WO2019160829A1 - Expansion of tumor infiltrating lymphocytes (tils) with adenosine a2a receptor antagonists and therapeutic combinations of tils and adenosine a2a receptor antagonists - Google Patents

Expansion of tumor infiltrating lymphocytes (tils) with adenosine a2a receptor antagonists and therapeutic combinations of tils and adenosine a2a receptor antagonists Download PDF

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Publication number
WO2019160829A1
WO2019160829A1 PCT/US2019/017572 US2019017572W WO2019160829A1 WO 2019160829 A1 WO2019160829 A1 WO 2019160829A1 US 2019017572 W US2019017572 W US 2019017572W WO 2019160829 A1 WO2019160829 A1 WO 2019160829A1
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Prior art keywords
tils
population
antagonist
adenosine
a2ar
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French (fr)
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Maria Fardis
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Iovance Biotherapeutics Inc
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Iovance Biotherapeutics Inc
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Priority to EP19710828.5A priority Critical patent/EP3752600A1/en
Priority to US16/969,362 priority patent/US20210137930A1/en
Priority to CA3090795A priority patent/CA3090795A1/en
Priority to JP2020564805A priority patent/JP2021512962A/ja
Publication of WO2019160829A1 publication Critical patent/WO2019160829A1/en
Anticipated expiration legal-status Critical
Priority to JP2023204262A priority patent/JP7851289B2/ja
Priority to JP2025244543A priority patent/JP2026062687A/ja
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Definitions

  • TILs tumor infiltrating lymphocytes
  • A2aR adenosine A2A receptor
  • vipadenant such as vipadenant, ciforadenant (CPI-444), SCH58261, SYN115, ZM241385, SCH420814, a xanthine superfamily A2aR antagonist, or related adenosine receptor 2A antagonist
  • SCH58261, SYN115, ZM241385, SCH420814, a xanthine superfamily A2aR antagonist, or related adenosine receptor 2A antagonist are disclosed herein.
  • therapeutic combinations of TILs and A2aR antagonists including compositions and uses thereof in the treatment of diseases such as cancer are disclosed herein.
  • TILs tumor infiltrating lymphocytes
  • Adenosine A2A (or A 2 A) receptors are members of the adenosine receptor group of G-protein-coupled receptors that also includes Ai, A 2B and A3, and are highly expressed in the spleen, thymus, leukocytes, blood platelets and the olfactory bulb.
  • A2A receptor (A2AR) antagonists are thus of interest as a novel form of checkpoint blockade for cancer immunotherapy. Leone, et al, Comp. Struct. Biotechnol. J.
  • the present invention provides the unexpected finding that adenosine receptor antagonists, such as an A2AR antagonist, are useful in the expansion of TILs from tumors, and are further useful in the treatment of patients in combination with TIL therapy.
  • adenosine receptor antagonists such as an A2AR antagonist
  • the invention provides a method of treating a cancer with a population of tumor infiltrating lymphocytes (TILs) comprising the steps of:
  • the second cell culture medium comprises IL-2, OKT-3 (anti-CD3 antibody), peripheral blood mononuclear cells (PBMCs), and optionally the TNFRSF agonist, and wherein the rapid expansion is performed over a period of 14 days or less;
  • a method of treating a cancer with a population of tumor infiltrating lymphocytes comprising the steps of:
  • the second cell culture medium comprises IL-2, OKT-3 (anti-CD3) antibody, peripheral blood mononuclear cells (PBMCs), and optionally the adenosine 2A receptor (A2aR) antagonist and a second adenosine 2A receptor (A2aR) antagonist, and wherein the rapid expansion is performed over a period of 14 days or less; (e) harvesting the third population of TILs; and
  • the invention provides a method for expanding tumor infiltrating lymphocytes (TILs).
  • the present invention provides a method for expanding tumor infiltrating
  • TILs lymphocytes comprising:
  • step (d) performing an initial expansion of said first population of TILs in a first cell culture medium to obtain a second population of TILs, wherein said first cell culture medium comprises IL-2 and at least one adenosine 2A receptor (A2aR) antagonist, wherein said initial expansion is performed in said closed container providing at least 100 cm 2 of gas-permeable surface area, wherein said initial expansion is performed within a first period of about 7-14 days to obtain a second population of TILs, wherein said second population of TILs is at least 50-fold greater in number than said first population of TILs, and wherein the transition from step (c) to step (d) occurs without opening the system;
  • A2aR adenosine 2A receptor
  • step (e) expanding said second population of TILs in a second cell culture medium, wherein said second cell culture medium comprises IL-2, OKT-3, and at least one adenosine 2A receptor (A2aR) antagonist, and peripheral blood mononuclear cells (PBMCs, also known as mononuclear cells (MNCs)), wherein said expansion is performed within a second period of about 7-14 days to obtain a third population of TILs, wherein said third population of TILs exhibits an increased subpopulation of effector T cells and/or central memory T cells relative to the second population of TILs, wherein said expansion is performed in a closed container providing at least 500 cm 2 of gas-permeable surface area, and wherein the transition from step (d) to step (e) occurs without opening the system;
  • PBMCs peripheral blood mononuclear cells
  • step (f) harvesting said third population of TILs obtained from step (e), wherein the transition from step (e) to step (f) occurs without opening the system;
  • step (g) transferring said harvested TIL population from step (f) to an infusion bag, wherein said transfer from step (f) to (g) occurs without opening the system.
