agent, and about 15 doses of an antisense compound targeting STAT3 in a treatment cycle.

[0083] Non-limiting examples of treatment cycles include: about 50 mg / m 2 ~about 70mg / m 2 a single dose of an immunomodulatory agent, such as cisplatin, at about 1 mg / kg to about 20 mg / kg, administered twice per week for two weeks; and an antisense compound targeting STAT3, such as AZD9150, at about 200 mg to about 400 mg, administered five times per week for three weeks. In some embodiments, the chemotherapeutic agent is administered about 12 hours to about two weeks before the immunomodulatory agent and / or antisense compound targeting STAT3, e.g., as described herein.

[0084] In some embodiments, the methods provided herein, e.g., administering all three of a chemotherapeutic agent, an immunomodulatory agent, and an antisense compound targeting STAT3, advantageously minimizes direct T cell death due to chemotherapy, enhances antigen presentation, and / or promotes T cell activation, thereby providing safer and more effective treatment for patients compared to administering only one or two of the agents. In some embodiments, the methods provided herein result in an expansion of CD11b+ / Ly6C+ dendritic cells compared to administering an immunomodulatory agent alone, an antisense compound targeting STAT3 alone, a chemotherapeutic agent alone, or a combination of any two of the agents, e.g., a chemotherapeutic agent and an immunomodulatory agent, and / or a chemotherapeutic agent and an antisense compound targeting STAT3. In some embodiments, CD11b+ / Ly6C+ cells suppress IL-17 production. In some embodiments, an expansion of CD11b+ / Ly6C+ cells inhibits tumor growth.

[0085] In some embodiments, the methods provided herein result in enhanced CD4 T cell function compared to methods administering only one or two of the three agents. In some embodiments, the methods provided herein result in a 1.1-fold, 1.2-fold, 1.3-fold, 1.4-fold, 1.5-fold, 1.6-fold, 1.7-fold, 1.8-fold, 1.9-fold, 2-fold, or more than 2-fold increase in interferon-γ (IFNγ) levels in a patient compared to methods administering only one or two of the three agents. In some embodiments, the methods provided herein result in a 1.1-fold, 1.2-fold, 1.3-fold, 1.4-fold, 1.5-fold, 1.6-fold, 1.7-fold, 1.8-fold, 1.9-fold, 2-fold, or more than 2-fold increase in interleukin-2 (IL-2) levels in a patient compared to methods administering only one or two of the three agents.

[0086] In some embodiments, the methods provided herein result in enhanced natural killer (NK) cell function compared to administering only one or two of the agents. In some embodiments, the methods provided herein result in a 1.1-fold, 1.2-fold, 1.3-fold, 1.4-fold, 1.5-fold, 1.6-fold, 1.7-fold, 1.8-fold, 1.9-fold, 2-fold, or greater than 2-fold increase in Granzyme B+ levels in a patient compared to administering only one or two of the three agents. In some embodiments, the methods provided herein result in a 1-fold, 1.3-fold, 1.5-fold, 1.8-fold, 2-fold, 2.3-fold, 2.5-fold, 2.8-fold, 3-fold, 3.3-fold, 3.5-fold, 3.8-fold, 4-fold, 4.3-fold, 4.5-fold, 4.8-fold, 5-fold, 10-fold, or greater than 10-fold increase in tumor necrosis factor alpha (TNFα) levels in a patient compared to administering only one or only two of the three agents.

[0087] In some embodiments, the patient has 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, the cancer is non-small cell lung cancer (NSCLC), squamous cell carcinoma, adenocarcinoma, large cell carcinoma, adenosquamous carcinoma, or sarcomatoid carcinoma. In some embodiments, the cancer is head and neck squamous cell carcinoma (HNSCC). In some embodiments, the cancer is diffuse large B-cell carcinoma (DLBCL).

