WO2023192478A1 - Polythérapie avec des anticorps anti-il-8 et des anticorps anti-pd-1 pour le traitement du cancer - Google Patents

Polythérapie avec des anticorps anti-il-8 et des anticorps anti-pd-1 pour le traitement du cancer Download PDF

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WO2023192478A1
WO2023192478A1 PCT/US2023/016896 US2023016896W WO2023192478A1 WO 2023192478 A1 WO2023192478 A1 WO 2023192478A1 US 2023016896 W US2023016896 W US 2023016896W WO 2023192478 A1 WO2023192478 A1 WO 2023192478A1
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antibody
seq
weeks
set forth
variable region
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Vivek Kumar ARORA
Bruce Stuart FISCHER
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Bristol-Myers Squibb Company
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/244—Interleukins [IL]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A61K2039/507—Comprising a combination of two or more separate antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/55—Medicinal preparations containing antigens or antibodies characterised by the host/recipient, e.g. newborn with maternal antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL

Definitions

  • Antibodies of these new class of inhibitors include, e.g., ipilimumab (YERVOY®), which binds to and inhibits Cytotoxic T- Lymphocyte Antigen-4 (CTLA-4), and nivolumab and pembrolizumab (formerly lambrolizumab; USAN Council Statement, 2013), which bind specifically to the Programmed Death-1 (PD-1) receptor and block the inhibitory PD-1/PD-1 ligand pathway.
  • CTL-4 Cytotoxic T- Lymphocyte Antigen-4
  • nivolumab and pembrolizumab previously lambrolizumab; USAN Council Statement, 2013
  • a certain population of cancer patients are refractory to or relapse following treatment with these antibodies. Accordingly, novel therapies that target this patient population are desired.
  • a third anti-cancer agent such as (i) an antagonist of an inhibitory signal on T cells (e.g., an anti-CTLA-4 antibody) and/or (ii) an agonist of a co-stimulatory receptor, both of which result in amplifying antigen-specific T cell responses (immune checkpoint regulators).
  • a method of treating a solid tumor in a human subject comprising administering to the subject an effective amount of each of: (a) an anti-IL-8 antibody comprising CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID NO: 7, and CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID NO: 8; (b) an anti-PD-1 antibody comprising CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID NO: 17, and CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID NO: 18; and optionally (c) an anti-CTLA-4 antibody comprising CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID NO: 27, and CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence set forth in
  • the anti-IL-8 antibody is administered at a fixed dose of 2400 mg, 2600 mg, 2800 mg, 3000 mg, 3200 mg, 3400 mg, 3600 mg, 3800 mg, 4000 mg, 4800 mg, 5400, or 6000 mg, or a fixed dose of about 2400 mg, 2600 mg, 2800 mg, 3000 mg, 3200 mg, 3400 mg, 3600 mg, 3800 mg, 4000 mg, 4800 mg, 5400, or 6000 mg.
  • the anti-IL-8 antibody is administered at a fixed dose of 3600 mg.
  • the anti-IL-8 antibody is administered at a fixed dose of 5400 mg.
  • the anti-PD-1 antibody is administered at a dose of 0.5 mg/kg, 1.0 mg/kg, 1.5 mg/kg, 2 mg/kg, or 3 mg/kg, or a dose of about 0.5 mg/kg, 1.0 mg/kg, 1.5 mg/kg, 2 mg/kg, or 3 mg/kg, or at a fixed dose of 240 mg, 360 mg, or 480 mg.
  • the anti-PD-1 antibody is administered at a dose of 1 mg/kg.
  • the anti-PD-1 antibody is administered at a dose of 3 mg/kg.
  • the anti-PD-1 antibody is administered at a fixed dose of 480 mg.
  • the anti-CTLA-4 antibody is administered at a dose of 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, or 10 mg/kg or a dose of about 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, or 10 mg/kg, or at a fixed dose of 5 mg, 10 mg, 50 mg, 100 mg, 150 mg, 200 mg, 150 mg, 300 mg, 250 mg, 360 mg, 380 mg, or 400 mg.
  • the anti- CTLA-4 antibody is administered at a dose of 1 mg/kg.
  • the anti- CTLA-4 antibody is administered at a dose of 3 mg/kg.
  • the anti-IL-8 antibody and anti-PD-1 antibody are administered at the following doses: (a) 3600 mg or 5400 mg anti-IL-8 antibody; and (b) 1 mg/kg or 3 mg/kg anti-PD-1 antibody.
  • the anti-IL-8 antibody and anti-PD-1 antibody are administered at the following doses: (a) 3600 mg or 5400 mg anti-IL-8 antibody; and (b) 240 mg or 480 mg anti-PD-1 antibody.
  • the anti-IL-8 antibody, anti-PD-1 antibody, and anti-CTLA-4 antibody are administered at the following doses: (a) 3600 mg anti- IL-8 antibody; (b) 1 mg/kg anti-PD-1 antibody; and (c) 3 mg/kg anti-CTLA-4 antibody.
  • the anti-IL-8 antibody, anti-PD-1 antibody, and anti-CTLA-4 antibody are administered at the following doses: (a) 3600 mg anti-IL-8 antibody; (b) 3 mg/kg anti-PD-1 antibody; and (c) 1 mg/kg anti-CTLA-4 antibody.
  • the anti-IL-8 antibody is administered every week. In some embodiments, the anti-IL-8 antibody is administered every 2 weeks. In some embodiments, the anti-IL-8 antibody is administered every 3 weeks. In some embodiments, the anti-IL-8 antibody is administered every 4 weeks. In some embodiments, the anti-PD-1 antibody is administered every 2 weeks. In some embodiments, the anti-PD-1 antibody is administered every 3 weeks. In some embodiments, the anti-PD-1 antibody is administered every 4 weeks.
  • the anti-CTLA-4 antibody is administered every 3 weeks. In some embodiments, the anti-CTLA-4 antibody is administered every 6 weeks. In some embodiments, the anti-IL-8 antibody is administered every 2 weeks and anti-PD- 1 antibody is administered every 3 weeks. In some embodiments, the anti-IL-8 antibody is administered every 2 weeks and anti-PD-1 antibody is administered every 4 weeks. In some embodiments, the anti-IL-8 antibody is administered every 2 weeks, anti-PD-1 antibody is administered every 3 weeks, and the CTLA-4 antibody is administered every 3 weeks. In some embodiments, the anti-IL-8 antibody is administered at a fixed dose of 3600 mg every 2 weeks. In some embodiments, the anti-IL-8 antibody is administered at a fixed dose of 3600 mg every 3 weeks.
  • the anti-IL-8 antibody is administered at a fixed dose of 3600 mg every 4 weeks. In some embodiments, the anti-IL-8 antibody is administered at a fixed dose of 5400 mg every 2, 3, 4, 5 or 6 weeks. In some embodiments, the anti-IL-8 antibody is administered at a fixed dose of 5400 mg every 3 weeks. In some embodiments, the anti-IL-8 antibody is administered at a fixed dose of 5400 mg every 4 weeks. In some embodiments, the anti-PD-1 antibody is administered at a dose of 1 mg/kg every 3 weeks. In some embodiments, the anti-PD-1 antibody is administered at a dose of 3 mg/kg every 2 weeks. In some embodiments, the anti-PD-1 antibody is administered at a dose of 3 mg/kg every 3 weeks.
  • the anti-PD-1 antibody is administered at a dose of 480 mg every 4 weeks. In some embodiments, the anti-PD-1 antibody is administered at a dose of 360 mg every 3 weeks. In some embodiments, the anti-PD-1 antibody is administered at a dose of 240 mg every 2 weeks. In some embodiments, the anti- CTLA-4 antibody is administered at a dose of 1 mg/kg every 3 weeks. In some embodiments, the anti- CTLA-4 antibody is administered at a dose of 1 mg/kg every 6 weeks. In some embodiments, the anti-CTLA-4 antibody is administered at a dose of 3 mg/kg every 3 weeks. In some embodiments, the anti-CTLA-4 antibody is administered at a dose of 3 mg/kg every 6 weeks.
  • the method comprises at least one administration cycle, wherein the cycle is a period of about 3-24 weeks. In some embodiments, the method comprises at least one administration cycle, wherein the cycle is a period of 6 weeks or 42 days. In some embodiments, the method comprises at least one administration cycle, wherein the cycle is a period of 12 weeks or 84 days. In some embodiments, the method comprises at least one administration cycle, wherein the cycle is a period of 6 weeks or 12 weeks, and wherein the anti- IL-8 antibody is administered at a fixed dose of 3600 mg, every 2 weeks, the anti-PD-1 antibody is administered at a dose of 1 mg/kg, every 3 weeks, and the anti-CTLA-4 antibody is administered at a dose of 3 mg/kg, every 3 weeks.
  • the at least one administration cycle is followed by a maintenance phase comprising administering the anti-IL-8 antibody once every two weeks and the anti-PD-1 antibody once every four weeks.
  • the anti-IL-8 antibody is administered at a fixed dose ranging from 2400 mg to 2600 mg, 2600 mg to 2800 mg, from 2800 mg to 3000 mg, from 3000 mg to 3200 mg, from 3200 mg to 3400 mg, from 3400 mg to 3600 mg, from 3600 mg to 3800 mg, from 3800 mg to 4000mg, from 4000 mg to 4200 mg, from 4200 mg to 4400 mg, from 4400 to 4600 mg, from 4600 mg to 4800 mg, from 4800 mg to 5000 mg, from 5000 mg 5200 mg, from 5200 mg to 5400 mg, from 5400 mg to 5600 mg, from 5600 mg to 5800 mg, or from 5800 mg to 6000 mg, or at a fixed dose of 3600 mg, 3800 mg, 4000 mg, 4200 mg
  • the anti-IL-8 antibody is administered at a fixed dose of 3600 mg or 5400 mg every 2 weeks, or at a fixed dose of 3600 mg or 5400 mg every 3 weeks, and (b) the anti-PD-1 antibody is administered at a fixed dose of 240 mg, 480 mg, every 2 weeks, every 3 weeks, or every 4 weeks.
  • the method comprises at least one administration cycle, wherein the cycle is a period of 12 weeks or 84 days, and wherein the anti-IL-8 antibody is administered at a fixed dose of 3600 mg, every 2 weeks, the anti-PD-1 antibody is administered at a dose of 1 mg/kg, every 3 weeks, and the anti-CTLA-4 antibody is administered at a dose of 3 mg/kg, every 3 weeks, followed by a maintenance phase comprising administering the anti-IL-8 antibody at a fixed dose of 3600 mg, every 2 weeks and the anti-PD-1 antibody at a fixed dose of 480 mg every 4 weeks.
  • the baseline serum IL-8 level in the subject is above the lower limit of quantitation, for example, at least or greater than 10 pg/mL, 9 pg/mL, 8 pg/mL, 7 pg/mL, 6 pg/mL, 5 pg/mL, 4 pg/mL, 3 pg/mL, 2 pg/mL, or 1 pg/mL, as assessed by, e.g., ELISA (e.g., sandwich ELISA).
  • the baseline serum IL-8 level in the subject is > 10 pg/mL.
  • the baseline serum IL-8 level in the subject is > 5 pg/mL.
  • the cancer has progressed or relapsed after anti-PD-1 or anti-PD-L1 therapy.
  • anti-IL8 antibody, anti-PD-1 antibody, and/or anti-CTLA-4 antibody are formulated (together or separately) for intravenous administration.
  • the anti-IL-8 antibody, anti-PD-1 antibody, and/or anti-CTLA-4 antibody are administered in any order.
  • the methods described herein produce at least one therapeutic effect chosen from a reduction in size of a tumor, reduction in number of metastatic lesions over time, complete response, partial response, and stable disease.
  • the methods described herein produce at least one therapeutic effect chosen from prolonged survival, such as progress free survival or overall survival, optionally compared to another therapy or placebo.
  • the methods described herein are used to treat a solid tumor (e.g., a metastatic, recurrent, and/or unresectable tumor) is associated with a cancer selected from the group consisting of: melanoma, non-small cell lung carcinoma, renal cell carcinoma, triple negative breast cancer, colorectal cancer, pancreatic ductal adenocarcinoma, and hepatocellular carcinoma.
  • a solid tumor e.g., a metastatic, recurrent, and/or unresectable tumor
  • a cancer selected from the group consisting of: melanoma, non-small cell lung carcinoma, renal cell carcinoma, triple negative breast cancer, colorectal cancer, pancreatic ductal adenocarcinoma, and hepatocellular carcinoma.
  • the anti-IL-8 antibody comprises heavy chain and light chain variable region CDRs comprising the amino acid sequences set forth in SEQ ID NOs: 1-3 and 4- 6, respectively; heavy and light chain variable region sequences set forth in SEQ ID NOs: 7 and 8, respectively; or heavy and light chain sequences set forth in SEQ ID NOs: 9 and 10, respectively.
  • the anti-PD-1 antibody comprises heavy chain and light chain variable region CDRs comprising the amino acid sequences set forth in SEQ ID NOs: 11- 13 and 14-16, respectively; heavy and light chain variable region sequences set forth in SEQ ID NOs: 17 and 18, respectively; or heavy and light chain sequences set forth in SEQ ID NOs: 19 and 20, respectively.
  • the anti-CTLA-4 antibody comprises heavy chain and light chain variable region CDRs comprising the amino acid sequences set forth in SEQ ID NOs: 21-23 and 24-26, respectively; or heavy and light chain sequences set forth in SEQ ID NOs: 29 and 30, respectively.
  • a method of treating a solid tumor in a human subject comprising (i) determining the baseline serum IL-8 level in the human subject; (ii) if the human subject has a baseline serum IL-8 level of at least 5 pg/mL, administering to the subject an effective amount of each of (a) an anti-IL-8 antibody comprising CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID NO: 7, and CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID NO: 8, (b) an anti-PD-1 antibody comprising CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID NO: 17, and CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID NO: 18, and (c) an anti-CTLA-4 antibody comprising CDR1, CDR2, and CDR3 domains of the
  • the human subject has a baseline serum IL-8 level of at least 10 pg/mL. In some embodiments, the human subject has a baseline serum IL-8 level between 10 pg/mL and 50 pg/mL, between 10 pg/mL and 25 pg/mL, or less than or equal to 23 pg/mL.
  • a method of determining likelihood of response of a human subject having a solid tumor to a therapy containing an anti- PD-1 antibody comprising determining the baseline serum IL-8 level of the human subject; wherein the human subject is likely to respond to the therapy if the baseline serum IL-8 level is between 10 pg/mL and 50 pg/mL.
  • the human subject is likely to respond to the therapy if the baseline serum IL-8 level is between 10 pg/mL and 25 pg/mL. In some embodiments, the human subject is likely to respond to the therapy if the baseline serum IL-8 level is less than or equal to 23 pg/mL.