  • the method is an in vitro or an ex vivo method.
  • the method further comprises harvesting in step (f) via a cell processing system, such as the LOVO system manufactured by Fresenius Kabi.
  • LOVO cell processing system also refers to any instrument or device manufactured by any vendor that can pump a solution comprising cells through a membrane or filter such as a spinning membrane or spinning filter in a sterile and/or closed system environment, allowing for continuous flow and cell processing to remove supernatant or cell culture media without pelletization.
  • the cell processing system can perform cell separation, washing, fluid-exchange, concentration, and/or other cell processing steps in a closed, sterile system.
  • the closed container is selected from the group consisting of a G-container and a Xuri cellbag.
  • the infusion bag in step (g) is a HypoThermosol-containing infusion bag.
  • the first period in step (d) and said second period in step (e) are each individually performed within a period of 10 days, 11 days, or 12 days.
  • the first period in step (d) and said second period in step (e) are each individually performed within a period of 11 days.
  • steps (a) through (g) are performed within a period of about 25 days to about 30 days.
  • steps (a) through (g) are performed within a period of about 20 days to about 25 days. [0018] In some embodiments, steps (a) through (g) are performed within a period of about 20 days to about 22 days.
  • steps (a) through (g) are performed in 22 days or less.
  • steps (c) through (f) are performed in a single container, wherein performing steps (c) through (f) in a single container results in an increase in TIL yield per resected tumor as compared to performing steps (c) through (f) in more than one container.
  • the PBMCs are added to the TILs during the second period in step (e) without opening the system.
  • the effector T cells and/or central memory T cells obtained from said third population of TILs exhibit one or more characteristics selected from the group consisting of expressing CD27+, expressing CD28+, longer telomeres, increased CD57 expression, and decreased CD56 expression relative to effector T cells and/or central memory T cells obtained from said second population of cells.
  • the effector T cells and/or central memory T cells obtained from said third population of TILs exhibit increased CD57 expression and decreased CD56 expression relative to effector T cells and/or central memory T cells obtained from said second population of cells.
  • the risk of microbial contamination is reduced as compared to an open system.
  • the TILs from step (g) are infused into a patient.
  • the TILs from step (g) are infused into a patient in combination with an adenosine A2A receptor antagonist.
  • the A2aR antagonist is CPI-444, or
  • the adenosine 2A receptor (A2aR) antagonist is selected from the group consisting of CPI-444, SCH58261, ZM241385, SCH420814, SYN115, 8-CSC, KW-6002, A2A receptor antagonist 1, ADZ4635, vipadenant, ST4206, KF21213, SCH412348, 7MMG-49, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, or prodrugs thereof, and combinations thereof.
  • TILs tumor infiltrating lymphocytes
  • step (d) performing an initial expansion of said first population of TILs in a first cell culture medium to obtain a second population of TILs, wherein said first cell culture medium comprises IL-2 and at least one adenosine 2A receptor (A2aR) antagonist, wherein said initial expansion is performed in said closed container providing at least 100 cm2 of gas-permeable surface area, wherein said initial expansion is performed within a first period of about 7-14 days to obtain a second population of TILs, wherein said second population of TILs is at least 50-fold greater in number than said first population of TILs, and wherein the transition from step (c) to step (d) occurs without opening the system;
  • A2aR adenosine 2A receptor
  • step (e) expanding said second population of TILs in a second cell culture medium, wherein said second cell culture medium comprises IL-2, OKT-3, and at least one adenosine 2A receptor (A2aR) antagonist, and peripheral blood mononuclear cells (PBMCs), wherein said expansion is performed within a second period of about 7-14 days to obtain a third population of TILs, wherein said third population of TILs exhibits an increased subpopulation of effector T cells and/or central memory T cells relative to the second population of TILs, wherein said expansion is performed in a closed container providing at least 500 cm 2 of gas-permeable surface area, and wherein the transition from step (d) to step (e) occurs without opening the system;
  • a closed container providing at least 500 cm 2 of gas-permeable surface area
  • step (f) harvesting said third population of TILs obtained from step (e), wherein the transition from step (e) to step (f) occurs without opening the system;
  • step (g) transferring said harvested TIL population from step (f) to an infusion bag, wherein said transfer from step (f) to (g) occurs without opening the system; and (h) administering a therapeutically effective amount of TIL cells from said infusion bag in step (g) to said patient.
  • the a therapeutically effective amount of TIL cells from said infusion bag from step (h) are administered to the patient in combination with an adenosine A2A receptor antagonist.