[0088] In some embodiments, the patient has a PD-L1-positive cancer. A "PD-L1-positive" cancer means that cells in the cancer sample exhibit immunohistochemical staining for PD-L1. The level of positivity that is biologically or clinically significant may vary based on tumor type and / or the immune status of the tumor environment. In some embodiments, the patient comprises cancer cells that express PD-L1. In some embodiments, at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or more than 80% of the cells in the patient's tumor are PD-L1-positive, as assessed using immunochemistry.

[0089] In some embodiments, the methods provided herein result in increased progression-free survival and / or overall survival compared to administration of an immunomodulatory agent alone, an antisense compound targeting STAT3 alone, or a chemotherapeutic agent alone. As used herein, "progression-free survival" refers to the length of time during and after treatment for a disease, e.g., cancer, during which a patient lives with the disease but does not worsen. Progression-free survival can typically be determined by one of skill in the art, for example, as an average from appropriately sized clinical trials. As used herein, "overall survival" refers to the length of time from the start of treatment for a disease, e.g., cancer, that a patient diagnosed with the disease is still alive. Overall survival can typically be determined as an average from appropriately sized clinical trials.

[0090] In some embodiments, the methods provided herein reduce and / or inhibit cancer tumor growth. Reduction in tumor growth can be measured, for example, by comparison to the growth of the patient's tumor at baseline, comparison to expected tumor growth, comparison to expected tumor growth based on a large patient population, or comparison to tumor growth in a control population.

[0091] In some embodiments, tumor response is measured to determine the effectiveness of a treatment, e.g., a method provided herein. In some embodiments, tumor response is measured using the Immune-related Response Criteria (irRc), e.g., as described in Wolchok et al., Cancer Therapy 15(23):7412-7420, 2009. In some embodiments, tumor response is measured using the Response Evaluation Criteria in Solid Tumors (RECIST), e.g., as described in Eisenhauer et al., Eur J Cancer 45:288-247, 2009. In some embodiments, tumor response is detectable at 4 weeks or later, e.g., at 7 weeks, 10 weeks, 13 weeks, 20 weeks, 25 weeks, 30 weeks, 35 weeks, 40 weeks, 41 weeks, 45 weeks, 50 weeks, or 52 weeks.

[0092] In certain embodiments, patients achieve disease control (DC). Disease control can be a complete response (CR), partial response (PR), or stable disease (SD). A "complete response" (CR) refers to the disappearance of all lesions, whether measurable or not, and the absence of new lesions. Confirmation can be obtained using repeated consecutive assessments for at least four weeks from the date of first documentation. New non-measurable lesions preclude a CR. A "partial response" (PR) refers to a reduction in tumor burden of more than 30% compared to baseline. Confirmation can be obtained using repeated consecutive assessments for at least four weeks from the date of first documentation. A "stable disease" (SD) indicates failure to demonstrate a reduction in tumor burden of less than about 30% compared to baseline and failure to demonstrate an increase of 20% or more compared to the nadir.

[0093] In some embodiments, the present disclosure provides a pharmaceutical composition comprising (a) a chemotherapeutic agent; and (b) an immunomodulatory agent, wherein the chemotherapeutic agent and the immunomodulatory agent are present in the pharmaceutical composition in a weight ratio of about 1:1 to about 1:4. In some embodiments, the chemotherapeutic agent and the immunomodulatory agent are present in the pharmaceutical composition in a weight ratio of about 1:2. The chemotherapeutic agent and the immunomodulatory agent are described herein. In some embodiments, the chemotherapeutic agent is cisplatin. In some embodiments, the immunomodulatory agent 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 tonicity agent, a preservative, a solubilizing agent, a complexing agent, a dispersing agent, 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.

[0094] In some embodiments, the present disclosure further provides a first pharmaceutical composition described herein, comprising (a) a chemotherapeutic agent; and (b) an immunomodulatory agent, wherein the chemotherapeutic agent and the immunomodulatory agent are present in the pharmaceutical composition at a weight ratio of 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, e.g., 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 immunomodulatory agent 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 pharmaceutical composition and the second pharmaceutical composition are provided to a patient in need of treatment. In some embodiments, the patient has cancer. Various types of cancer are described herein.