  • kits for treating a solid tumor in a human subject comprising at least one dose of an anti-IL-8 antibody comprising CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID NO: 7, and CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID NO: 8, at least one dose of an anti-PD-1 antibody comprising CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID NO: 17, and CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID NO: 18, at least one dose of an anti-CTLA-4 antibody comprising CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID NO: 27, and CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID NO: 28, and instructions for use.
  • an anti-IL-8 antibody comprising CDR
  • the anti-IL-8 antibody in the kit comprises heavy chain and light chain variable region CDRs comprising the amino acid sequences set forth in SEQ ID NOs: 1-3 and 4-6, respectively
  • the anti-PD-1 antibody in the kit comprises heavy chain and light chain variable region CDRs comprising the amino acid sequences set forth in SEQ ID NOs: 11-13 and 14-16, respectively
  • the anti-CTLA-4 antibody in the kit comprises heavy chain and light chain variable region CDRs comprising the amino acid sequences set forth in SEQ ID NOs: 21-23 and 24-26, respectively.
  • 1A-1D are KM-Plots of overall survival (OS) by IL-8 baseline quartiles (Q1 being the lowest quartile by serum IL-8 baseline level) in study CA209-067, for all treated subjects (FIG.1A), subjects treated with nivolumab (FIG.1B), subjects treated with ipilimumab (FIG. 1C), and subjects treated with a combination of nivolumab and ipilimumab (FIG.1D).
  • the analysis shows that baseline IL-8 is prognostic for OS.
  • FIGs.2A-2C are KM-Plots of overall survival (OS) by IL-8 baseline quartiles (Q1 being the lowest quartile by serum IL-8 baseline level) in study CA209-057, for all treated subjects (2A), subjects treated with nivolumab (2B), or subjects treated with Docetaxel (2C). The analysis shows that baseline IL-8 is prognostic for OS.
  • FIGs.3A-3C are KM-Plots of overall survival (OS) by IL-8 baseline quartiles (Q1 being the lowest quartile by serum IL-8 baseline level) in study CA209-017, for all treated subjects (A), subjects treated with nivolumab (B), or subjects treated with Docetaxel (C).
  • FIGs. 4A-4C are KM-Plots of overall survival (OS) by IL-8 baseline quartiles (Q1 being the lowest quartile by serum IL-8 baseline level) in study CA209-025, for all treated subjects (FIG.4A), subjects treated with nivolumab (FIG.4B), or subjects treated with Everolimus (FIG. 4C).
  • the analysis shows that baseline IL-8 is prognostic for OS.
  • FIG. 5 is a KM-Plot of overall survival (OS) by IL-8 baseline quartiles (Q1 being the lowest quartile by serum IL-8 baseline level) for all pooled subjects treated with nivolumab containing therapy only.
  • the analysis shows that baseline IL-8 is prognostic for OS.
  • F IG. 6 is a time-dependent receiver operating characteristic (ROC) curve analysis of 12- month OS for all nivo-based therapies combined across the four studies.
  • ROC receiver operating characteristic
  • FIG.7 is a KM-Plot of overall survival (OS) by IL-8 baseline tertile for all patients treated with nivolumab-containing therapy in CheckMate trials -038, -064, -063, -017, -057, - 016, -025, and -009.
  • Preliminary pan-tumor analysis showed that patients with elevated serum IL-8 at baseline have worse outcomes.
  • FIG.8 is a KM-Plot of overall survival (OS) by IL-8 baseline quartile for all patients treated with nivolumab-containing therapy in CheckMate trials -017, -057, -067, and -025.
  • Validated pan-tumor analysis confirmed reduced survival in patients with elevated serum IL-8 levels at baseline.
  • FIG.9 shows KM-Plots of overall survival (OS) by IL-8 baseline quartile for patients treated with nivolumab-containing therapy within each phase 3 trial pooled in FIG.8. Analysis by tumor type showed reduced survival in patients with elevated serum IL-8 levels at baseline.
  • FIG.10 shows ROC curve analyses of OS, PFS, or ORR, along with validated pooled baseline serum IL-8 data from patients treated with nivolumab-containing therapy in CheckMate trials -017, -057, -067, and -025.
  • Sensitivity is the true-positive rate, and 1-specificity is the false-positive rate, where “positivity” is defined as OS event (within 12 months) or PFS event (within 6 months) for 12-month OS or 6-month PFS, respectively, and responder for ORR.
  • Statistical analyses identifies a baseline serum IL-8 threshold below which patients were more likely to benefit from NIVO-based therapy.
  • FIG.11 shows OS ROC analysis of CheckMate-067 data to assess the relative association of OS with serum IL-8 levels at baseline, week 7, and change from baseline.
  • FIG.12 shows correlation of tumoral gene expression and circulating blood biomarkers with baseline serum IL-8 levels in patients with melanoma across six trials. In columns 1-3, darker, larger dots represent a higher positive correlation between serum IL-8 level and factor shown. In columns 4-7, darker, larger dots represent a higher negative correlation between serum IL-8 level and factor shown. A positive correlation was observed between tumoral CXCL8 mRNA and serum IL-8 level across tumor types.
  • FIGS.13A and 13B show correlative analyses in patients with melanoma using baseline serum IL-8 data dichotomized by IL-8 level ( ⁇ 23 pg/mL or > 23 pg/mL).
  • 13A Correlation between tumoral CXCL8 mRNA and baseline serum IL-8 level.
  • 13B Correlation between T-cell and IFN- ⁇ inflammatory gene signatures, respectively, and baseline serum IL-8 level.
  • FIG.14 shows the trial design for the randomized, double-blind assessment of anti-IL-8 antibody combination therapy.
  • FIG.15 shows the dosing schedule of anti-IL-8 antibody in combination with nivolumab and ipilimumab.
  • DETAILED DESCRIPTION Provided herein are methods of treatment of cancer with anti-IL-8 antibodies (e.g., HuMax-IL8) and anti-PD-1 antibodies (e.g., nivolumab) in patients. Definitions In order that the present description may be more readily understood, certain terms are first defined. Additional definitions are set forth throughout the detailed description.
  • the terms “IL-8” as used herein refers to interleukin-8, which is also referred to in the art as neutrophil-activating protein, neutrophil chemotactic factor, and T-cell chemotactic factor.
  • the term also refers to and includes any variants or isoforms which are naturally expressed by cells or are expressed by cells transfected with the IL-8 gene.
  • the term “antibody” as used to herein includes whole antibodies and any antigen binding fragments (i.e., “antigen-binding portions”) or single chains thereof.
  • An “antibody” refers, in one embodiment, to a glycoprotein comprising at least two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds, or an antigen binding portion thereof.
  • Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as V H ) and a heavy chain constant region.
  • V H heavy chain variable region
  • the heavy chain constant region is comprised of three domains, CH1, CH2 and CH3.
  • each light chain is comprised of a light chain variable region (abbreviated herein as V L ) and a light chain constant region.
  • the light chain constant region is comprised of one domain, CL.
  • the V H and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR).
  • CDR complementarity determining regions
  • FR framework regions
  • Each V H and V L is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.
  • the variable regions of the heavy and light chains contain a binding domain that interacts with an antigen.
  • the constant regions of the antibodies may mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (Clq) of the classical complement system.
  • Antibodies typically bind specifically to their cognate antigen with high affinity, reflected by a dissociation constant (K D ) of 10 -5 to 10 -11 M or less. Any K D greater than about 10 -4 M is generally considered to indicate nonspecific binding.
  • an antibody that "binds specifically" to an antigen refers to an antibody that binds to the antigen and substantially identical antigens with high affinity, which means having a K D of 10 -7 M or less, preferably 10 -8 M or less, even more preferably 5 x 10 -9 M or less, and most preferably between 10 -8 M and 10 -10 M or less, but does not bind with high affinity to unrelated antigens.
  • An antigen is "substantially identical" to a given antigen if it exhibits a high degree of sequence identity to the given antigen, for example, if it exhibits at least 80%, at least 90%, preferably at least 95%, more preferably at least 97%, or even more preferably at least 99% sequence identity to the sequence of the given antigen.
  • An immunoglobulin may be from any of the commonly known isotypes, including but not limited to IgA, secretory IgA, IgG and IgM.
  • the IgG isotype is divided in subclasses in certain species: IgG1, IgG2, IgG3 and IgG4 in humans, and IgG1, IgG2a, IgG2b and IgG3 in mice.
  • Immunoglobulins e.g., IgG1 exist in several allotypes, which differ from each other in at most a few amino acids.
  • Antibody includes, by way of example, both naturally occurring and non-naturally occurring antibodies; monoclonal and polyclonal antibodies; chimeric and humanized antibodies; human and nonhuman antibodies; wholly synthetic antibodies; and single chain antibodies.
  • An antibody can be part of an antibody multimer (or multimeric antibody), e.g., dimer, trimer, tetramer, pentamer and hexamer.
  • the term “monoclonal antibody,” as used herein, refers to an antibody that displays a single binding specificity and affinity for a particular epitope or a composition of antibodies in which all antibodies display a single binding specificity and affinity for a particular epitope. Accordingly, the term “human monoclonal antibody” refers to an antibody or antibody composition that display(s) a single binding specificity and which has variable and optional constant regions derived from human germline immunoglobulin sequences.
  • human monoclonal antibodies are produced by a hybridoma which includes a B cell obtained from a transgenic non-human animal, e.g., a transgenic mouse, having a genome comprising a human heavy chain transgene and a light chain transgene fused to an immortalized cell.
  • a "human” antibody refers to an antibody having variable regions in which both the framework and CDR regions are derived from human germline immunoglobulin sequences. Furthermore, if the antibody contains a constant region, the constant region also is derived from human germline immunoglobulin sequences.
  • the antibodies described herein may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo).
  • human antibody as used herein, is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.
  • human antibodies and “fully human” antibodies are used synonymously.
  • a “humanized” antibody refers to an antibody in which some, most or all of the amino acids outside the CDR domains of a non-human antibody are replaced with corresponding amino acids derived from human immunoglobulins.
  • a humanized form of an antibody some, most or all of the amino acids outside the CDR domains have been replaced with amino acids from human immunoglobulins, whereas some, most or all amino acids within one or more CDR regions are unchanged. Small additions, deletions, insertions, substitutions or modifications of amino acids are permissible as long as they do not abrogate the ability of the antibody to bind to a particular antigen.
  • a “humanized” antibody retains an antigenic specificity similar to that of the original antibody.
  • a “chimeric antibody” refers to an antibody in which the variable regions are derived from one species and the constant regions are derived from another species, such as an antibody in which the variable regions are derived from a mouse antibody and the constant regions are derived from a human antibody.
  • isotype refers to the antibody class (e.g., IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgD, and IgE antibody) that is encoded by the heavy chain constant region genes.
  • An “isolated antibody,” as used herein, is intended to refer to an antibody which is substantially free of other antibodies having different antigenic specificities.
  • Programmed Death-1 (PD-1) refers to an immunoinhibitory receptor belonging to the CD28 family. PD-1 is expressed predominantly on previously activated T cells in vivo, and binds to two ligands, PD-L1 and PD-L2.
  • PD-1 as used herein includes human PD-1 (hPD-1), variants, isoforms, and species homologs of hPD-1, and analogs having at least one common epitope with hPD-1.
  • the complete hPD-1 sequence can be found under GenBank Accession No. U64863.
  • "Programmed Death Ligand-1 (PD-L1)” is one of two cell surface glycoprotein ligands for PD-1 (the other being PD-L2) that down-regulate T cell activation and cytokine secretion upon binding to PD-1.
  • PD-L1 as used herein includes human PD-L1 (hPD-L1), variants, isoforms, and species homologs of hPD-L1, and analogs having at least one common epitope with hPD-L1.
  • the complete hPD-L1 sequence can be found under GenBank Accession No. Q9NZQ7.
  • an antagonist (inhibitor or blocking agent) of a protein that inhibits T cell activation includes antibodies which bind to CTLA-4, PD-1, PD-L1, PD-L2, or LAG-3, or any of the following proteins: TIM-3, Galectin 9, CEACAM-1, BTLA, CD69, Galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, CD73, PD1H, LAIR1, TIM-1, TIM-4, CD39.
  • An agonist of a protein that stimulates T cell activation includes antibodies which bind to B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, GITR, GITRL, ICOS, ICOS-L, OX40, OX40L, CD70, CD27, CD40, DR3 or CD28H.
  • Cytotoxic T-Lymphocyte Antigen-4 (CTLA-4, CD152)” is a T cell costimulatory receptor which binds to ligands B7-1 and B7-2 on APC. CTLA-4 is up-regulated after T cell activation and antagonizes T cell activation, interferes with IL-2 production and IL-2 receptor expression, and interrupts cell cycle progression of activated T cells.
  • CTLA-4" as used herein includes human CTLA-4 (hCTLA-4), variants, isoforms, and species homologs of hCTLA-4, and analogs having at least one common epitope with hCTLA-4.
  • the complete hCTLA-4 sequence can be found under GenBank Accession No. AAL07473.1.
  • the terms “specific binding,” “selective binding,” “selectively binds,” and “specifically binds,” refer to antibody binding to an epitope on a predetermined antigen.
  • the antibody (i) binds with an equilibrium dissociation constant (K D ) of approximately less than 10 -7 M, such as approximately less than 10 -8 M, 10 -9 M or 10 -10 M or even lower when determined by, e.g., surface plasmon resonance (SPR) technology in a BIACORE 2000 instrument using the predetermined antigen, as the analyte and the antibody as the ligand, or Scatchard analysis of binding of the antibody to antigen positive cells, and (ii) binds to the predetermined antigen with an affinity that is at least two-fold greater than its affinity for binding to a non-specific antigen (e.g., BSA, casein) other than the predetermined antigen or a closely-related antigen.
  • K D equilibrium dissociation constant
  • conservative sequence modifications include conservative nucleotide and amino acid substitutions, as well as, nucleotide and amino acid additions and deletions.
  • modifications can be introduced into a sequence by standard techniques known in the art, such as site-directed mutagenesis and PCR-mediated mutagenesis.
  • Conservative amino acid substitutions include ones in which the amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined in the art.
  • amino acids with basic side chains e.g., lysine, arginine, histidine
  • acidic side chains e.g., aspartic acid, glutamic acid
  • uncharged polar side chains e.g glycine asparagine glutamine serine threonine tyrosine cysteine tryptophan
  • nonpolar side chains e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine
  • beta-branched side chains e.g., threonine, valine, isoleucine
  • aromatic side chains e.g., tyrosine, phenylalanine, tryptophan, histidine
  • the term “substantial homology” indicates that two polypeptides, or designated sequences thereof, when optimally aligned and compared, are identical, with appropriate amino acid insertions or deletions, in at least about 80% of the amino acids, usually at least about 90% to 95%, and more preferably at least about 98% to 99.5% of the amino acids.
  • the comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm, as described in the non-limiting examples below.