  • the A2aR antagonist is CPI-444, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, or prodrugs thereof, and combinations thereof.
  • the adenosine 2A receptor (A2aR) antagonist is selected from the group consisting of CPI-444, SCH58261, ZM241385, SCH420814, SYN115, 8-CSC, KW-6002, A2A receptor antagonist 1, ADZ4635, vipadenant, ST4206, KF21213, SCH412348, 7MMG-49, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, or prodrugs thereof, and combinations thereof.
  • the present invention also comprises a population of tumor infiltrating lymphocytes (TILs) for use in treating cancer, wherein the population of TILs is obtainable from a method comprising the steps of: (b) processing a tumor sample obtained from a patient wherein said tumor sample comprises a first population of TILs into multiple tumor fragments; (c) adding said tumor fragments into a closed container; (d) performing an initial expansion of said first population of TILs in a first cell culture medium to obtain a second population of TILs, wherein said first cell culture medium comprises IL-2, wherein said initial expansion is performed in said closed container providing at least 100 cm 2 of gas-permeable surface area, wherein said initial expansion is performed within a first period of about 7-14 days to obtain a second population of TILs, wherein said second population of TILs is at least 50-fold greater in number than said first population of TILs, and wherein the transition from step (c) to step (d) occurs without opening the system; (e)
  • the method comprises a first step (a) obtaining the tumor sample from a patient, wherein said tumor sample comprises the first population of TILs.
  • the population of TILs is for administration from said infusion bag in step (g) in a therapeutically effective amount.
  • the third population of TILs is maintained in a medium or formulation comprising an adenosine 2A receptor (A2aR) antagonist.
  • A2aR antagonist is CPI-444, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, or prodrugs thereof, and combinations thereof.
  • the adenosine 2A receptor (A2aR) antagonist is selected from the group consisting of CPI-444, SCH58261, ZM241385, SCH420814, SYN115, 8-CSC, KW-6002, A2A receptor antagonist 1, ADZ4635, vipadenant, ST4206, KF21213, SCH412348, 7MMG-49, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, or prodrugs thereof, and combinations thereof.
  • a non-myeloablative lymphodepletion regimen prior to administering a therapeutically effective amount of TIL cells in step (h), a non-myeloablative lymphodepletion regimen has been administered to said patient.
  • the populations of TILs is for administration to a patient who has undergone a non-myeloablative lymphodepltion regimen.
  • the non-myeloablative lymphodepletion regimen comprises the steps of administration of cyclophosphamide at a dose of 60 mg/m 2 /day for two days followed by administration of fludarabine at a dose of 25 mg/m 2 /day for five days.
  • the method further comprises the step of treating said patient with a high-dose IL-2 regimen starting on the day after administration of said TIL cells to said patient in step (h).
  • the populations of TILs is for administration prior to a high-dose IL-2 regimen.
  • the population of TILs is for administration one day before the start of the high-dose IL-2 regimen.
  • the high-dose IL-2 regimen comprises 600,000 or 720,000 IU/kg administered as a 15-minute bolus intravenous infusion every eight hours until tolerance.
  • the effector T cells and/or central memory T cells obtained from said third population of TILs exhibit one or more characteristics selected from the group consisting of expressing CD27+, expressing CD28+, longer telomeres, increased CD57 expression, and decreased CD56 expression relative to effector T cells and/or central memory T cells obtained from said second population of cells.
  • the effector T cells and/or central memory T cells obtained from said third population of TILs exhibit increased CD57 expression and decreased CD56 expression relative to effector T cells and/or central memory T cells obtained from said second population of cells.
  • the present invention also provides a method for expanding tumor infiltrating lymphocytes (TILs) comprising the steps of (a) adding processed tumor fragments into a closed system; (b) performing in a first expansion of said first population of TILs in a first cell culture medium to obtain a second population of TILs, wherein said first cell culture medium comprises IL-2 and at least one adenosine 2A receptor (A2aR) antagonist, wherein said first expansion is performed in a closed container providing a first gas-permeable surface area, wherein said first expansion is performed within a first period of about 3-14 days to obtain a second population of TILs, wherein said second population of TILs is at least 50-fold greater in number than said first population of TILs, and wherein the transition from step (a) to step (b) occurs without opening the system; (c) expanding said second population of TILs in a second cell culture medium, wherein said second cell culture medium comprises IL-2, OKT-3, and at least one aden
  • the method further comprises the step of cryopreserving the infusion bag comprising the harvested TIL population using a cryopreservation process.
  • the cryopreservation process is performed using a 1 : 1 ratio of harvested TIL population to CS10 media.
  • the method further comprises the addition of an adenosine 2A receptor (A2aR) antagonist to the first TIL culture medium.
  • A2aR antagonist is CPI-444, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, or prodrugs thereof, and combinations thereof.