[0095] In some embodiments, the present disclosure further provides a kit for treating cancer, comprising: (a) a chemotherapeutic agent; (b) an immunomodulator; and (c) an antisense compound targeting STAT3. The chemotherapeutic agent, immunomodulator, and antisense compound 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.

[0096] In some embodiments, the kits include a sterile container containing one or more therapeutic compositions, which may be a box, ampoule, bottle, vial, tube, bag, pouch, blister pack, or other suitable container known in the art. Such containers may be made of plastic, glass, laminated paper, metal foil, or other materials suitable for holding pharmaceuticals.

[0097] In some embodiments, the kit further comprises instructions for administering a chemotherapeutic agent (e.g., cisplatin), an immunomodulatory agent (e.g., MEDI4736), and an antisense compound targeting STAT3 (e.g., AZD9150) to a subject with cancer. In some embodiments, the instructions comprise at least one of the following: a description of the therapeutic agent; dosing regimen and administration for the treatment or prevention of cancer or its symptoms; cautions; warnings; indications; counter-indications; overdose information; adverse reactions; animal pharmacology; clinical studies; and / or references. The instructions, if present, may be printed directly on the container, or as a label affixed to the container, or as a separate sheet, pamphlet, card, or folder provided within or with the container.

[0098] All references cited herein, such as patents, patent applications, papers, and textbooks, and the references cited therein, to the extent that they have not already been cited, are incorporated herein by reference in their entirety. [Example]

[0099] Example 1. Identification of low-dose cisplatin treatment Cisplatin 5 mg / kg (approximately 60 mg / m 2 A low dose treatment of 100 mg / kg (equivalent to a human dose of 100 mg / kg) was tested in MC-38 OVA mice for antitumor activity. The results in Figures 1A-1C show that this dose resulted in the most tumor growth inhibition.

[0100] Example 2. Antitumor activity of therapeutic agent combinations Various combinations and dosing schedules of cisplatin, anti-PD-L1 antibody, and STAT3 antisense oligonucleotide (ASO) were tested for efficacy in the MC-38 OVA mouse model, and also to assess the activity of cross-primed dendritic cells derived from tumor-draining lymph nodes in a coculture assay with OTI / OTII T cells. The therapeutic combinations tested are shown in Table 1.

[0101] [Table 1]

[0102] The results in Figures 2A-2D and 2F-2M show tumor growth after administration of agents according to Table 1. The combination of cisplatin and anti-PD-L1 antibody (Figures 2C and 2D) had similar anti-tumor efficacy and was improved over the PBS control (Figure 2A) or cisplatin alone (Figure 2B). Figures 2F-2M further demonstrate that the combination of cisplatin, anti-PD-L1 antibody, and STAT3 ASO (Figures 2K-2M) had the best ability to induce tumor regression compared to the PBS control or control ASO (Figure 2F), cisplatin alone (Figure 2G), cisplatin in combination with anti-PD-L1 antibody (Figure 2H) or STAT3 ASO (Figure 2I), or anti-PD-L1 antibody in combination with STAT3 ASO (Figures 2I and 2J). Figure 2E shows the body weights of mice treated with the agents shown in Figures 2A-2D.

[0103] Figure 3A shows a graph combining the results from Figures 2A-2B. All three of the tested "triple combinations" (i.e., cisplatin, anti-PD-L1 antibody, and STAT3 ASO) resulted in tumor stasis and greater anti-tumor efficacy compared with combinations of only two of the three agents. Figure 3B shows a graph combining the weight change associated with each treatment.