  • the percent identity between two nucleotide or amino acid sequences can also be determined using the algorithm of E. Meyers and W. Miller (CABIOS, 4:11-17 (1989)) which has been incorporated into the ALIGN program (version 2.0), using a PAM120 weight residue table, a gap length penalty of 12 and a gap penalty of 4.
  • the percent identity between two amino acid sequences can be determined using the Needleman and Wunsch (J. Mol. Biol.
  • nucleic acid and protein sequences described herein can further be used as a “query sequence” to perform a search against public databases to, for example, identify related sequences. Such searches can be performed using the NBLAST and XBLAST programs (version 2.0) of Altschul, et al. (1990) J. Mol. Biol.215:403-10.
  • Gapped BLAST can be utilized as described in Altschul et al., (1997) Nucleic Acids Res.25(17):3389-3402.
  • the default parameters of the respective programs e.g., XBLAST and NBLAST
  • administering refers to the physical introduction of a composition comprising a therapeutic agent to a subject, using any of the various methods and delivery systems known to those skilled in the art, e.g., intravenous.
  • Routes of administration for antibodies described herein include intravenous, intraperitoneal, intramuscular, subcutaneous, spinal or other parenteral routes of administration, for example by injection or infusion.
  • parenteral administration means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intraperitoneal, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion, as well as in vivo electroporation.
  • an antibody described herein can be administered via a non-parenteral route, such as a topical, epidermal or mucosal route of administration, for example, intranasally, orally, vaginally, rectally, sublingually or topically.
  • Administering can also be performed, for example, once, a plurality of times, and/or over one or more extended periods.
  • Administration of a composition comprising a therapeutic agent to a subject may be conducted according to a defined administration cycle which includes administration of a defined dose over a defined period of time.
  • an administration cycle can include a dose of 3600 mg of an anti-IL-8 antibody (e.g., HuMax-IL8) once every 2 weeks (Q2W) over a period, e.g., a 12 week period.
  • an anti-IL-8 antibody e.g., HuMax-IL8
  • Q2W 2 weeks
  • the terms “maintenance” and “maintenance phase” are used interchangeably and refer to the second phase of treatment.
  • treatment is continued as long as clinical benefit is observed or until unacceptable toxicity, disease progression or deterioration occurs.
  • cancer refers a broad group of diseases characterized by the uncontrolled growth of abnormal cells in the body.
  • Unregulated cell division may result in the formation of malignant tumors or cells that invade neighboring tissues and may metastasize to distant parts of the body through the lymphatic system or bloodstream.
  • the terms “treat,” “treating,” and “treatment,” as used herein, refer to any type of intervention or process performed on, or administering an active agent to, the subject with the objective of reversing, alleviating, ameliorating, inhibiting, or slowing down or preventing the progression, development, severity or recurrence of a symptom, complication, condition or biochemical indicia associated with a disease. Treatment can be of a subject having a disease or a subject who does not have a disease (e.g., for prophylaxis).
  • an effective dose or “effective dosage” is defined as an amount sufficient to achieve or at least partially achieve a desired effect.
  • a "therapeutically effective amount” or “therapeutically effective dosage” of a drug or therapeutic agent is any amount of the drug that, when used alone or in combination with another therapeutic agent, promotes disease regression evidenced by a decrease in severity of disease symptoms, an increase in frequency and duration of disease symptom-free periods, or a prevention of impairment or disability due to the disease affliction.
  • a therapeutically effective amount or dosage of a drug includes a "prophylactically effective amount” or a “prophylactically effective dosage”, which is any amount of the drug that, when administered alone or in combination with another therapeutic agent to a subject at risk of developing a disease or of suffering a recurrence of disease, inhibits the development or recurrence of the disease.
  • a therapeutic agent to promote disease regression or inhibit the development or recurrence of the disease can be evaluated using a variety of methods known to the skilled practitioner, such as in human subjects during clinical trials, in animal model systems predictive of efficacy in humans, or by assaying the activity of the agent in in vitro assays.
  • an anti-cancer agent is a drug that promotes cancer regression in a subject.
  • a therapeutically effective amount of the drug promotes cancer regression to the point of eliminating the cancer.
  • Promoted cancer regression means that administering an effective amount of the drug, alone or in combination with an anti- neoplastic agent, results in a reduction in tumor growth or size, necrosis of the tumor, a decrease in severity of at least one disease symptom, an increase in frequency and duration of disease symptom-free periods, a prevention of impairment or disability due to the disease affliction, or otherwise amelioration of disease symptoms in the patient.
  • the terms "effective” and “effectiveness” with regard to a treatment includes both pharmacological effectiveness and physiological safety.
  • Pharmacological effectiveness refers to the ability of the drug to promote cancer regression in the patient, and/or to prolong survival of the patient, such as progression- free survival or overall survival.
  • Physiological safety refers to the level of toxicity, or other adverse physiological effects at the cellular, organ and/or organism level (adverse effects) resulting from administration of the drug.
  • a therapeutically effective amount or dosage of the drug preferably inhibits cell growth or tumor growth by at least about 20%, more preferably by at least about 40%, even more preferably by at least about 60%, and still more preferably by at least about 80% relative to untreated subjects.
  • a therapeutically effective amount or dosage of the drug completely inhibits cell growth or tumor growth, i.e., preferably inhibits cell growth or tumor growth by 100%.
  • the ability of a compound to inhibit tumor growth can be evaluated using the assays described infra. Alternatively, this property of a composition can be evaluated by examining the ability of the compound to inhibit cell growth, such inhibition can be measured in vitro by assays known to the skilled practitioner. In other preferred embodiments described herein, tumor regression may be observed and continue for a period of at least about 20 days, more preferably at least about 40 days, or even more preferably at least about 60 days.
  • patient includes human and other mammalian subjects that receive either prophylactic or therapeutic treatment.
  • the term “subject” includes any human or non-human animal.
  • the methods and compositions described herein can be used to treat a subject having cancer.
  • the term “about” refers to any value which lies within the range defined by a number up to ⁇ 10% of the value.
  • Anti-IL-8 antibodies The anti-IL-8 antibodies suitable for use in the methods described herein may be monoclonal antibodies. Antigen binding fragments of such antibodies may also be used. Exemplary anti-IL-8 antibodies, or antigen-binding fragments thereof, which can be used in the methods described herein include, but are not limited to, those disclosed in U.S. Patent No. 7,282,568 (the contents of which are herein incorporated by reference).
  • anti-IL-8 antibodies can also be used, for example, the anti-IL8 antibodies disclosed in patent application publications such as WO2009026117, WO2013166099, WO2014149733, WO2015017146, WO2015010100, WO2013106489, WO2013106485, US5831032, WO2006113643, US20050142136, WO2002077172, WO199858671, WO2003080117, WO200009560, WO199602576, WO1996022785, WO1997001354, WO199837200, and WO199937779, which are incorporated herein by reference.
  • the anti-IL-8 antibody, or antigen-binding portion thereof may be 10F8 disclosed in U.S. Patent No.7,282,568 (also referred to as HuMax-IL8).
  • the anti-IL-8 antibody, or antigen binding fragment thereof comprises the CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO: 7, and the CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence set forth in SEQ ID NO: 8.
  • the anti-IL-8 antibody, or antigen binding fragment thereof comprises heavy chain CDR1, CDR2, and CDR3 sequences set forth SEQ ID NOs: 1-3, and light chain CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 4-6.
  • the anti-IL-8 antibody has one or more of the following characteristics: (a) inhibits IL-8 binding to its receptors (CXCR1 and CXCR2); (b) inhibits IL-8 induced proinflammatory effects; (c) inhibits IL-8 induced chemotactic activity for neutrophils; (d) inhibits IL-8 induced calcium influx; (e) inhibits IL-8 induced changes in expression levels of adhesion molecules on neutrophils; (f) inhibits IL-8 induced increased expression of CD11b (Mac-1) and inhibits IL-8 induced decreased expression of L-selectin on neutrophils; (g) does not cross-react with related chemokines selected from the group consisting of human GRO-alpha, human GRO-beta, human IP-10, and human NAP-2; (h) significantly inhibits chemotaxis induced by biological fluids which contain multiple chemotactic factors including IL-8.
  • the anti-IL-8 antibody, or antigen binding fragment thereof comprises a heavy chain variable region comprising the sequence set forth in SEQ ID NO: 7, and a light chain variable region comprising the sequence set forth in SEQ ID NO: 8.
  • the anti-IL-8 antibody, or antigen binding fragment thereof comprises a heavy chain comprising the sequence set forth in SEQ ID NO: 9, and a light chain comprising the sequence set forth in SEQ ID NO: 10.
  • the anti-IL-8 antibody comprises heavy and light chain variable region sequences that are at least 85%, 90%, 95%, 98%, or 99% identical with the heavy and light chain variable region sequences set forth in SEQ ID NOs: 7 and 8, respectively.
  • the anti-IL-8 antibody comprises heavy and light chain sequences that are at least 85%, 90%, 95%, 98%, or 99% identical with the heavy and light chain sequences set forth in SEQ ID NOs: 9 and 10, respectively.
  • the anti-IL-8 antibody is of an isotype selected from IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, secretory IgA, IgD, and IgE.
  • the anti-IL-8 antibody has an Fc region with one or more art- recognized alterations in order to change functional or pharmacokinetic properties of the antibody (e.g., decreased or increased C1q binding, complement-dependent toxicity (CDC), Fc ⁇ R binding, antibody-dependent cellular toxicity (ADCC), and FcRn binding).
  • Antibodies and antigen binding fragments thereof may be obtained using hybridoma and recombinant procedures well known in the art, such as those described in U.S. Patent Nos.
  • the antibodies described herein can be produced by culturing a host cell (e.g., E. coli or a eukaryotic cells such as CHO cells, NS/0 cells, HEK293 cells, plant cells, fungi, yeast cells), which has been transformed with an expression vector that includes one or more expression cassettes containing a promoter operably linked to a first DNA sequence encoding a signal peptide linked in proper reading frame to a second DNA sequence encoding the antibody protein.
  • a host cell e.g., E. coli or a eukaryotic cells such as CHO cells, NS/0 cells, HEK293 cells, plant cells, fungi, yeast cells
  • an expression vector that includes one or more expression cassettes containing a promoter operably linked to a first DNA sequence encoding a signal peptide linked in proper reading frame to a second DNA sequence encoding the antibody protein.
  • the antibody protein can then be collected and isolated.
  • IL-8 antibodies e.g., 10F8
  • transgenic mice such as HuMAb mice
  • An anti-IL-8 antibody may be administered with an anti-PD-1 antibody or an anti-PD-L1 antibody.
  • PD-1 is a key immune checkpoint receptor expressed by activated T and B cells and mediates immunosuppression.
  • PD-1 is a member of the CD28 family of receptors, which includes CD28, CTLA-4, ICOS, PD-1, and BTLA.
  • PD-1 Programmed Death Ligand-1
  • PD-L2 Programmed Death Ligand-2
  • HuMAbs that bind specifically to PD-1 with high affinity have been disclosed in U.S. Patent Nos.8,008,449 and 8,779,105.
  • Other anti-PD-1 monoclonal antibodies have been described in, for example, U.S. Patent Nos.
  • Each of the anti-PD-1 HuMAbs disclosed in U.S. Patent No. 8,008,449 has been demonstrated to exhibit one or more of the following characteristics: (a) binds to human PD-1 with a K D of 1 x 10 -7 M or less, as determined by surface plasmon resonance using a Biacore biosensor system; (b) does not substantially bind to human CD28, CTLA-4 or ICOS; (c) increases T-cell proliferation in a Mixed Lymphocyte Reaction (MLR) assay; (d) increases interferon- ⁇ production in an MLR assay; (e) increases IL-2 secretion in an MLR assay; (f) binds to human PD-1 and cynomolgus monkey PD-1; (g) inhibits the binding of PD-L1 and/or PD-L2 to PD-1; (h) stimulates anti
  • Anti-PD-1 antibodies useful for the present invention include antibodies that bind specifically to human PD-1 and exhibit at least one, preferably at least five, of the preceding characteristics.
  • the anti-PD-1 antibody is nivolumab.
  • Nivolumab also known as "OPDIVO ® "; formerly designated 5C4, BMS-936558, MDX-1106, or ONO-4538
  • S228P fully human IgG4
  • PD-1 immune checkpoint inhibitor antibody that selectively prevents interaction with PD-1 ligands (PD-L1 and PD-L2), thereby blocking the down-regulation of antitumor T-cell functions
  • Nivolumab can also be referred to as BMS-936558, MDX-1106 ONO-4538, or by its CAS Registry No. 946414-94-4, and is disclosed as antibody 5C4 in WO 2006/121168, incorporated herein by reference in its entirety and for all purposes.
  • Nivolumab is a human monoclonal antibody that specifically binds to PD-1 and comprises a heavy chain variable region provided as SEQ ID NO: 17, and a light chain variable region provided as SEQ ID NO: 18.
  • Nivolumab may also be described as an antibody comprising a heavy chain CDR1 having amino acids 24-34 of SEQ ID NO: 17, a heavy chain CDR2 having amino acids 50-56 of SEQ ID NO: 17, and a heavy chain CDR3 having amino acids 89-97 of SEQ ID NO: 17; and comprising a light chain CDR1 having amino acids 31-35 of SEQ ID NO: 18, a light chain CDR2 having amino acids 50-66 of SEQ ID NO: 18, and a light chain CDR3 having amino acids 99-102 of SEQ ID NO: 18.
  • the heavy and light chain sequences of nivolumab are set forth in SEQ ID NOs: 19 and 20.
  • anti-PD-1 antibodies comprising heavy and light chain variable region sequences that are at least 85%, 90%, 95%, 98%, or 99% identical with the heavy and light chain variable region sequences set forth in SEQ ID NOs: 17 and 18, respectively.
  • the anti-PD-1 antibody comprises heavy and light chain sequences that are at least 85%, 90%, 95%, 98%, or 99% identical with the heavy and light chain sequences set forth in SEQ ID NOs: 19 and 20, respectively.
  • Pharmaceutical compositions of nivolumab include all pharmaceutically acceptable compositions comprising nivolumab and one or more diluents, vehicles and/or excipients. Nivolumab may be administered by I.V.
  • the anti-PD-1 antibody is pembrolizumab.
  • Pembrolizumab also known as "KEYTRUDA ® ", lambrolizumab, and MK-3475
  • KEYTRUDA ® a humanized monoclonal IgG4 antibody directed against human cell surface receptor PD-1 (programmed death-1 or programmed cell death-1).
  • Pembrolizumab has been approved by the FDA for the treatment of relapsed or refractory melanoma.
  • the anti-PD-1 antibody is Pidilizumab (CT-011), which is a humanized monoclonal antibody. Pidilizumab is described in US Pat. No. 8,686,119 B2 or WO 2013/014668 A1. The specificity of CT-011 for PD-1 binding has been questioned.