  • the adenosine 2A receptor (A2aR) antagonist is selected from the group consisting of CPI-444, SCH58261, ZM241385, SCH420814, SYN115, 8-CSC, KW-6002, A2A receptor antagonist 1, ADZ4635, vipadenant, ST4206, KF21213, SCH412348, 7MMG-49, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, or prodrugs thereof, and combinations thereof.
  • the method further comprises the addition of an adenosine 2A receptor (A2aR) antagonist to the second TIL culture medium.
  • A2aR antagonist is CPI-444, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, or prodrugs thereof, and combinations thereof.
  • the adenosine 2A receptor (A2aR) antagonist is selected from the group consisting of CPI-444, SCH58261, ZM241385, SCH420814, SYN115, 8-CSC, KW-6002, A2A receptor antagonist 1, ADZ4635, vipadenant, ST4206, KF21213, SCH412348, 7MMG-49, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, or prodrugs thereof, and combinations thereof.
  • the antigen-presenting cells are peripheral blood mononuclear cells (PBMCs). In some embodiments, the antigen-presenting cells are artificial antigen- presenting cells.
  • PBMCs peripheral blood mononuclear cells
  • the harvesting in step (d) is performed using a LOVO cell processing system.
  • the multiple fragments comprise about 50 fragments, wherein each fragment has a volume of about 27 mm 3 . In some embodiments, the multiple fragments comprise about 30 to about 60 fragments with a total volume of about 1300 mm 3 to about 1500 mm3. In some embodiments, the multiple fragments comprise about 50 fragments with a total volume of about 1350 mm 3 . In some embodiments, the multiple fragments comprise about 50 fragments with a total mass of about 1 gram to about 1.5 grams.
  • the second cell culture medium is provided in a container selected from the group consisting of a G-container and a Xuri cellbag.
  • the infusion bag in step (e) is a HypoThermosol-containing infusion bag.
  • the first period in step (b) and said second period in step (c) are each individually performed within a period of 10 days, 11 days, or 12 days. In some embodiments, the first period in step (b) and said second period in step (c) are each individually performed within a period of 11 days.
  • the steps (a) through (e) are performed within a period of about 25 days to about 30 days. In some embodiments, the steps (a) through (e) are performed within a period of about 20 days to about 25 days. In some embodiments, the steps (a) through (e) are performed within a period of about 20 days to about 22 days. In some embodiments, the steps (a) through (e) are performed in 22 days or less. In some embodiments, the steps (a) through (e) and cryopreservation are performed in 22 days or less.
  • the steps (b) through (e) are performed in a single closed system, wherein performing steps (b) through (e) in a single container results in an increase in TIL yield per resected tumor as compared to performing steps (b) through (e) in more than one container.
  • the antigen-presenting cells are added to the TILs during the second period in step (c) without opening the system.
  • the effector T cells and/or central memory T cells obtained from said third population of TILs exhibit one or more characteristics selected from the group consisting of expressing CD27+, expressing CD28+, longer telomeres, increased CD57 expression, and decreased CD56 expression relative to effector T cells and/or central memory T cells obtained from said second population of cells.
  • the effector T cells and/or central memory T cells obtained from said third population of TILs exhibit increased CD57 expression and decreased CD56 expression relative to effector T cells and/or central memory T cells obtained from said second population of cells.
  • the risk of microbial contamination is reduced as compared to an open system.
  • the TILs from step (e) are infused into a patient.
  • the TILs from step (e) are infused into a patient in
  • the A2aR antagonist is CPI-444, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, or prodrugs thereof, and combinations thereof.
  • the adenosine 2A receptor (A2aR) antagonist is selected from the group consisting of CPI-444, SCH58261, ZM241385, SCH420814, SYN115, 8-CSC, KW-6002, A2A receptor antagonist 1, ADZ4635, vipadenant, ST4206, KF21213, SCH412348, 7MMG-49, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, or prodrugs thereof, and combinations thereof.
  • the present invention also comprises a population of tumor infiltrating lymphocytes (TILs) for use in treating cancer that are administered to a patient who is receiving an adenosine 2A receptor antagonist (A2aR).
  • TILs tumor infiltrating lymphocytes
  • A2aR is administered orally.
  • the A2aR is first co-administered with a population of tumor infiltrating lymphocytes (TILs) and further administered orally.
  • TILs tumor infiltrating lymphocytes
  • the A2aR is administered once per day orally.
  • the A2aR is administered twice per day orally.
  • the A2aR is administered three times per day orally.
  • the A2aR is CPI-444, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, or prodrugs thereof, and combinations thereof.
  • the adenosine 2A receptor (A2aR) antagonist is selected from the group consisting of CPI-444, SCH58261, ZM241385, SCH420814, SYN115, 8-CSC, KW-6002, A2A receptor antagonist 1, ADZ4635, vipadenant, ST4206, KF21213, SCH412348, 7MMG-49, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, or prodrugs thereof, and combinations thereof.
  • the method further comprises treating the patient with an adenosine 2A receptor antagonist (A2aR) before performing step (a).