[0104] Additional data from experiments testing anti-PD-L1 antibodies and STAT3 ASOs alone or in combination are shown in Figures 4A-4D. Figure 4B shows tumor growth in MC38 mice following treatment with vehicle, STAT3 ASO, anti-PD-L1 antibody, and STAT3 ASO and anti-PD-L1 antibody. Figure 4A shows the combined data from Figure 4B. Figure 4D shows tumor growth in MC38 mice following treatment with a control antibody, anti-PD-L1 antibody, STAT3 ASO alone, or the combination of anti-PD-L1 antibody and STAT3 ASO. Figure 4C shows the combined data from Figure 4D.

[0105] Triple-combination treated mice (i.e., the combination of cisplatin, anti-PD-L1 antibody, and STAT3 ASO) demonstrated a 20% response rate, while all other treatment groups had zero complete responses. Flow cytometry studies with triple-combination treated mice demonstrated enhanced CD4 T cell function (1.6x increased IFNγ, p<0.001, and 1.2x increased IL-2, p=0.001), and enhanced NK function (1.3x increased granzyme B+, p<0.01; 4.3x increased TNFα, p<0.001).

[0106] Sequence Listing SEQ ID NO: 1 corresponds to the nucleotide sequence of a nucleic acid encoding STAT3 described in embodiments herein.

[0107] SEQ ID NO: 2 corresponds to the nucleotide sequence of AZD9150, which is an antisense compound targeted to STAT3 described in embodiments herein.

[0108] SEQ ID NOs: 3-10 correspond to the amino acid sequence of MEDI4736, which is an anti-PD-L1 antibody described in embodiments 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.

[0109] SEQ ID NO: 11 corresponds to the nucleotide sequence of the mouse STAT3 antisense oligonucleotide described in the embodiments herein.

[0110] SEQ ID NO: 12 corresponds to the nucleotide sequence of the control antisense oligonucleotide described in the embodiments herein.

[0111] SEQ ID NOs: 13-20 correspond to the amino acid sequences of tremelimumab, which is an anti-CTLA-4 antibody described in embodiments herein.

[0112] SEQ ID NO: 21 corresponds to the amino acid sequence of the CTLA-4 protein described in the embodiments herein.

[0113] SEQ ID NO: 22 corresponds to the amino acid sequence of the OX40 protein described in embodiments herein.

[0114] SEQ ID NOs: 23 to 38 correspond to the amino acid or nucleotide sequences of the OX40 agonists described in the embodiments herein.

[0115] All references cited herein, such as patents, patent applications, papers, and textbooks, and the references cited therein, to the extent they have not already been cited, are incorporated herein by reference in their entirety.

Claims

1. 1. A method of treating cancer in a patient, comprising administering to said patient: a) Approximately 50mg / m ２ ~Approx. 70mg / m ２ and a chemotherapeutic agent; b) an immunomodulator; c) antisense compounds targeting STAT3; Administering

2. 10. The method of claim 1, wherein the immunomodulatory agent is an immune checkpoint inhibitor.

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

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

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

11. 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.

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

13. The method of any one of claims 1 to 12, wherein the chemotherapeutic agent administered to the patient is cisplatin.

14. Approximately 55mg / m ２ ~Approx. 65mg / m ２ 14. The method of claim 13, comprising administering cisplatin.

15. 60 mg / m ２ 15. The method of claim 14, comprising administering cisplatin.

16. The method of any one of claims 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.

17. 17. The method of claim 16, wherein the lung cancer is non-small cell lung cancer (NSCLC).

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

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

20. The method of any one of claims 1 to 19, wherein the patient has a PD-L1 positive cancer.

21. 21. The method of claim 20, wherein the patient comprises cancer cells that express PD-L1.

22. 22. The method of any one of claims 1 to 21, wherein in a treatment cycle, the chemotherapeutic agent, the immunomodulatory agent, and the antisense compound targeting STAT3 are administered simultaneously to the patient.

23. 22. The method of any one of claims 1 to 21, wherein in a treatment cycle, the chemotherapeutic agent is administered to the patient prior to the immunomodulatory agent and the antisense compound targeting STAT3.