  • Anti-PD-1 antibodies useful for the disclosed compositions also include isolated antibodies that bind specifically to human PD-1 and compete or cross-compete for binding to human PD-1 with nivolumab (see, e.g., U.S. Patent Nos.8,008,449 and 8,779,105; WO 2013/173223) or other anti-PD-1 antibodies.
  • Anti-PD-1 antibodies suitable for use in the disclosed compositions are antibodies that bind to PD-1 with high specificity and affinity, block the binding of PD-L1 and or PD-L2, and inhibit the immunosuppressive effect of the PD-1 signaling pathway.
  • an anti-PD-1 "antibody” includes an antigen-binding portion or fragment that binds to the PD-1 receptor and exhibits the functional properties similar to those of whole antibodies in inhibiting ligand binding and upregulating the immune system.
  • the anti-PD-1 antibodies or antigen-binding portion thereof cross-competes with nivolumab for binding to human PD-1.
  • the anti-PD-1 antibodies or antigen- binding portion thereof is a chimeric, humanized, or human monoclonal antibodies or a portion thereof.
  • the antibody is a humanized antibody. In other embodiments, the antibody is a human antibody.
  • Antibodies of an IgG1, IgG2, IgG3 or IgG4 isotype can be used.
  • the anti-PD-1 antibody or antigen-binding portion thereof comprises a heavy chain constant region which is of a human IgG1 or IgG4 isotype.
  • the sequence of the IgG4 heavy chain constant region of the anti-PD-1 antibody or antigen-binding portion thereof contains an S228P mutation which replaces a serine residue in the hinge region with the proline residue normally found at the corresponding position in IgG1 isotype antibodies.
  • the antibody comprises a light chain constant region which is a human kappa or lambda constant region.
  • the anti-PD-1 antibody or antigen-binding portion thereof is a monoclonal antibody or an antigen-binding portion thereof.
  • the anti-PD-1 antibody is nivolumab.
  • the anti-PD-1 Ab is pembrolizumab.
  • the anti-PD-1 antibody is chosen from the human antibodies 17D8, 2D3, 4H1, 4A11, 7D3 and 5F4 described in U.S. Patent No.8,008,449.
  • the anti-PD-1 Ab is MEDI0608 (formerly AMP-514), AMP-224, or Pidilizumab (CT-011).
  • the antibody to be administered with an anti-IL-8 antibody is an anti-PD-L1 antibody.
  • an anti-PD-L1 antibody can be substituted for the anti-PD-1 antibody in any of the therapeutic methods or compositions disclosed herein.
  • the anti-PD-L1 antibody is BMS-936559 (formerly 12A4 or MDX-1105) (see, e.g., U.S.
  • an anti-PD-L1 antibody is MEDI4736 (also known as Anti-B7-H1), MPDL3280A (also known as RG7446, atezolizumab and TECENTRIQ), MSB0010718C (WO2013/79174), or rHigM12B7.
  • anti-PD-L1 antibodies Any of the anti-PD-L1 antibodies disclosed in WO2013/173223, WO2011/066389, WO2012/145493, U.S. Patent Nos. 7,635,757 and 8,217,149 and U.S. Publication No.2009/145493 may also be used.
  • Anti-PD-L1 antibodies that compete with and/or bind to the same epitope as that of any of these antibodies may also be used in the treatments described herein.
  • a PD-1/PD-L1 antagonist agent that may be used in the methods described herein include nivolumab, pembrolizumab, atelozilumab, durvalumab, REGN2810, PDR001, AMP-514 (MEDI0608), AMP-224, BGB-A317 or a PD-1 or PD-L1 antagonist described in any one of the following publications: WO 2009/014708, WO 03/099196, WO 2009/114335 and WO 2011/161699.
  • Anti-CTLA-4 antibodies CTLA-4 is an activation-induced T cell surface molecule that also binds to CD80 and CD86, but with greater avidity than CD28.
  • CTLA-4 ligation down-regulates T cell responses, which results in abrogation of the effects provided by T cell activation.
  • the blockade of CTLA- 4 interaction with CD80/86 results in increased T cell activation.
  • the anti-CTLA-4 antibody is ipilimumab.
  • Ipilimumab (Yervoy®) is a fully human IgG1 ⁇ monoclonal antibody targeting CTLA-4 that inhibits the negative downstream signaling that occurs when CTLA-4 engages its ligands, CD80 and CD86, on APCs.
  • activated T cells are able to maintain their CD28 mediated signaling resulting in IL-2 secretion and proliferation of CD8 T cells in response to an antigen.
  • Ipilimumab is described, for example, in U.S. Patent No.8,119,129. Ipilimumab has been approved by the FDA for the treatment of metastatic melanoma, for which it has shown an overall survival advantage (Hodi FS et al. (2010) N Engl J Med 363:711-723). Ipilimumab specifically binds to CTLA-4 and comprises a heavy chain variable region provided as SEQ ID NO: 27, and a light chain variable region provided as SEQ ID NO: 28.
  • Ipilimumab may also be described as an antibody comprising heavy chain CDR1, CDR2, and CDR3 regions having the amino acid sequences set forth in SEQ ID NOs: 21, 22, and 23, respectively, and light chain CDR1, CDR2, and CDR3 regions having the amino acid sequences set forth in SEQ ID NOs: 24, 25, and 26, respectively .
  • the heavy and light chain sequences of ipilimumab are set forth in SEQ ID NOs: 29 and 30.
  • anti-CTLA-4 antibodies comprising heavy and light chain variable region sequences that are at least 85%, 90%, 95%, 98%, or 99% identical with the heavy and light chain variable region sequences set forth in SEQ ID NOs: 27 and 28, respectively.
  • the anti-CTLA-4 antibody comprises heavy and light chain sequences that are at least 85%, 90%, 95%, 98%, or 99% identical with the heavy and light chain sequences set forth in SEQ ID NOs: 29 and 30, respectively.
  • Pharmaceutical compositions of ipilimumab include all pharmaceutically acceptable compositions comprising ipilimumab and one or more diluents, vehicles and/or excipients. Ipilimumab may be administered by I.V.
  • Anti-CTLA-4 antibodies useful for the disclosed compositions also include isolated antibodies that bind specifically to human CTLA-4 and compete or cross-compete for binding to human CTLA-4 with ipilimumab.
  • anti-PD-1 antibodies suitable for use in the disclosed compositions are antibodies that bind to CTLA-4 with high specificity and affinity, block the binding of CTLA-4, and inhibit the immunosuppressive effect of the CTLA-4 signaling pathway.
  • an anti- CTLA-4 "antibody” includes an antigen-binding portion or fragment that binds to the CTLA-4 and exhibits the functional properties similar to those of whole antibodies in inhibiting ligand binding and upregulating the immune system.
  • the anti- CTLA-4 antibodies or antigen-binding portion thereof cross-competes with ipilimuab for binding to human CTLA-4.
  • the anti- CTLA-4 antibodies or antigen-binding portion thereof is a chimeric, humanized or human monoclonal antibodies or a portion thereof.
  • the antibody is a humanized antibody.
  • the antibody is a human antibody.
  • Antibodies of an IgG1, IgG2, IgG3 or IgG4 isotype can be used.
  • the anti- CTLA-4 antibody or antigen-binding portion thereof comprises a heavy chain constant region which is of a human IgG1 or IgG4 isotype.
  • the antibody comprises a light chain constant region which is a human kappa or lambda constant region.
  • the anti- CTLA-4 antibody or antigen-binding portion thereof is a monoclonal antibody or an antigen-binding portion thereof.
  • the anti- CTLA-4 antibody is ipilimumab.
  • Pharmaceutical Compositions Further provided are compositions, e.g., a pharmaceutical compositions, containing anti- IL-8 antibodies in combination with anti-PD-1 antibodies (e.g., nivolumab), and, optionally, an anti-cancer agent, e.g., an anti-CTLA-4 antibody, formulated together or separately with a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible.
  • the carrier is suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal or epidermal administration (e.g., by injection or infusion).
  • the pharmaceutical compounds described herein may include one or more pharmaceutically acceptable salts.
  • a “pharmaceutically acceptable salt” refers to a salt that retains the desired biological activity of the parent compound and does not impart any undesired toxicological effects (see e.g., Berge, S.M., et al. (1977) J. Pharm. Sci.66:1-19).
  • Acid addition salts include those derived from nontoxic inorganic acids, such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, phosphorous and the like, as well as from nontoxic organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, aromatic acids, aliphatic and aromatic sulfonic acids and the like.
  • nontoxic inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, phosphorous and the like
  • nontoxic organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, aromatic acids, aliphatic and aromatic sulfonic acids and the like.
  • Base addition salts include those derived from alkaline earth metals, such as sodium, potassium, magnesium, calcium and the like, as well as from nontoxic organic amines, such as N,N'- dibenzylethylenediamine, N-methylglucamine, chloroprocaine, choline, diethanolamine, ethylenediamine, procaine and the like.
  • a pharmaceutical composition described herein may also include a pharmaceutically acceptable anti-oxidant.
  • antioxidants examples include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
  • water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
  • oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), le
  • aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
  • compositions may be sterilized both by sterilization procedures, supra, and by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
  • Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. The use of such media and agents for pharmaceutically active substances is known in the art.
  • a pharmaceutical composition may comprise a preservative or may be devoid of a preservative.
  • Supplementary active compounds can be incorporated into the compositions.
  • Therapeutic compositions typically must be sterile and stable under the conditions of manufacture and storage.
  • the composition can be formulated as a solution, microemulsion, liposome, or other ordered structure suitable to high drug concentration.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • a coating such as lecithin
  • surfactants it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition.
  • Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, monostearate salts and gelatin.
  • Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by sterilization microfiltration.
  • dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated herein.
  • a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated herein.
  • the preferred methods of preparation are vacuum drying and freeze-drying (lyophilization) that yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • Methods of treating cancer/treatment protocols Provided herein are methods of treating a subject having cancer (e.g., an advanced solid tumor) with a combination therapy comprising an anti-IL-8 antibody, an anti-PD-1 antibody, and, optionally, a third anti-cancer agent, e.g., an anti-CTLA-4 antibody wherein optionally, the baseline serum IL-8 levels in the subject is above the lower limit of quantitation (LLOQ).
  • Serum IL-8 levels can be detected using standard assays known in the art, such as commercial ELISA that detects both the monomer and dimer form of IL-8 (e.g., Human IL-8 ELISA set; BD Bioescience Pharmingen).
  • the subjects have baseline serum IL-8 levels of at least or >10 pg/ml, 9 pg/mL, 8 pg/mL, 7 pg/mL, 6 pg/mL, 5 pg/mL, 4 pg/mL, 3 pg/mL, 2 pg/mL, or 1 pg/mL, e.g., as assessed by ELISA (e.g., sandwich ELISA).
  • the subjects have baseline serum IL-8 levels >10 pg/ml.
  • an anti-IL-8 antibody may be administered to a subject having cancer, e.g., an advanced solid tumor, as a combination therapy with an anti-PD-1 antibody, and, optionally, an anti-CTLA-4 antibody, e.g., at a flat dose of 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg, 1900 mg, 2000 mg, 2100 mg, 2200 mg, 2300 mg, 2400 mg, 2500 mg, 2600 mg, 2700 mg, 2800 mg, 2900 mg, 3000 mg, 3200 mg, 3400 mg, 3600 mg, 3800 mg, 4000, 4800, 5400, or 6000 mg of an anti-IL-8 antibody, once every week, once every two weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks, once every 7 weeks, once every 8 weeks, once every 9 weeks, or once every 10 weeks.
  • the treatment may be administered in, e.g., 2-week cycles, 3-week cycles, 4-week cycles, or 4 to 15-week cycles, e.g., one 6-week cycle, one 12- week cycle, two 12-week cycles, three 12-week cycles, four 12-week cycles, five 12-week cycles, six 12-week cycles, or more, for example, up to, e.g., 2612-week cycles.
  • one cycle is 84 days long.
  • the anti-IL-8 antibody, anti-PD-1 antibody, and, optionally, anti- CTLA-4 antibody may be administered on Day 1 of each cycle.
  • the anti-PD-1 antibody may be administered at a dose of, e.g., 0.5 mg/kg, 1.0 mg/kg, 1.5 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 10-20 mg/kg, 30-40 mg/kg, 50-100 mg/kg.
  • the anti-PD-1 antibody may be administered at a flat dose of, e.g., 100-500 mg, 200 mg-500 mg, 300-500 mg, 400-500 mg, 450-500 mg, 460-490 mg, 470-490 mg, 240 mg, 360 mg, 480 mg, 500 mg, or 520 mg.
  • the anti-CTLA-4 antibody may be administered at a dose of, e.g., 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 5-10 mg/kg, 20 mg/kg, 30-40 mg/kg, or 50-100 mg/kg.
  • an administration cycle may be followed by a maintenance phase during which the anti-IL-8 antibody, anti-PD-1 antibody, and, optionally, anti-CTLA-4 antibody, continue to be administered.
  • the anti-IL-8 antibody may be administered alone or with either or both of the anti-PD-1 antibody and anti- CTLA-4 antibody, at a flat dose of 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg, 1900 mg, 2000 mg, 2100 mg, 2200 mg, 2300 mg, 2400 mg, 2500 mg, 2600 mg, 2700 mg, 2800 mg, 2900 mg, 3000 mg, 3200 mg, 3400 mg, 3600 mg, 3800 mg, 4000 mg, 4800 mg, 5400 mg, or 6000 mg of an anti-IL-8 antibody, once every week, once every two weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks, once every 7 weeks, once every 8 weeks, once every 9 weeks, or once every 10 weeks.
  • the treatment may be administered in, e.g., 2-week cycles, 3- week cycles, 4-week cycles, or 4 to 15-week cycles, e.g., one 6-week cycle, one 12-week cycle, two 12-week cycles, three 12-week cycles, four 12-week cycles, five 12-week cycles, six 12- week cycles, or more, for example, up to, e.g., 2612-week cycles.
  • the anti-IL-8 antibody may be administered at a flat dose of 3600 mg. In some embodiments, the anti-IL-8 antibody may be administered at a flat dose of 5400 mg. In some embodiments, the anti-IL-8 antibody may be administered every 2 weeks. In some embodiments, the anti-IL-8 antibody may be administered every 3 weeks.
  • the anti-PD-1 antibody may be administered (either alone or with the anti-IL-8 antibody and/or anti-CTLA-4 antibody) at a flat dose of, e.g., 100-500 mg, 200 mg-500 mg, 300-500 mg, 400-500 mg, 450-500 mg, 460-490 mg, 470-490 mg, 240 mg, 360 mg, 480 mg, 500 mg, or 520 mg, once every week, once every two weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, or once every 6 weeks.
  • a flat dose e.g., 100-500 mg, 200 mg-500 mg, 300-500 mg, 400-500 mg, 450-500 mg, 460-490 mg, 470-490 mg, 240 mg, 360 mg, 480 mg, 500 mg, or 520 mg, once every week, once every two weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, or once every 6 weeks.