  • the patient is treated for at least one day; two days; three or more days; seven days; more than seven days; less than 14 days; 14 or more days.
  • the closed container comprises a single bioreactor.
  • the closed container comprises a G-REX-10.
  • the closed container comprises a G-REX-100.
  • the closed container comprises a G- Rex 500.
  • the closed container comprises a Xuri or Wave bioreactor gas permeable bag.
  • the present disclosure provides a method for expanding tumor infiltrating lymphocytes (TILs) into a therapeutic population of TILs comprising:
  • step (c) performing a first expansion by culturing the first population of TILs in a cell culture medium comprising IL-2 and at least one adenosine 2A receptor (A2aR) antagonist to produce a second population of TILs, wherein the first expansion is performed in a closed container providing a first gas-permeable surface area, wherein the first expansion is performed for about 3-14 days to obtain the second population of TILs, wherein the second population of TILs is at least 50-fold greater in number than the first population of TILs, and wherein the transition from step (b) to step (c) occurs without opening the system;
  • A2aR adenosine 2A receptor
  • step (d) performing a second expansion by supplementing the cell culture medium of the second population of TILs with additional IL-2, OKT-3, and at least one adenosine 2 A receptor (A2aR) antagonist, and antigen presenting cells (APCs), to produce a third population of TILs, wherein the second expansion is performed for about 7-14 days to obtain the third population of TILs, wherein the third population of TILs is a therapeutic population of TILs which comprises an increased subpopulation of effector T cells and/or central memory T cells relative to the second population of TILs, wherein the second expansion is performed in a closed container providing a second gas-permeable surface area, and wherein the transition from step (c) to step
  • step (e) harvesting the therapeutic population of TILs obtained from step (d), wherein the transition from step (d) to step (e) occurs without opening the system; and (f) transferring the harvested TIL population from step (e) to an infusion bag, wherein the transfer from step (e) to (f) occurs without opening the system.
  • the method also comprises as a first step:
  • the method is an in vitro or an ex vivo method.
  • the present disclosure provides a method for expanding tumor infiltrating lymphocytes (TILs) into a therapeutic population of TILs comprising:
  • step (c) performing a first expansion by culturing the first population of TILs in a cell culture medium comprising IL-2 and at least one adenosine 2A receptor (A2aR) antagonist to produce a second population of TILs, wherein the first expansion is performed in a closed container providing a first gas-permeable surface area, wherein the first expansion is performed for about 3-14 days to obtain the second population of TILs, wherein the second population of TILs is at least 50-fold greater in number than the first population of TILs, and wherein the transition from step (b) to step (c) occurs without opening the system;
  • A2aR adenosine 2A receptor
  • step (d) performing a second expansion by supplementing the cell culture medium of the second population of TILs with additional IL-2, OKT-3, and optionally at least one adenosine 2 A receptor (A2aR) antagonist, and antigen presenting cells (APCs), to produce a third population of TILs, wherein the second expansion is performed for about 7-14 days to obtain the third population of TILs, wherein the third population of TILs is a therapeutic population of TILs which comprises an increased subpopulation of effector T cells and/or central memory T cells relative to the second population of TILs, wherein the second expansion is performed in a closed container providing a second gas-permeable surface area, and wherein the transition from step (c) to step (d) occurs without opening the system; (e) harvesting the therapeutic population of TILs obtained from step (d), wherein the transition from step (d) to step (e) occurs without opening the system; and
  • step (f) transferring the harvested TIL population from step (e) to an infusion bag, wherein the transfer from step (e) to (f) occurs without opening the system.
  • the method is an in vitro or an ex vivo method.
  • the method further comprises the step of cryopreserving the infusion bag comprising the harvested TIL population in step (f) using a cryopreservation process.
  • the cryopreservation process is performed using a 1 : 1 ratio of harvested TIL population to cryopreservation media. In some embodiments, the
  • cryopreservation media comprises dimethylsulfoxide.
  • the sulfoxide comprises dimethylsulfoxide.
  • cryopreservation media is selected from the group consisting of Cryostor CS10, HypoThermasol, or a combination thereof.
  • the antigen-presenting cells are peripheral blood mononuclear cells (PBMCs).
  • PBMCs peripheral blood mononuclear cells
  • the PBMCs are irradiated and allogeneic.
  • the PBMCs are added to the cell culture on any of days 9 through 14 in step (d).
  • the antigen-presenting cells are artificial antigen-presenting cells.
  • the harvesting in step (e) is performing using a LOVO cell processing system.
  • the tumor fragments are multiple fragments and comprise about 4 to about 50 fragments, wherein each fragment has a volume of about 27 mm 3 .
  • the multiple fragments comprise about 30 to about 60 fragments with a total volume of about 1300 mm 3 to about 1500 mm 3 .
  • the multiple fragments comprise about 50 fragments with a total volume of about 1350 mm 3 .
  • the multiple fragments comprise about 50 fragments with a total mass of about 1 gram to about 1.5 grams.