24. 22. The method of any one of claims 1 to 21, wherein in a treatment cycle, the chemotherapeutic agent and the immunomodulatory agent are administered to the patient prior to the antisense compound targeting STAT3.

25. 22. The method of any one of claims 1 to 21, wherein the immunomodulatory agent and the chemotherapeutic agent are administered to the patient in a lower dose than the antisense compound targeted to STAT3 in a treatment cycle.

26. 26. The method of claim 25, wherein the patient is administered about 1 dose of the chemotherapeutic agent, about 2 to about 5 doses of the immunomodulatory agent, and about 5 to about 20 doses of the antisense compound targeted to STAT3 in a treatment cycle.

27. 27. The method of any one of claims 22 to 26, wherein the treatment cycle is 1 week, 2 weeks, 3 weeks, or 4 weeks.

28. 28. The method of any one of claims 22 to 27, comprising 2 to 8 treatment cycles.

29. 29. The method of any one of claims 1 to 28, which results in an expansion of CD11b+ / Ly6C+ dendritic cells compared to administration of the immunomodulatory agent alone, administration of the antisense compound targeting STAT3 alone, or administration of the chemotherapeutic agent alone.

30. 29. The method of any one of claims 1 to 28, which results in increased progression-free survival and / or overall survival compared to administration of the immunomodulatory agent alone, administration of the antisense compound targeting STAT3 alone, or administration of the chemotherapeutic agent alone.

31. 1. A method of treating cancer in a patient, comprising administering to said patient: a) Approximately 50mg / m ２ ~about 60mg / m ２ cisplatin; b) about 1 mg / kg to about 20 mg / kg of MEDI4736; and c) about 200 mg to about 400 mg of AZD9150 Administering

32. Approximately 60mg / m ２ cisplatin, about 10 mg / kg MEDI4736, and about 300 mg AZD9150.

33. a) a chemotherapeutic agent; and b) immunomodulators wherein said chemotherapeutic agent and said immunomodulatory agent are in said pharmaceutical composition in a weight ratio of about 1:1 to about 1:

4.

34. 34. The pharmaceutical composition of claim 33, wherein the chemotherapeutic agent is cisplatin.

35. 35. The pharmaceutical composition of claim 33 or 34, wherein the immunomodulatory agent is an immune checkpoint inhibitor.

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

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

38. The pharmaceutical composition of any one of claims 33 to 36, wherein the immunomodulatory agent is an anti-PD-L1 antibody.

39. 39. The pharmaceutical composition of claim 38, wherein the anti-PD-L1 antibody is MEDI4736.

40. 40. The pharmaceutical composition of any one of claims 33 to 39, wherein the chemotherapeutic agent and the immunomodulatory agent are present in the pharmaceutical composition in a weight ratio of about 1:

2.

41. (a) a chemotherapeutic agent; (b) an immunomodulator; and (c) Antisense compounds targeting STAT3 A kit for treating cancer, comprising:

42. 42. The kit of claim 41, wherein the chemotherapeutic agent is cisplatin.

43. 43. The kit of claim 41 or 42, wherein the immunomodulatory agent is an immune checkpoint inhibitor.

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

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

46. The kit of any one of claims 41 to 44, wherein the immunomodulatory agent is an anti-PD-L1 antibody.

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

48. 48. The kit of any one of claims 41 to 47, wherein the antisense compound that targets STAT3 does not inhibit STAT1, STAT4, or STAT6.

49. The kit of any one of claims 41 to 48, wherein the antisense compound targeted to STAT3 is an antisense oligonucleotide.

50. 50. The kit of any one of claims 41 to 49, wherein the antisense compound targeting STAT3 is AZD9150.

51. 51. The kit of any one of claims 41 to 50, wherein the chemotherapeutic agent is cisplatin, the immunomodulatory agent is MEDI4736, and the antisense compound targeting STAT3 is AZD9150.

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