  • the treatment may be administered in, e.g., 2-week cycles, 3-week cycles, 4-week cycles, or 4 to 15-week cycles, e.g., one 6-week cycle, one 12-week cycle, two 12-week cycles, three 12-week cycles, four 12-week cycles, five 12-week cycles, six 12-week cycles, or more, for example, up to, e.g., 2612-week cycles.
  • the anti-PD-1 antibody may be administered at a flat dose of 480 mg. In some embodiments, the anti-PD-1 antibody may be administered every 4 weeks.
  • the anti-CTLA-4 antibody may be administered (either alone or with the anti-IL-8 antibody and/or the anti-PD-1 antibody), e.g., at a flat dose of 1 mg/kg, 2, mg/kg, 3 mg/kg, 4 mg/kg, 5-10 mg, 20 mg, 30-40 mg, 50-100 mg, 100- 200 mg, 200-300 mg, 300-400 mg, or 400-500 mg, once every week, once every two weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks, once every 7 weeks, once every 8 weeks, once every 9 weeks, or once every 10 weeks.
  • the treatment may be administered in, e.g., 2-week cycles, 3-week cycles, 4-week cycles, or 4 to 15-week cycles, e.g., one 6-week cycle, one 12-week cycle, two 12-week cycles, three 12-week cycles, four 12-week cycles, five 12-week cycles, six 12-week cycles, or more, for example, up to, e.g., 2612-week cycles.
  • Exemplary combination therapies comprise an anti-IL-8 antibody, an anti-PD-1 antibody, and, optionally, an anti-CTLA-4 antibody.
  • the combination or antibodies may be administered in any order.
  • an anti-IL-8 antibody may be administered first, followed by an administration of an anti-PD-1 antibody and an anti-CTLA-4 antibody.
  • Each antibody may be administered by infusion.
  • an anti-IL-8 antibody may be administered by infusion for a period of 60-120 minutes, followed by an infusion of an anti-PD-1 antibody over a period of 30-60 minutes and infusion of an anti-CTLA-4 antibody over a period of 30-60 minutes.
  • an anti-PD-1 antibody may be administered by infusion for a period of 30-60 minutes, followed by an infusion of an anti-IL-8 antibody over a period of 60-120 minutes and infusion of an anti-CTLA-4 antibody over a period of 30-60 minutes.
  • an anti-CTLA-4 antibody may be administered by infusion for a period of 30-60 minutes, followed by an infusion of an anti-IL-8 antibody over a period of 60-120 minutes and infusion of an anti-CTLA-4 antibody over a period of 30-60 minutes.
  • administration of the combination of antibodies may be followed by an observation period.
  • an anti-IL-8 antibody e.g., 10F8 or HuMax-IL8
  • an anti-PD-1 antibody e.g., nivolumab
  • an anti-CTLA-4 antibody e.g., ipilimumab
  • an anti-IL-8 antibody (e.g., 10F8 or HuMax-IL8) may be administered at a flat dose of 3600 mg or about 3600 mg by infusion for 60 minutes, followed by an observation period of 30 minutes, and then an anti-PD-1 antibody (e.g., nivolumab) may be administered at a dose of 1 mg/kg by infusion for 30 minutes, followed by an observation period of 30 minutes, and then an anti-CTLA-4 antibody (e.g., ipilimumab) may be administered at a dose of 3 mg/kg for 30 minutes.
  • the anti-IL-8 antibody, anti-PD-1 antibody, and, optionally, anti-CTLA-4 antibody may be administered at the same time, and may be coformulated.
  • An exemplary combination therapy comprises administering an anti-IL-8 antibody in combination with nivolumab and/or ipilimumab.
  • the IL-8 antibody may be administered at a flat dose of 1200 mg, 2400 mg, 3200 mg, 3400 mg, 3600 mg, 3800 mg, 4000 mg, 4800 mg, 5400 mg, or 6000 mg every two weeks, or at a flat dose of 1200 mg, 2400 mg, 3200 mg, 3400 mg, 3600 mg, 3800 mg, 4000 mg, 4800 mg, 5400 mg, or 6000 mg every three weeks.
  • Nivolumab may be administered at a dose of 0.1 mg/kg, 1 mg/kg, 2 mg/kg, or 3 mg/kg every two or three weeks, or at a flat dose of 120 mg, 240 mg, 360 mg, or 480 mg every two, three or four weeks.
  • Ipilimumab may be administered at a dose of 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, or 5 mg/kg every three weeks.
  • An anti-IL-8 antibody, an anti-PD-1 antibody, and/or an anti-CTLA-4 antibody for administration by infusion may be provided as a formulation.
  • an anti-IL-8 antibody e.g., 10F8 or HuMax-IL8 of 1 mg/ml, 2 mg/ml, 3 mg/ml, 4 mg/ml, 5 mg/ml, 6 mg/ml, 7 mg/ml, 8 mg/ml, 9 mg/ml, 10 mg/ml, 20 mg/ml, 30 mg/ml or more.
  • the anti-IL-8 antibody may be provided as a formulation of 3600 mg/ml.
  • An exemplary combination treatment comprises administering to a subject having a solid tumor a 3600 mg flat dose of an anti-IL-8 antibody, an anti-PD-1 antibody (e.g., nivolumab) at a dose of 1 mg/kg, and an anti-CTLA-4 antibody at a dose of 3 mg/kg, administered together or separately, as one, two, or three IV infusions, e.g., over 30-60 minutes each, every 2 or 3 weeks.
  • an anti-IL-8 antibody e.g., nivolumab
  • an anti-CTLA-4 antibody at a dose of 3 mg/kg
  • a treatment may comprise administering to a subject having a solid tumor a 3600 mg flat dose of an anti-IL-8 antibody, an anti-PD-1 antibody at a dose of 1 mg/kg, and/or an anti-CTLA- 4 antibody at a dose of 3 mg/kg administered together or separately, as one or more IV infusions, e.g., over 30-60 minutes each, every 2 or 3 weeks.
  • a treatment may comprise administering to a subject having an advanced solid tumor a 2400mg, 3600 mg or 5400 mg flat dose of an anti-IL-8 antibody (e.g., 10F8 or HuMax-IL8) every two weeks or every three weeks, an anti-PD-1 antibody (e.g., nivolumab) at a dose of 1 mg/kg every three weeks, and/or an anti-CTLA-4 antibody (e.g., ipilimumab) at a dose of 3 mg/kg every three weeks, for 12 weeks or more, followed by a maintenance phase comprising a 2400 mg, 3600 mg or 5400 mg flat dose of an anti-IL-8 antibody (e.g., 10F8 or HuMax-IL8) every two weeks or every three weeks and an anti-PD-1 antibody (e.g., nivolumab) at a flat dose of 480 mg every four weeks.
  • an anti-IL-8 antibody e.g., 10F8 or HuMax-IL8
  • Suitable protocols for treating a solid tumor (e.g., an advanced solid tumor) in a human subject, optionally with detectable levels of serum IL-8 include, for example, administering to a subject an effective amount of each of: (a) an anti-IL-8 antibody comprising CDR1, CDR2 and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID NO: 7, and CDR1, CDR2 and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID NO: 8; (b) an anti-PD-1 antibody comprising CDR1, CDR2 and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID NO: 17, and CDR1, CDR2 and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID NO: 18; and, optionally, (c) an anti-CTLA-4 antibody comprising CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID NO: 27, and CDR1, CDR
  • the method may comprise at least one administration cycle.
  • the at least one administration cycle may be a period of one week or 7 days, 2 weeks or 14 days, 3 weeks or 21 days, 4 weeks or 28 days, 5 weeks or 35 days, 6 weeks or 42 days, 7 weeks or 49 days, 8 weeks or 56 days, 9 weeks or 63 days, 10 weeks or 70 days, 11 weeks or 77 days, 12 weeks or 84 days, or 16 or more weeks.
  • one dose of the anti-IL-8 antibody may be administered at a fixed dose ranging from 100 mg to 10,000 mg, from 200 mg to 400 mg, from 400 mg to 600 mg, from 600 mg to 800 mg, from 800 mg to 1000 mg, from 1000 mg to 1200 mg, from 1200 mg to 1400 mg, from 1400 mg to 1600 mg, from 1600 mg to 1800 mg, from 1800 mg to 2000 mg, from 2000 mg to 2200 mg, from 2200 mg to 2400 mg, from 2400 mg to 3000 mg, from 3000 mg to 3600 mg, or from 3600 mg to 5000 mg.
  • one dose of the anti-IL-8 antibody may be administered at a fixed dose of 600 mg, 1200 mg, 2400 mg, 3000 mg, 3200 mg, 3400 mg, 3600mg, 4200 mg, 4800 mg, 5400 mg, or 6000 mg, or a fixed dose of about 600 mg, 1200 mg, 2400 mg, 3000 mg, 3200 mg, 3400 mg, 3600 mg, 4200 mg, 4800 mg, 5400 mg, or 6000 mg.
  • one dose of the anti-PD-1 antibody may be administered at a dose ranging from 0.5 to 0.75 mg/kg, 1.0 to 5 mg/kg, or 10 to 20 mg/kg, 30 to 40 mg/kg, 50 to 60 mg/kg, 70 to 80 mg/kg, 90 to 100 mg/kg, or a fixed dose of ranging from 120 to 600 mg, from 240 to 360 mg, or from 360 to 480 mg.
  • one dose of the anti-PD-1 antibody may be administered at dose of 1 mg/kg, 2 mg/kg, 3 mg/kg, 5 mg/kg, 10 mg/kg, 20 mg/kg, or 30 mg/kg, or a flat dose of 120 mg, 240 mg, 360 mg, or 480 mg, or a flat dose of about 120 mg, 240 mg, 360 mg, or 480 mg.
  • one dose of the anti-CTLA-4 antibody may be administered at a dose ranging from 1 to 2 mg/kg, 3 to 4 mg/kg, 5 to 10 mg/kg, or 20 to 50 mg/kg.
  • one dose of the anti-CTLA-4 antibody may be administered at dose of 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 10 mg/kg, from 20 mg/kg to 50 mg/kg, or a flat dose of about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 120 mg, 240 mg, 360 mg, or 480 mg.
  • the treatment consists of up to 2 cycles, 3 cycles, 4 cycles, 6 cycles, or 12 cycles. In some embodiments, the treatment consists of up to 2 cycles. In some embodiments, the treatment consists of up to 4 cycles.
  • the cancer in the patient has progressed or relapsed after an anti- PD-1 or anti-PD-L1 therapy.
  • the anti-IL-8 antibody, anti- PD-1 antibody and, optionally, anti-CTLA-4 antibody may be administered as a second line of treatment (e.g., after the initial or first treatment, including after relapse and/or where the first treatment has failed, e.g., after first line PD-L1 treatment).
  • the anti-IL-8 antibody, anti-PD-1 antibody, and anti-CTLA-4 antibody may be administered at the following doses: (a) 3600 mg anti-IL-8 antibody, 1 mg/kg of anti-PD-1 antibody, and 3 mg/kg of anti- CTLA-4 antibody; (b) 2400-5400 mg anti-IL-8 antibody, 0.5-3 mg/kg of anti-PD-1 antibody, and 1-5 mg/kg of anti-CTLA-4 antibody; or (c) 3600 mg anti-IL-8 antibody, and 240 mg, 360 mg, or 480 mg of anti-PD-1 antibody, and optionally 1-3 mg/kg of anti-CTLA-4 antibody.
  • the anti-IL-8 antibody, anti-PD-1 antibody, and anti-CTLA-4 antibody may be administered at the following doses: (a) 5400 mg anti-IL-8 antibody, 1 mg/kg of anti-PD-1 antibody, and optionally 3 mg/kg of anti-CTLA-4 antibody; (b) 3600 mg anti-IL-8 antibody, 1 mg/kg of anti-PD-1 antibody, and optionally 3 mg/kg of anti-CTLA-4 antibody; (c) 1200-5400 mg anti-IL-8 antibody, 0.5-3 mg/kg of anti-PD-1 antibody, and optionally 1-5 mg/kg of anti-CTLA-4 antibody; (d) 5400 mg anti-IL-8 antibody, and 240 mg, 360 mg, or 480 mg of anti-PD-1 antibody, and optionally 1-3 mg/kg of anti-CTLA-4 antibody; (e) 3600 mg anti-IL-8 antibody, and 240 mg, 360 mg, or 480 mg of anti-PD-1 antibody, and optionally 1-3 mg/kg of anti-CTLA-4 antibody; or (f) 1200-5400
  • the dose of the anti-IL-8, anti-PD-1 antibody, and/or anti-CTLA- 4 antibody may be varied over time.
  • the anti-IL-8, anti-PD-1 antibody, and/or anti- CTLA-4 antibody may be initially administered at a high dose and may be lowered over time.
  • the anti-IL-8, anti-PD-1 antibody, and/or anti-CTLA-4 antibody may be initially administered at a low dose and increased over time.
  • the invention features any of the aforementioned embodiments, wherein the anti-PD-1 antibody is replaced by, or combined with, an anti-PD-L1 or anti-PD-L2 antibody.
  • the anti-IL-8 antibody comprises a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 1, a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 2, a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 3, a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 4, a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 5, and a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 6.
  • the anti-IL-8 antibody comprises heavy and light chain variable regions comprising the sequences set forth in SEQ Id NOs: 7 and 8, respectively.
  • the anti-IL-8 antibody comprises heavy and light chain sequences comprising the sequences set forth in SEQ Id NOs: 9 and 10, respectively. In certain embodiments, the anti-IL-8 antibody comprises heavy and light chain variable region sequences that are at least 85%, 90%, 95%, 98%, or 99% identical with the heavy and light chain variable region sequences set forth in SEQ Id NOs: 7 and 8, respectively. In certain embodiments, the anti-IL-8 antibody comprises heavy and light chain sequences that are at least 85%, 90%, 95%, 98%, or 99% identical with the heavy and light chain sequences set forth in SEQ Id NOs: 9 and 10, respectively.
  • the anti-PD-1 antibody comprises a heavy chain variable region CDR1, CDR2, and CDR3 comprising the sequences set forth in SEQ Id NOs: 11-13, respectively, and light chain variable region CDR1, CDR2, and CDR3 comprising the sequences set forth in SEQ Id NOs: 14-16, respectively.
  • the anti-PD-1 antibody comprises heavy and light chain variable regions sequences set forth in SEQ Id NOs: 17 and 18, respectively.
  • the anti-PD-1 antibody comprises heavy and light chain sequences set forth in SEQ Id NOs: 19 and 20, respectively.
  • the anti-PD-1 antibody comprises heavy and light chain variable region sequences that are at least 85%, 90%, 95%, 98%, or 99% identical with the heavy and light chain variable region sequences set forth in SEQ Id NOs: 17 and 18, respectively. In certain embodiments, the anti-PD-1 antibody comprises heavy and light chain sequences that are at least 85%, 90%, 95%, 98%, or 99% identical with the heavy and light chain sequences set forth in SEQ Id NOs: 19 and 20, respectively.