  • the cell culture medium is provided in a container selected from the group consisting of a G-container and a Xuri cellbag.
  • the infusion bag in step (f) is a HypoThermosol-containing infusion bag.
  • the first period in step (c) and the second period in step (e) are each individually performed within a period of 10 days, 11 days, or 12 days. In some embodiments, the first period in step (c) and the second period in step (e) are each individually performed within a period of 10 days, 11 days, or 12 days. In some
  • the first period in step (c) and the second period in step (e) are each individually performed within a period of 11 days. In some embodiments, steps (a) through (f) are performed within a period of about 25 days to about 30 days. In some embodiments, steps (a) through (f) are performed within a period of about 20 days to about 25 days. In some embodiments, steps (a) through (f) are performed within a period of about 20 days to about 22 days. In some
  • steps (a) through (f) are performed in 22 days or less. In some embodiments, steps (a) through (f) and cryopreservation are performed in 22 days or less.
  • the therapeutic population of TILs harvested in step (e) comprises sufficient TILs for a therapeutically effective dosage of the TILs.
  • the number of TILs sufficient for a therapeutically effective dosage is from about 2.3x 1010 to about 13.7x 1010.
  • steps (b) through (e) are performed in a single container, wherein performing steps (b) through (e) in a single container results in an increase in TIL yield per resected tumor as compared to performing steps (b) through (e) in more than one container.
  • the antigen-presenting cells are added to the TILs during the second period in step (d) without opening the system.
  • the effector T cells and/or central memory T cells in the therapeutic population of TILs exhibit one or more characteristics selected from the group consisting of expressing CD27+, expressing CD28+, longer telomeres, increased CD57 expression, and decreased CD56 expression relative to effector T cells, and/or central memory T cells obtained from the second population of cells.
  • the effector T cells and/or central memory T cells obtained from the third population of TILs exhibit increased CD57 expression and decreased CD56 expression relative to effector T cells and/or central memory T cells obtained from the second population of cells.
  • the risk of microbial contamination is reduced as compared to an open system.
  • the invention provides a method of treating a cancer with a population of tumor infiltrating lymphocytes (TILs) comprising the steps of:
  • A2aR adenosine 2A receptor
  • TNFRSF tumor necrosis factor receptor superfamily
  • the second cell culture medium comprises IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally the TNFRSF agonist, and wherein the rapid expansion is performed over a period of 14 days or less;
  • the invention provides a method of treating a cancer with a population of tumor infiltrating lymphocytes (TILs) comprising the steps of:
  • A2aR adenosine 2A receptor
  • TNFRSF tumor necrosis factor receptor superfamily
  • the second cell culture medium comprises IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally the TNFRSF agonist, and wherein the rapid expansion is performed over a period of 14 days or less;
  • TNFRSF agonist is a 4-1BB agonist
  • 4- 1BB agonist is selected from the group consisting of urelumab, utomilumab, EU-101 and fragments, derivatives, variants, biosimilars, and combinations thereof.
  • the invention provides a method of treating a cancer with a population of tumor infiltrating lymphocytes (TILs) comprising the steps of:
  • the second cell culture medium comprises IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally the TNFRSF agonist, and wherein the rapid expansion is performed over a period of 14 days or less;
  • TNFRSF agonist is a 4-1BB agonist
  • 4- 1BB agonist is a 4-1BB agonist fusion protein
  • the invention provides a method of treating a cancer with a population of tumor infiltrating lymphocytes (TILs) comprising the steps of:
  • A2aR adenosine 2A receptor
  • TNFRSF tumor necrosis factor receptor superfamily
  • the second cell culture medium comprises IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally the TNFRSF agonist, and wherein the rapid expansion is performed over a period of 14 days or less;
  • the TNFRSF agonist is a 4-1BB agonist fusion protein
  • the 4-1BB agonist fusion protein comprises (i) a first soluble 4-1BB binding domain, (ii) a first peptide linker, (iii) a second soluble 4-1BB binding domain, (iv) a second peptide linker, and (v) a third soluble 4-1BB binding domain, further comprising an additional domain at the N-terminal and/or C-terminal end, and wherein the additional domain comprises a Fc fragment domain and hinge domain, and wherein the fusion protein is a dimeric structure according to structure I-A or structure I-B.
  • the invention provides a method of treating a cancer with a population of tumor infiltrating lymphocytes (TILs) comprising the steps of:
  • A2aR adenosine 2A receptor
  • TNFRSF tumor necrosis factor receptor superfamily
  • the second cell culture medium comprises IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally the TNFRSF agonist, and wherein the rapid expansion is performed over a period of 14 days or less;
  • the TNFRSF agonist is a 0X40 agonist
  • the 0X40 agonist is selected from the group consisting of tavolixizumab, GSK3174998, MEDI6469, MEDI6383, MOXR0916, PF-04518600, Creative Biolabs MOM-18455, and fragments, derivatives, variants, biosimilars, and combinations thereof.
  • the invention provides a method of treating a cancer with a population of tumor infiltrating lymphocytes (TILs) comprising the steps of:
  • A2aR adenosine 2A receptor
  • TNFRSF tumor necrosis factor receptor superfamily
  • the second cell culture medium comprises IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally the TNFRSF agonist, and wherein the rapid expansion is performed over a period of 14 days or less;
  • TNFRSF agonist is an 0X40 agonist
  • 0X40 agonist is an 0X40 agonist fusion protein
  • the invention provides a method of treating a cancer with a population of tumor infiltrating lymphocytes (TILs) comprising the steps of:
  • A2aR adenosine 2A receptor
  • TNFRSF tumor necrosis factor receptor superfamily
  • the second cell culture medium comprises IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally the TNFRSF agonist, and wherein the rapid expansion is performed over a period of 14 days or less;
  • the TNFRSF agonist is an 0X40 agonist fusion protein
  • the 0X40 agonist fusion protein comprises (i) a first soluble 0X40 binding domain, (ii) a first peptide linker, (iii) a second soluble 0X40 binding domain, (iv) a second peptide linker, and (v) a third soluble 0X40 binding domain, further comprising an additional domain at the N-terminal and/or C-terminal end, and wherein the additional domain comprises a Fc fragment domain and hinge domain, and wherein the fusion protein is a dimeric structure according to structure I-A or structure I-B.
  • the invention provides a method of treating a cancer with a population of tumor infiltrating lymphocytes (TILs) comprising the steps of:
  • A2aR adenosine 2A receptor
  • TNFRSF tumor necrosis factor receptor superfamily
  • the second cell culture medium comprises IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally the TNFRSF agonist, and wherein the rapid expansion is performed over a period of 14 days or less;
  • TNFRSF agonist is a CD27 agonist
  • CD27 agonist is varlilumab, or a fragment, derivative, variant, or biosimilar thereof.
  • the invention provides a method of treating a cancer with a population of tumor infiltrating lymphocytes (TILs) comprising the steps of:
  • A2aR adenosine 2A receptor
  • TNFRSF tumor necrosis factor receptor superfamily
  • the second cell culture medium comprises IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally the TNFRSF agonist, and wherein the rapid expansion is performed over a period of 14 days or less;
  • TNFRSF agonist is a CD27 agonist
  • CD27 agonist is an CD27 agonist fusion protein
  • the invention provides a method of treating a cancer with a population of tumor infiltrating lymphocytes (TILs) comprising the steps of:
  • the TNFRSF agonist is a CD27 agonist
  • the CD27 agonist fusion protein comprises (i) a first soluble CD27 binding domain, (ii) a first peptide linker, (iii) a second soluble CD27 binding domain, (iv) a second peptide linker, and (v) a third soluble CD27 binding domain, further comprising an additional domain at the N-terminal and/or C-terminal end, and wherein the additional domain comprises a Fc fragment domain and hinge domain, and wherein the fusion protein is a dimeric structure according to structure I- A or structure I-B.
  • the invention provides a method of treating a cancer with a population of tumor infiltrating lymphocytes (TILs) comprising the steps of:
  • A2aR adenosine 2A receptor
  • TNFRSF tumor necrosis factor receptor superfamily
  • the second cell culture medium comprises IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally the TNFRSF agonist, and wherein the rapid expansion is performed over a period of 14 days or less;
  • the TNFRSF agonist is a GITR agonist
  • the GITR agonist is selected from the group consisting of TRX518, 6C8, 36E5, 3D6, 61G6, 6H6, 61F6, 1D8, 17F10, 35D8, 49A1, 9E5, 31H6, 2155, 698, 706, 827, 1649, 1718, 1D7, 33C9, 33F6, 34G4, 35B10, 41E11, 41G5, 42A11, 44C1, 45A8, 46E11, 48H12, 48H7, 49D9, 49E2, 48A9, 5H7, 7A10, 9H6, and fragments, derivatives, variants, biosimilars, and combinations thereof.
  • the invention provides a method of treating a cancer with a population of tumor infiltrating lymphocytes (TILs) comprising the steps of:
  • A2aR adenosine 2A receptor
  • TNFRSF tumor necrosis factor receptor superfamily
  • the second cell culture medium comprises IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally the TNFRSF agonist, and wherein the rapid expansion is performed over a period of 14 days or less;
  • TNFRSF agonist is an GITR agonist
  • GITR agonist is a GITR agonist fusion protein
  • the invention provides a method of treating a cancer with a population of tumor infiltrating lymphocytes (TILs) comprising the steps of:
  • A2aR adenosine 2A receptor
  • TNFRSF tumor necrosis factor receptor superfamily
  • the second cell culture medium comprises IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally the TNFRSF agonist, and wherein the rapid expansion is performed over a period of 14 days or less;
  • the TNFRSF agonist is a GITR agonist fusion protein
  • the GITR agonist fusion protein comprises (i) a first soluble GITR binding domain, (ii) a first peptide linker, (iii) a second soluble GITR binding domain, (iv) a second peptide linker, and (v) a third soluble GITR binding domain, further comprising an additional domain at the N-terminal and/or C-terminal end, and wherein the additional domain comprises a Fc fragment domain and hinge domain, and wherein the fusion protein is a dimeric structure according to structure I-A or structure I-B.