  • the anti-CTLA-4 antibody comprises a heavy chain variable region CDR1, CDR2, and CDR3 comprising the sequences set forth in SEQ Id NOs: 21-23, respectively, and light chain variable region CDR1, CDR2, and CDR3 comprising the sequences set forth in SEQ Id NOs: 24-26, respectively.
  • the anti- CTLA-4 antibody comprises heavy and light chain variable regions sequences set forth in SEQ Id NOs: 27 and 28, respectively.
  • the anti- CTLA-4 antibody comprises heavy and light chain sequences set forth in SEQ Id NOs: 29 and 30, respectively.
  • the anti- CTLA-4 antibody comprises heavy and light chain variable region sequences that are at least 85%, 90%, 95%, 98%, or 99% identical with the heavy and light chain variable region sequences set forth in SEQ Id NOs: 27 and 28, respectively.
  • the anti- CTLA-4antibody comprises heavy and light chain sequences that are at least 85%, 90%, 95%, 98%, or 99% identical with the heavy and light chain sequences set forth in SEQ Id NOs: 29 and 30, respectively.
  • an anti-IL-8 antibody may be administered to subjects who have a solid tumor associated with a cancer selected from the group consisting of: melanoma, non- small cell lung carcinoma (NSCLC), renal cell carcinoma (RCC), triple negative breast cancer (TNBC), colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDA), and hepatocellular carcinoma (HCC).
  • a cancer selected from the group consisting of: melanoma, non- small cell lung carcinoma (NSCLC), renal cell carcinoma (RCC), triple negative breast cancer (TNBC), colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDA), and hepatocellular carcinoma (HCC).
  • an anti-IL-8 antibody may be administered to subjects who have a solid tumor associated with a cancer selected from the group consisting of Malignant Pleural Mesothelioma, Hodgkin's Disease, Head and Neck Cancer, Urothelial Carcinoma (UCC), Esophage
  • the solid tumor may be selected from melanoma, non-small cell lung carcinoma (NSCLC), squamous NSCLC, non-squamous NSCLC, renal cell carcinoma, triple negative breast cancer, colorectal cancer, pancreatic ductal adenocarcinoma, and hepatocellular carcinoma, esophageal cancer, gastric cancer, rectal cancer, squamous cell carcinoma of the head and neck (SCCHN), small cell lung cancer (SCLC), prostate cancer, e.g., metastatic castration-resistant prostate cancer (mCRPC) or castration-sensitive prostate cancer (CSPC), glioblastoma multiforme (GBM), bladder cancer, neoplasm of the central nervous system (CNS), primary CNS lymphoma, spinal axis tumor, brain cancer, brain stem glioma, head and neck cancer, pancreatic cancer (PAC), liver cancer, hepatoma, stomach cancer, kidney cancer, colon carcinoma, germ cell tumor, pediatric sarcom
  • the cancer is an advanced, unresectable, metastatic, refractory cancer, and/or recurrent cancer.
  • the solid tumor may be selected from melanoma, RCC, UCC, NSCLC, HCC, and CRC.
  • the solid tumor may be selected from hepatoblastoma, neuroblastoma, glioblastoma, osteosarcoma, ependymoma, rhabdomyosarcoma, Ewing’s sarcoma, medulloblastoma, nephroblastoma (Wilms’ tumor), atypical teratoid rhabdoid tumor, and chordoma.
  • the methods described herein may be used to treat a cancer which is a hematological malignancy.
  • Hematological malignancies include liquid tumors derived from either of the two major blood cell lineages, i.e., the myeloid cell line (which produces granulocytes, erythrocytes, thrombocytes, m acrophages and mast cells) or the lymphoid cell line (which produces B, T, NK and plasma cells), including all types of leukemias, lymphomas, and myelomas.
  • Hematological malignancies that may be treated using the present combination therapy methods include, for example, cancers selected from acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), Hodgkin’s lymphoma (HL), non-Hodgkin’s lymphomas (NHLs), multiple myeloma, smoldering myeloma, monoclonal gammopathy of undetermined significance (MGUS), advanced, metastatic, refractory and/or recurrent hematological malignancies, and any combinations of said hematological malignancies.
  • ALL acute lymphoblastic leukemia
  • AML acute myelogenous leukemia
  • CLL chronic lymphocytic leukemia
  • CML chronic myelogenous leukemia
  • NHLs Hodgkin’s lymphoma
  • NHLsmoldering myeloma
  • the hematological malignancy is a cancer selected from acute, chronic, lymphocytic (lymphoblastic) and/or myelogenous leukemias, such as ALL, AML, CLL, and CML; lymphomas, such as HL, NHLs, of which about 85% are B cell lymphomas, including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), mantle cell lymphoma, marginal zone B-cell lymphomas (mucosa-associated lymphoid tissue (MALT) lymphoma, nodal marginal zone B-cell lymphoma, and splenic marginal zone B- cell lymphoma), Burkitt lymphoma, lymphoplasmacytoid lymphoma (LPL; also known as Waldenström’s macroglobulinemia (WM)), hairy cell lymphoma,
  • LPL
  • the present methods are also applicable to treatment of advanced, metastatic, refractory and/or recurrent hematological malignancies.
  • the tumor is metastatic.
  • the tumor is recurrent.
  • the tumor is unresectable.
  • the tumor is metastatic, recurrent, and/or unresectable.
  • the subject has a cancer selected from non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), melanoma, bladder cancer, pancreatic cancer, gastric cancer, colon cancer, renal cell carcinoma (RCC), small-cell lung cancer (SCLC), triple negative breast cancer (TNBC), colorectal cancer (CRC), hepatocellular carcinoma (HCC), mesothelioma, prostate cancer, e.g., metastatic castration-resistant prostate cancer (mCRPC) or castration-sensitive prostate cancer (CSPC), multiple myeloma, and combinations of said cancers.
  • NSCLC non-small cell lung cancer
  • HNSCC head and neck squamous cell carcinoma
  • melanoma bladder cancer
  • pancreatic cancer gastric cancer
  • colon cancer renal cell carcinoma
  • RCC renal cell carcinoma
  • SCLC small-cell lung cancer
  • TNBC triple negative breast cancer
  • CRCC colorectal cancer
  • HCC hepatocellular carcinoma
  • the subject has a cancer selected from NSCLC, melanoma, RCC, TNBC, CRC, HCC, pancreatic cancer, and combinations of said cancers.
  • the subject has a cancer selected from NSCLC, melanoma and RCC and combinations of said cancers.
  • the subject has prostate cancer, e.g., metastatic castration-resistant prostate cancer (mCRPC) or castration-sensitive prostate cancer (CSPC).
  • mCRPC metastatic castration-resistant prostate cancer
  • CSPC castration-sensitive prostate cancer
  • an anti-IL-8 antibody may be administered in combination with an anti-PD-1 antibody (e.g., nivolumab) and, optionally, an anti-CTLA-4 antibody, e.g., ipilimumab.
  • an anti-IL-8 antibody may be administered in combination with an anti-PD-1 antibody (e.g., nivolumab) and, optionally, an anti-CTLA-4 antibody, e.g., ipilimumab, in subjects with histologic or cytologic confirmation of a solid tumor that is advanced (metastatic, recurrent and/or unresectable) with measurable disease per RECIST v1.1, and have an Eastern Cooperative Oncology Group Performance Status of 0 or 1.
  • an anti-PD-1 antibody e.g., nivolumab
  • an anti-CTLA-4 antibody e.g., ipilimumab
  • subjects having a solid tumor e.g., advanced solid tumor, such as NSCLC
  • an anti-IL-8 antibody as combination therapy with an anti-PD-1 antibody (e.g., nivolumab), and, optionally, an anti-CTLA-4 antibody, e.g., ipilimumab
  • the subjects have histologically or cytologically confirmed, advanced (i.e., unresectable or metastatic) NSCLC of either squamous or non-squamous histology; the subjects have had radiologically documented progressive or recurrent disease either during or within 3 months after anti-PD-L1 therapy (administered as monotherapy or as part of a combination); the subjects have not had intervening systemic therapy between anti-PD-L1 treatment and the combination treatment; the subjects have documented PD-L1 status; the subjects have received platinum-based chemotherapy in the recurrent or metastatic setting; the subjects have a known EGFR and ALK status; and/or the
  • subjects having a solid tumor e.g., advanced solid tumor, such as RCC (e.g., with a clear cell component) are treated with an anti-IL-8 antibody as combination therapy with an anti-PD-1 antibody (e.g., nivolumab), and, optionally, an anti- CTLA-4 antibody, e.g., ipilimumab
  • an anti-PD-1 antibody e.g., nivolumab
  • an anti-CTLA-4 antibody e.g., ipilimumab
  • the subjects have radiologically documented progressive or recurrent disease either during or within 3 months after anti-PD-(L)1 therapy (administered as monotherapy or as part of a combination); the subjects have had no intervening systemic therapy between anti-PD-(L)1 treatment and the combination treatment; and/or subjects have received at least 1 but not more than 2 prior anti-angiogenic therapy regimens (including but not limited to bevacizumab, axitinib,
  • subjects having a solid tumor e.g., advanced solid tumor, such as melanoma
  • an anti-IL-8 antibody as combination therapy with an anti-PD-1 or anti-PD-L1 antibody, e.g., nivolumab, and, optionally, an anti-CTLA-4 antibody, e.g., ipilimumab
  • the subjects have histologically confirmed, unresectable Stage III or Stage IV melanoma, as specified in the American Joint Committee on Cancer staging system; the subjects have a documented PD-L1 status; the subjects have radiologically documented progressive or recurrent disease either during or within 3 months after anti-PD-L1 monotherapy or after anti- PD-L1 component of the combination therapy with other agent including but not limited to anti- CTLA-4; and/or the subjects have a known BRAF (V600) mutation status.
  • an anti-PD-1 or anti-PD-L1 antibody e.g., nivolumab
  • an anti-CTLA-4 antibody e
  • subjects having a solid tumor e.g., advanced solid tumor, such as triple negative breast cancer (TNBC)
  • TNBC triple negative breast cancer
  • an anti-IL-8 antibody as combination therapy with an anti-PD-1 or anti-PD-L1 antibody, e.g., nivolumab, and, optionally, an anti-CTLA-4 antibody, e.g., ipilimumab
  • the subjects have histologically documented, locally advanced, unresectable, or metastatic TNBC; the subjects have a negative estrogen receptor/progesterone receptor and HER2 status; and/or the subjects have radiologically documented progression on, or after, or been intolerant to (or are not candidates for) at least 1 line of standard therapy.
  • subjects having a solid tumor e.g., advanced solid tumor, such as colorectal cancer (CRC)
  • an anti-IL-8 antibody as combination therapy with an anti-PD-1 or anti-PD-L1 antibody, e.g., nivolumab, and, optionally, an anti- CTLA-4 antibody, e.g., ipilimumab
  • the subjects have histologically documented, locally advanced, unresectable, or metastatic CRC;
  • the subjects have known microsatellite instability status (MSS) (e.g., expression of MLH1, MSH2, MSH6, and PMS2 by immunohistochemistry (IHC) or absence of instability in microsatellite markers by polymerase chain reaction (PCR));
  • the subjects have radiologically documented progression on, or after, or been intolerant to (or are not candidates for) at least 1 line of standard therapy.
  • MSS microsatellite instability status
  • IHC immunohistochemistry
  • PCR polymerase chain reaction
  • subjects having a solid tumor e.g., advanced solid tumor, such as pancreatic ductal carcinoma (PDC)
  • an anti-IL-8 antibody as combination therapy with an anti-PD-1 or anti-PD-L1 antibody, e.g., nivolumab, and, optionally, an anti-CTLA-4 antibody, e.g., ipilimumab
  • the subjects have histologically documented, locally advanced, unresectable, or metastatic PDC; and/or the subjects have radiologically documented progression on, or after, or been intolerant to (or are not candidates for) at least 1 line of standard therapy.
  • subjects having a solid tumor e.g., advanced solid tumor, such as hepatocellular carcinoma (HCC)
  • an anti-IL-8 antibody as combination therapy with an anti-PD-1 or anti-PD-L1 antibody, e.g., nivolumab, and, optionally, an anti-CTLA-4 antibody, e.g., ipilimumab
  • the subjects have histologically documented HCC that is ineligible for ablative techniques or liver transplant
  • the subjects, who progressed after locoregional therapy for HCC have completed the locoregional therapy for HCC at least 4 weeks prior to the baseline scan
  • the subjects have resolved all acute toxic effects of any prior local treatment to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.03 Grade > 1 or been deemed irreversible
  • the subjects have previous progressive disease, or been intolerant to, at least 1 line of therapy or refused treatment with sorafenib
  • the subjects have a Child
  • the subjects have serum IL-8 levels above the LLOQ.
  • the subjects have baseline serum IL-8 levels >10 pg/ml as assessed, e.g., by sandwich ELISA.
  • the subjects have baseline serum IL-8 levels > 0.1 pg/mL, > 1 pg/ mL, > 2 pg/ mL, > 3 pg/ mL, > 4 pg/ mL, > 5 pg/ml, > 6 pg/ml, > 7 pg/ml, > 8 pg/ml, > 9 pg/ml, > 10 pg/ml, > 11 pg/ml, > 12 pg/ml, > 13 pg/ml, > 14 pg/ml, > 15 pg/ml, > 16 pg/ml, >17 pg/ml, > 18 pg/ml, >19
  • the subjects have baseline serum IL-8 levels of at least 1 pg/ml, 2 pg/ml, 3 pg/ml, 4 pg/ml, 5 pg/ml, 6 pg/ml, 7 pg/ml, 8 pg/ml, 9 pg/ml, 10 pg/ml, 11 pg/ml, 12 pg/ml, 13 pg/ml, 14 pg/ml, 15 pg/ml, 16 pg/ml, 17 pg/ml, 18 pg/ml, 19 pg/ml, 20 pg/ml, 21 pg/ml, 22 pg/ml, 23 pg/ml, 24 pg/ml, 25 pg/ml, 26 pg/ml, 27 pg/ml, 28 pg/ml, 29 pg/ml, 30 pg/m
  • the subjects have baseline serum IL-8 levels of at least 10 pg/ml, 11 pg/ml, 12 pg/ml, 13 pg/ml, 14 pg/ml, 15 pg/ml, 16 pg/ml, 17 pg/ml, 18 pg/ml, 19 pg/ml, 20 pg/ml, 21 pg/ml, 22 pg/ml, 23 pg/ml, 24 pg/ml, 25 pg/ml, 26 pg/ml, 27 pg/ml, 28 pg/ml, 29 pg/ml, or 30 pg/ml.
  • the subjects have baseline serum IL-8 levels of at least 20 pg/ml, 21 pg/ml, 22 pg/ml, 23 pg/ml, 24 pg/ml, or 25 pg/ml. In some embodiments, the subjects have baseline serum IL-8 levels of at least 26 pg/ml, 27 pg/ml, 28 pg/ml, 29 pg/ml, or 30 pg/ml.
  • the subjects have baseline serum IL-8 levels of less than or equal to 15 pg/ml, 16 pg/ml, 17 pg/ml, 18 pg/ml, 19 pg/ml, 20 pg/ml, 21 pg/ml, 22 pg/ml, 23 pg/ml, 24 pg/ml, 25 pg/ml, 26 pg/ml, 27 pg/ml, 28 pg/ml, 29 pg/ml, 30 pg/ml, 32 pg/ml, 34 pg/ml, 36 pg/ml, 38 pg/ml, 40 pg/ml, 42 pg/ml, 44 pg/ml, 46 pg/ml, 48 pg/ml, or 50 pg/ml.
  • the subjects have baseline serum IL-8 levels of less than or equal to 23 pg/ml, 24 pg/ml, 25 pg/ml, 26 pg/ml, 27 pg/ml, 28 pg/ml, 29 pg/ml, or 30 pg/ml. In some embodiments, the subjects have baseline serum IL-8 levels of less than or equal to 23 pg/ml.
  • the subjects have baseline serum IL-8 levels of 1-300 pg/ml, 5-300 pg/ml, 5-150 pg/ml, 10-150 pg/ml, 10- 120 pg/ml, 10-100 pg/ml, 10-80 pg/ml, 10-60 pg/ml, 10-40 pg/ml, 10-30 pg/ml, or 10-20 pg/ml.
  • the subjects have baseline serum IL-8 levels of 10-30 pg/ml, 10-25 pg/ml, 10-23 pg/ml, 10-20 pg/ml, 10-15 pg/ml, 12-30 pg/ml, 12-25 pg/ml, 12-23 pg/ml, 12-20 pg/ml, 12-15 pg/ml, 15-30 pg/ml, 15-25 pg/ml, 15-23 pg/ml, 20-30 pg/ml, 25-35 pg/ml, 30-40 pg/ml, 35-45 pg/ml, 15-20 pg/ml, 20-25 pg/ml, 25-30 pg/ml, 30-35 pg/ml, or 35-50 pg/ml.
  • the subjects have baseline serum IL-8 levels of 10-15 pg/ml, 10-16 pg/ml, 10-17 pg/ml, 10-18 pg/ml, 10-19 pg/ml, 10-20 pg/ml, 10-21 pg/ml, 10-22 pg/ml, 10-23 pg/ml, 10-24 pg/ml, 10-25 pg/ml, 15-18 pg/ml, 15-20 pg/ml, 15-23, pg/ml, 15-25 pg/ml, 18-20 pg/ml, 18-23 pg/ml, 18-25 pg/ml, 20-22 pg/ml, 22-24 pg/ml, 24-26 pg/ml, 26-28 pg/ml, or 28-30 pg/ml.
  • the subjects have baseline serum IL-8 levels of 10-50 pg/ml, 10-40 pg/ml, 10-30 pg/ml, 10-25 pg/ml, 10-23 pg/ml, or 10-20 pg/ml.
  • the subjects have baseline serum IL-8 levels >10 pg/mL; adequate hematologic function defined as 1) Neutrophils ⁇ 1,500 ⁇ /L, 2) Platelets ⁇ 80 ⁇ 10 3 / ⁇ L, and 3) Hemoglobin ⁇ 8 g/dL; adequate hepatic function defined as 1) ALT and AST ⁇ 3 ⁇ ULN limit of normal (ULN), 2) Total bilirubin ⁇ 1.5 ⁇ ULN (except subjects with Gilbert's Syndrome who must have normal direct bilirubin), 3) Prothrombin time-international normalized ratio ⁇ 2.3 or prothrombin time ⁇ 6 seconds above control for those with HCC, 4) Adequate hepatic function as documented by (a) Serum albumin ⁇ 2.8 g/dL, (b) Total bilirubin ⁇ 3 mg/dL, (c) AST and ALT ⁇ 5 ⁇ the institutional ULN for those with HCC; normal thyroid function or stable on hormone supplementation; and/or
  • a patient receiving a treatment described herein may be a patient having one or more of the inclusion criteria set forth in Example 1, or not having one or more of the exclusion criteria set forth in Example 1.
  • subjects having a solid tumor e.g., advanced solid tumor, such as melanoma, non-small cell lung carcinoma (NSCLC), renal cell carcinoma (RCC), triple negative breast cancer (TNBC), colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDA), and hepatocellular carcinoma (HCC)
  • a solid tumor e.g., advanced solid tumor, such as melanoma, non-small cell lung carcinoma (NSCLC), renal cell carcinoma (RCC), triple negative breast cancer (TNBC), colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDA), and hepatocellular carcinoma (HCC)
  • an anti-IL-8 antibody as combination therapy with an anti-PD-1 antibody
  • the subjects have no known or suspected primary CNS malignancies, or tumors with CNS metastases as the only site of disease, except that the subject may have controlled brain metastases (i.e., no radiographic progression for at least 4 weeks following radiation
  • Anti-tumor activity of an anti-IL-8 antibody e.g., 10F8 or HuMax-IL8 in combination with an anti-PD-1 antibody (e.g., nivolumab), and an anti-CTLA-4 antibody (e.g., ipilimumab), may be evidenced by an increase in overall survival relative to a subject treated with a placebo.
  • Efficacy of treatment may be determined by measurement of the objective response rate (ORR). ORR and corresponding 2- sided exact 95% exact confidence interval by the Clopper and Pearson method may be determined. Median duration of response and corresponding two-sided 95% confidence interval may be determined. Duration of response may be analyzed using the Kaplan- Meier method and corresponding two-sided 95% CI using Brookmeyer and Crowley methodology.
  • responses to therapy may include: Partial Response (PR) At least a 30% decrease in the sum of the (RECIST V1.1) diameters of target lesions, taking as o t t ut o t accounts for the size and growth kinetics of both old and new lesions as they appear. , Complete Response (CR) Disappearance of all non-target lesions.
  • PR Partial Response
  • All lymph nodes must be non-pathological ll y u jec s rea e accor ng o e me o s sc ose eren pre era y experence improvement in at least one sign of cancer.
  • improvement is measured by a reduction in the quantity and/or size of measurable tumor lesions.
  • lesions can be measured on chest x-rays or CT or MRI films.
  • cytology or histology can be used to evaluate responsiveness to a therapy.
  • the subject treated exhibits a complete response (CR), a partial response (PR), stable disease (SD), immune-related complete disease (irCR), immune-related partial response (irPR), or immune-related stable disease (irSD).
  • the patient treated experiences tumor shrinkage and/or decrease in growth rate ie suppression of tumor growth
  • unwanted cell proliferation is reduced or inhibited.
  • one or more of the following can occur: the number of cancer cells can be reduced; tumor size can be reduced; cancer cell infiltration into peripheral organs can be inhibited, retarded, slowed, or stopped; tumor metastasis can be slowed or inhibited; tumor growth can be inhibited; recurrence of tumor can be prevented or delayed; one or more of the symptoms associated with cancer can be relieved to some extent.
  • the methods described herein produce at least one therapeutic effect chosen from prolonged survival, such as progress free survival or overall survival, optionally compared to another therapy or placebo.
  • administration of effective amounts of the anti-IL-8 antibody, anti- PD-1 antibody, and optionally anti-CTLA-4 antibody, according to any of the methods provided herein produces at least one therapeutic effect selected from the group consisting of reduction in size of a tumor, reduction in number of metastatic lesions appearing over time, complete remission, partial remission, or stable disease.
  • the improvement of clinical benefit rate is about 20% 20%, 30%, 40%, 50%, 60%, 70%, 80% or more compared to an anti-IL-8 antibody or anti-PD-1 antibody alone.
  • kits which include a pharmaceutical composition containing an anti-IL-8 antibody, such as 10F8 or HuMax-IL8, an anti-PD-1 antibody, an anti-CTLA-4 antibody, and a pharmaceutically-acceptable carrier, in a therapeutically effective amount adapted for use in the methods described herein.
  • the kits optionally also can include instructions, e.g., comprising administration schedules, to allow a practitioner (e.g., a physician, nurse, or patient) to administer the composition contained therein to administer the composition to a patient having cancer (e.g., a solid tumor).
  • the kit also can include a syringe.
  • kits include multiple packages of the single-dose pharmaceutical compositions each containing an effective amount of the anti-IL-8, anti-PD-1 antibody, or anti- CTLA-4 antibody for a single administration in accordance with the methods provided above.
  • Instruments or devices necessary for administering the pharmaceutical composition(s) also may be included in the kits.
  • a kit may provide one or more pre-filled syringes containing an amount of the anti-IL-8 antibody, anti-PD-1 antibody, or anti-CTLA-4 antibody.
  • kits for treating a solid tumor in a human subject comprising: (a) a dose of an anti-IL-8 antibody comprising CDR1, CDR2 and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID NO: 7, and CDR1, CDR2 and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID NO: 8; (b) a dose of an anti-PD-1 antibody comprising CDR1, CDR2 and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID NO: 9, and CDR1, CDR2 and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID NO: 10; (c) an anti-CTLA-4 antibody comprising CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID NO: 27, and CDR1, CDR2, and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID NO: 28
  • Subjects must be at least 18 years of age and have histologic or cytologic confirmation of a solid tumor that is advanced (i.e., metastatic, recurrent, and/or unresectable) with measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, and have at least 1 lesion accessible for biopsy. Subjects must have a detectable serum level of IL-8 at baseline. Objectives The primary objective is to characterize the safety, tolerability, and DLTs, and to determine the RP2D of HuMax-IL8 administered in combination with nivolumab in subjects with advanced solid tumors.
  • RECIST Solid Tumors
  • Secondary objectives include evaluating the preliminary efficacy of HuMax-IL8 in combination with nivolumab in subjects with advanced solid tumors, characterizing the PK and immunogenicity of HuMax-IL8 administered in combination with nivolumab in subjects with advanced solids tumors, and assessing serum IL-8 levels at baseline (i.e., screening) and changes in IL-8 levels on treatment.
  • Exploratory objectives include measuring MDSC, assessing MDSC changes over time and in association with response, characterizing selected biomarker measures in the tumor and peripheral blood and explore their potential association with anti-tumor activity prior to treatment and following administration of HuMax-IL8 in combination with nivolumab, exploring associations between HuMax-IL8 serum PK, safety, efficacy, and clinical biomarkers, assessing PFS and OS in subjects treated with HuMax-IL8 in combination with nivolumab, characterizing the PK and immunogenicity of nivolumab when administered in combination with HuMax-IL8, and assessing the potential effect of HuMax-IL8 on QTc interval.
  • Study Design This is a Phase 1b/2, open-label study of HuMax-IL8 administered in combination with nivolumab in subjects with advanced solid tumors (i.e., metastatic, recurrent, and/or unresectable) who have detectable levels of serum IL-8.
  • the study is comprised of 2 parts.
  • the first part includes a safety evaluation lead-in followed by a randomized dose-finding phase.
  • the second part includes a dose expansion phase.
  • Part 1 Safety Evaluation Lead-in and Randomized Dose-finding Phase
  • the safety of HuMax-IL8 in combination with nivolumab is evaluated in subjects with refractory melanoma non-small cell lung cancer (NSCLC) or renal cell carcinoma (RCC) who have progressed on or relapsed after anti-PD-(L)1 therapy.
  • the safety evaluation lead-in (Part 1A) begins with a cohort of subjects who receive a 2,400 mg flat dose of HuMax-IL8 combined with a 480 mg flat dose of nivolumab every 4 weeks (Q4W).
  • a slightly higher dose (32 mg/kg or 2,560 mg administered every 2 weeks (Q2W); yielding an overall dose of 64 mg/kg or 5,120 mg per month) of HuMax-IL8 monotherapy has been shown to be safe and well tolerated.
  • Safety is confirmed based on use of the Bayesian Logistic Regression Model-Copula method and assessment of available safety data for the first 4 participants.
  • the dose-limiting toxicity (DLT) and the totality of available data the randomized, dose-finding phase (Part 1B) is initiated. Up to 56 additional subjects are enrolled into Part 1B to determine the recommended Phase 2 dose (RP2D) of HuMax-IL8.
  • Subjects are assigned in a 1:1:1 ratio to Cohorts B1, B2, and B3, respectively, so that approximately 20 subjects are treated in parallel in each cohort.
  • Dosing for each cohort is as follows: • Cohort B1: 2,400 mg of BMS-986253 and 480 mg of nivolumab Q4W • Cohort B2: 1,200 mg of BMS-986253 and 480 mg of nivolumab Q4W • Cohort B3: 600 mg of BMS-986253 and 480 mg of nivolumab Q4W.
  • the safety lead-in cohort of Part 1A recommends evaluation of a lower dose of BMS-986253 (1,200 mg) prior to starting the randomized dose-finding phase
  • a cohort of 4 subjects is treated with BMS-986253 (1,200 mg) in combination with 480 mg of nivolumab Q4W.
  • Part 2 Dose Expansion Phase After determination of the RP2D from Part 1, the dose expansion phase (Part 2) is initiated to gather additional safety, tolerability, preliminary efficacy, pharmacokinetic (PK), and pharmacodynamic (PD) information in specific patient populations.
  • Part 2 Dose Expansion Phase
  • Subjects with anti-PD-(L)1 refractory melanoma, RCC, or NSCLC, as well as subjects with advanced triple-negative breast cancer, colorectal cancer, pancreatic ductal adenocarcinoma, or HCC who have failed prior therapies are enrolled in up to 7 independent cohorts.
  • Each anti-PD-(L)1 refractory cohort consists of up to 40 subjects treated at the RP2D of HuMax-IL8 in combination with nivolumab
  • each signal seeking cohort consists of up to 20 subjects treated at the RP2D of HuMax-IL8 in combination with nivolumab.
  • Treatment HuMax-IL8 is administered in combination with nivolumab once Q4W (or 28 days), defined as 1 cycle of the treatment period. All subjects are treated for up to 104 weeks (2 years) (corresponding to 26 cycles of 28 days each) or until disease progression, intolerance to treatment, meeting discontinuation criteria, or withdrawal of consent. Doses are determined as follows. In the safety evaluation lead-in phase (Part 1A), a starting dose of 2,400 mg of HuMax-IL8 is administered in combination with 480 mg of nivolumab Q4W.
  • HuMax- IL8 is infused intravenously (IV) first over the recommended time based on the randomization schedule. A 30-minute observation period follows HuMax-IL8 infusion. Nivolumab is then infused over 30 minutes. A 60-minute observation period follows the nivolumab infusion.
  • Safety follow-up Period Upon completion of study treatment or a decision is made to discontinue treatment, all subjects enter a safety follow-up period. After the end of treatment (EOT) visit, all subjects are evaluated for any new adverse events (AEs) for at least 100 days after the last dose of study treatment. Follow-up visits occur at Days 30, 60, and 100 ( ⁇ 7 days for each visit) after the last dose, or the date of discontinuation ( ⁇ 7 days). All subjects are required to complete 3 clinical safety follow-up visits, regardless of whether new anti-cancer therapy is started.
  • Response Follow-up Period At the time of the EOT visit or at the time of study treatment discontinuation, all subjects undergo radiologic and clinical tumor assessments every 12 weeks (Q12W) until subsequent tumor-directed therapy is initiated.
  • Subjects who remain free of subsequent therapy continue to receive tumor assessment scans Q12W for the first year after discontinuation of study treatment/EOT visit. After the first year of follow-up, visits are per standard of care guidelines, at a minimum of every 6 months up to 2 years following the last dose of study treatment. Radiological assessments for subjects who have ongoing clinical benefit and remain free of subsequent therapy may continue to be collected after they complete the survival follow-up period. • Survival Follow-up Period: In parallel with the safety follow-up period, all subjects start the survival follow-up period. Subjects are followed up Q12W (from EOT) for 2 years or until death, loss to follow-up, withdrawal of consent, or conclusion of the study, whichever comes first. The response follow-up and survival follow-up periods occur simultaneously during the 2-year follow-up period.
  • Subjects must have an Eastern Cooperative Oncology Group Performance Status of 0 or 1.
  • the following tumor histologies are permitted, except for subjects with primary CNS tumors, or with CNS metastases as the only site of active disease.
  • i) Non-Small Cell Lung Carcinoma 1. Histologically or cytologically confirmed, advanced (i.e., unresectable or metastatic) NSCLC of either squamous or non-squamous histology. 2.
  • PD-(L)1 status must be documented if available. PD-(L)1 status is also be re-tested using tissue acquired from the mandatory pre-treatment biopsy. 4. Subjects must have received platinum-based chemotherapy in the recurrent or metastatic setting. 5. Epidermal growth factor receptor and anaplastic lymphoma kinase status must be known. ROS and KRAS mutational status should be documented if available. For subjects harboring genetic alteration for which there is an approved therapy specific to the alteration, prior progression or intolerance to that therapy is required. ii) Renal Cell Carcinoma with a clear cell component. 1.
  • MSS Microsatellite instability status
  • Pancreatic ductal adenocarcinoma Histologically documented, locally advanced, unresectable, or metastatic. 2. Must have radiologically documented progression on, or after, or been intolerant to (or are not candidates for) at least 1 line of standard therapy. 3. Subjects must also have been considered for all other potentially efficacious therapies. viii) Hepatocellular carcinoma 1. For subjects with histologically documented HCC that is ineligible for ablative techniques or liver transplant. For subjects who progressed after locoregional therapy, locoregional therapy for HCC must be completed at least 4 weeks prior to the baseline scan.
  • NCI National Cancer Institute
  • CCAE Common Terminology Criteria for Adverse Events
  • Subjects with radiological diagnosis may be enrolled for screening but histological confirmation is mandatory prior to initiation of study therapy.
  • Previous progressive disease, or been intolerant to, at least 1 line of therapy or refused treatment with sorafenib 4.
  • a Child-Pugh Class A (6 points or less) 5.
  • hepatitis B surface antigen hepatitis B surface antibody, hepatitis B core antibody, hepatitis B deoxyribonucleic acid (DNA) PCR, hepatitis C antibody and hepatitis C ribonucleic acid (RNA) PCR; 6.
  • DNA deoxyribonucleic acid
  • RNA hepatitis C ribonucleic acid
  • HCV hepatitis C virus
  • active HCV infection as defined by any detectable HCV RNA and positive antibody titer
  • Resolved HCV infection as evidenced by undetectable HCV RNA and positive antibody titer
  • Subjects on antiviral therapy for HCV are permitted and should continue treatment during the study.
  • Subjects with active HCV who are not on antiviral therapy at screening cannot be enrolled in the study. 9.
  • Other tumor types could be considered at the time of expansion based on scientific rationale and be added to the study by subsequent amendment. 2.
  • ALT Alanine aminotransferase
  • AST aspartate aminotransferase
  • AEs are coded using the most current version of Medical Dictionary for Regulatory Activities and the incidence of observed AEs are tabulated and reviewed for potential significance and clinical importance. AEs are assessed continuously during the study and for 100 days after the last dose of HuMax-IL8 combined with nivolumab. Both AEs and laboratory tests are graded using the National Cancer Institute Common Terminology Criteria for Adverse Events v4.03.
  • PK Assessments The PK of HuMax-IL8 and nivolumab is derived from serum concentration versus time data over single and multiple dose administrations.
  • the PK parameters that are assessed include: maximum observed plasma concentration (Cmax), time of maximum observed serum concentration (Tmax), area under the serum concentration-time curve (AUC) from time zero to the time of the last quantifiable concentration (AUC(0-T)), AUC in 1 dosing interval (AUC(TAU)), observed serum concentration at the end of a dosing interval (Ctau), Trough observed serum concentrations (this includes pre-dose concentrations [C0] and Ctau) (Ctrough), total body clearance (CLT), average serum concentration over a dosing interval at steady state (Css-avg), accumulation index for AUC and Cmax (AI), and terminal elimination half-life (T-HALF).
  • PK parameter values are derived by non-compartmental methods by a validated PK analysis program. Actual times are used for the final analyses.
  • Immunogenicity Assessments Serum samples for HuMax-IL8 or nivolumab anti-drug antibodies are collected from all subjects at specified time points. Samples collected from subjects in each treatment arm will be evaluated for development of ADA for HuMax- IL8/nivolumab by validated immunoassays. Samples are also analyzed for neutralizing ADA response to HuMax-IL8/nivolumab. Serum samples designated for PK or biomarker assessments may also be used for immunogenicity analysis if required (e.g., insufficient volume for complete immunogenicity assessment or to follow up on suspected immunogenicity related AE).
  • Biomarker Assessments Biomarker measures of baseline and on-treatment peripheral blood, serum, and tumor samples are used to identify PD markers associated with treatment. Additional biomarkers related to mechanism of action, safety biomarkers, and associations with response to HuMax-IL8 in combination with nivolumab are explored. • Serum-based biomarkers: HuMax-IL8 binds to and neutralizes circulating IL-8 and causes significant decreases in serum IL-8 levels in vivo. Therefore, quantitation of serum IL-8 may be used not only for participant selection purposes but also on-treatment as a PD marker to ascertain binding to and neutralization of circulating IL-8 by HuMax-IL8.
  • tumor-based biomarkers to be explored for PD purposes may include, but not be limited to, expression of CD15 by IHC to ascertain impact of treatment on intra-tumoral neutrophils and polymorphonuclear-MDSC populations.
  • tumor may be used to assess impact of treatment on general immune response within tumors.
  • Biomarkers to address this may include, but not be limited to, changes in CD8, PD-1, PD-(L)1 and FoxP3 cell populations on-treatment (all via IHC).
  • Gene expression profiling and T-cell receptor sequencing in tumor tissue may also be used to assess impact of treatment on immune cell activation.
  • IL-8 can induce and maintain the EMT phenotype in cancer cells and can stimulate growth of endothelial cells thus facilitating angiogenesis. Therefore, the impact of treatment on EMT and endothelial cells in tumor samples is evaluated.
  • Biomarkers to assess this may include, but not be limited to, changes in expression of E-cadherin, vimentin, and CD31 (markers of epithelial, mesenchymal, and endothelial cells, respectively) via IHC.
  • Predictive biomarkers In addition to serum levels of IL-8, molecular- based biomarkers including, but not limited to, tumor mutational burden and gene expression profiling in tumor samples obtained at screening may be explored retrospectively to assess association with participant response. Retrospective analysis of the expression of immune cell markers in tumor samples obtained at screening may also be performed to assess association with response to treatment. These markers may include, but not be limited to, CD15, CD8, PD-1, PD-(L)1 and FoxP3.
  • Efficacy assessments for the anti-tumor activity of HuMax-IL8 in combination with nivolumab are based on tumor measurements, using RECIST v1.1, with computed tomography and/or magnetic resonance imaging, as appropriate, at baseline and every 8 weeks ( ⁇ 1 week).
  • Example 2 Efficacy assessments for the anti-tumor activity of HuMax-IL8 in combination with nivolumab are based on tumor measurements, using RECIST v1.1, with computed tomography and/or magnetic resonance imaging, as appropriate, at baseline and every 8 weeks ( ⁇ 1 week). Example 2.
  • nivolumab Approximately 272 patients were randomized to receive nivolumab, at a dose of 3 mg per kilogram of body weight every 2 weeks, or docetaxel, at a dose of 75 mg per square meter of body-surface area every 3 weeks.
  • Study CA209-057 which is a randomized, open-label, international phase 3 study that assigned patients with nonsquamous non-small-cell lung cancer (NSCLC) that had progressed during or after platinum-based doublet chemotherapy to receive nivolumab at a dose of 3 mg per kilogram of body weight every 2 weeks or docetaxel at a dose of 75 mg per square meter of body-surface area every 3 weeks.
  • NSCLC nonsquamous non-small-cell lung cancer
  • Serum IL-8 was measured by immunoassay.
  • Kaplan-Meier curve analyses of overall survival by baseline IL-8 quartiles were performed for each study and for all nivolumab-based therapies combined across the four studies.
  • Time-dependent receiver operating characteristic (ROC) curve analyses (Heagerty and Saha, Biometrics.2000;56(2):337-44) were conducted for 12-month OS for each study and for all nivo-based therapies combined across the four studies.
  • ROC curves were used to determine IL-8 cutoffs associated with response. Additional tumor and peripheral correlative markers were assessed.
  • Serum IL-8 may serve as a biomarker of response to immuno-oncology therapy
  • NIVO nivolumab
  • Modeling analysis of IL-8/OS correlation accounting for tumor burden and tumor PD-L1 expression Cox proportional hazard models for OS were developed for individual studies as well as pooled data from patients treated with NIVO-based therapy, with baseline IL-8 levels, baseline tumor burden, and baseline tumor PD-L1 expression adjusted.
  • Gene expression analyses Gene expression data (HTG EdgeSeq [HTG Molecular Diagnostics, Inc] or RNA sequencing) were generated from archival biopsies or biopsies obtained at screening prior to baseline serum sample acquisition. Patient data were dichotomized on the basis of optimal IL-8 threshold.
  • Statistical analyses Kaplan-Meier analyses were performed on data in FIGs.7–9.
  • Stratification of serum IL-8 into tertile ranges showed an inverse correlation between baseline serum IL-8 and OS.
  • Validated pan-tumor analysis confirmed reduced survival in patients with elevated serum IL-8 levels at baseline.
  • Analysis of pooled data from 1,344 patients receiving NIVO-based therapy in four phase 3 trials (CheckMate trials -017, -057, -067, -025), spanning RCC, melanoma, and squamous and non-squamous NSCLC confirmed that elevated baseline IL-8 levels were associated with decreased OS (FIG. 8).
  • Analysis by tumor type within each NIVO phase 3 trial pooled in FIG.8 showed reduced survival in patients with elevated serum IL-8 levels at baseline (FIG.9).
  • OS ROC analysis identified a baseline serum IL-8 level of 23 pg/mL as a threshold to segment patients likely to respond to NIVO-based therapy ( ⁇ 23 pg/mL) from those unlikely to respond (> 23 pg/mL).
  • OS ROC analysis of CheckMate-067 data was applied to assess the relative association of OS with serum IL-8 levels at baseline, week 7, and change from baseline (FIG.11).
  • IL-8 level at baseline or on-treatment at week 7 were better associated with OS than change from baseline IL-8 in patients with melanoma.
  • Peripheral immune cell subsets and established immune gene signatures were compared with baseline serum IL-8 levels in patients with advanced cancer across 6 NIVO trials (FIG.12).
  • Example 4 Phase 2 Evaluation in Patients Having Advanced Melanoma A randomized, double-blind, phase 2 evaluation in patients with advanced melanoma that progressed on or after anti–PD-(L)1 therapy is conducted.
  • the study includes two arms as follows: (2A) administration of an anti–IL-8 monoclonal antibody (BMS-986253; also referred to herein as HuMax-IL8) in combination with an anti-PD-1 antibody (nivolumab) and an anti CTLA-4 antibody (ipilimumab); and (2B) administration of placebo with an anti-PD-1 antibody (nivolumab) and an anti CTLA-4 antibody (ipilimumab).
  • BMS-986253 also referred to herein as HuMax-IL8
  • HuMax-IL8 an anti-PD-1 antibody
  • ipilimumab anti CTLA-4 antibody
  • ipilimumab anti CTLA-4 antibody
  • BMS-986253 + nivolumab BMS-986253 + nivolumab
  • DLTs dose-limiting toxicities
  • preliminary antitumor activity was observed with BMS-986253 + nivolumab, including partial responses in 5 of 28 patients with melanoma that had progressed on or after prior anti–PD-(L)1 therapy, a population with high unmet medical need.
  • Study design The trial design for phase 2 evaluation is summarized in FIG.14 and the order of infusion is summarized in FIG.15.
  • participant will receive combination therapy as follows in order of infusion: nivolumab 1 mg/kg every three weeks (Q3W) (x4 doses), ipilimumab 3 mg/kg Q3W IV (x4 doses), and BMS-9862533600 mg every two weeks (Q2W) IV (x6 doses) or placebo Q2W IV (x 6 doses).
  • Q3W nivolumab 1 mg/kg every three weeks
  • ipilimumab 3 mg/kg Q3W IV ipilimumab 3 mg/kg Q3W IV (x4 doses)
  • BMS-9862533600 mg every two weeks Q2W
  • placebo Q2W IV x 6 doses
  • the secondary objectives include the following: - To compare the combination therapy of BMS-986253, nivolumab, and ipilimumab in patients with advanced melanoma for: o PFS (per RECIST v1.1) by BICR, regardless of baseline serum IL-8 o objective response rate (ORR) per RECIST v1.1 by BICR and overall survival (OS) in patients with serum IL-8 concentrations of > 10 pg/mL and regardless of baseline serum IL-8 levels - To compare the safety of the combination therapy of BMS-986253, nivolumab, and ipilimumab with that of the combination therapy of placebo, nivolumab, and ipilimumab (adverse events, serious adverse events, and/or adverse events leading to discontinuation, death, or laboratory abnormalities) - To characterize the pharmacokinetics (PK) and immunogenicity (anti-drug antibody or ADAs) of the combination therapy of BMS-98

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Abstract

L'invention concerne des méthodes de traitement clinique de tumeurs (par exemple, des tumeurs solides avancées) chez des patients au moyen d'un anticorps anti-IL-8 en combinaison avec un anticorps anti-PD-1 et, éventuellement, un anticorps anti-CTLA-4.
PCT/US2023/016896 2022-04-01 2023-03-30 Polythérapie avec des anticorps anti-il-8 et des anticorps anti-pd-1 pour le traitement du cancer WO2023192478A1 (fr)

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