  • the invention provides a method of treating a cancer with a population of tumor infiltrating lymphocytes (TILs) comprising the steps of:
  • A2aR adenosine 2A receptor
  • TNFRSF tumor necrosis factor receptor superfamily
  • the second cell culture medium comprises IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally the TNFRSF agonist, and wherein the rapid expansion is performed over a period of 14 days or less;
  • the invention provides a method of treating a cancer with a population of tumor infiltrating lymphocytes (TILs) comprising the steps of: (a) resecting a tumor from a patient;
  • A2aR adenosine 2A receptor
  • TNFRSF tumor necrosis factor receptor superfamily
  • the second cell culture medium comprises IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally the TNFRSF agonist, and wherein the rapid expansion is performed over a period of 14 days or less;
  • TNFRSF agonist is an HVEM agonist
  • HVEM agonist is a HVEM agonist fusion protein
  • the invention provides a method of treating a cancer with a population of tumor infiltrating lymphocytes (TILs) comprising the steps of:
  • A2aR adenosine 2A receptor
  • TNFRSF tumor necrosis factor receptor superfamily
  • the second cell culture medium comprises IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally the TNFRSF agonist, and wherein the rapid expansion is performed over a period of 14 days or less;
  • the TNFRSF agonist is a HVEM agonist fusion protein
  • the HVEM agonist fusion protein comprises (i) a first soluble HVEM binding domain, (ii) a first peptide linker, (iii) a second soluble HVEM binding domain, (iv) a second peptide linker, and (v) a third soluble HVEM binding domain, further comprising an additional domain at the N-terminal and/or C-terminal end, and wherein the additional domain comprises a Fc fragment domain and hinge domain, and wherein the fusion protein is a dimeric structure according to structure I- A or structure I-B.
  • the invention provides a method of treating a cancer with a population of tumor infiltrating lymphocytes (TILs) comprising the steps of:
  • the invention provides a method of treating a cancer with a population of tumor infiltrating lymphocytes (TILs) comprising the steps of:
  • A2aR adenosine 2A receptor
  • TNFRSF tumor necrosis factor receptor superfamily
  • the second cell culture medium comprises IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally the TNFRSF agonist, and wherein the rapid expansion is performed over a period of 14 days or less;
  • the invention provides a method of treating a cancer with a population of tumor infiltrating lymphocytes (TILs) comprising the steps of:
  • A2aR adenosine 2A receptor
  • TNFRSF tumor necrosis factor receptor superfamily
  • the second cell culture medium comprises IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally the TNFRSF agonist, and wherein the rapid expansion is performed over a period of 14 days or less;
  • TNFRSF agonist is selected from the group consisting of urelumab, utomilumab, EU-101, tavolixizumab, Creative Biolabs MOM-18455, and fragments, derivatives, variants, biosimilars, and combinations thereof.
  • the invention provides a method of treating a cancer with a population of tumor infiltrating lymphocytes (TILs) comprising the steps of:
  • A2aR adenosine 2A receptor
  • TNFRSF tumor necrosis factor receptor superfamily
  • the second cell culture medium comprises IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally the TNFRSF agonist, and wherein the rapid expansion is performed over a period of 14 days or less;
  • the invention provides a method of treating a cancer with a population of tumor infiltrating lymphocytes (TILs) comprising the steps of:
  • A2aR adenosine 2A receptor
  • TNFRSF tumor necrosis factor receptor superfamily
  • the second cell culture medium comprises IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally the TNFRSF agonist, and wherein the rapid expansion is performed over a period of 14 days or less;
  • the invention provides a method of treating a cancer with a population of tumor infiltrating lymphocytes (TILs) comprising the steps of:
  • A2aR adenosine 2A receptor
  • TNFRSF tumor necrosis factor receptor superfamily
  • the second cell culture medium comprises IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally the TNFRSF agonist, and wherein the rapid expansion is performed over a period of 14 days or less;
  • TNFRSF agonist and at least one adenosine 2A receptor (A2aR) antagonist is added to the second cell culture medium during the rapid expansion at an interval selected from the group consisting of every day, every two days, every three days, every four days, every five days, every six days, every seven days, and every two weeks.
  • the invention provides a method of treating a cancer with a population of tumor infiltrating lymphocytes (TILs) comprising the steps of:
  • A2aR adenosine 2A receptor
  • TNFRSF tumor necrosis factor receptor superfamily
  • the second cell culture medium comprises IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally the TNFRSF agonist, and wherein the rapid expansion is performed over a period of 14 days or less;
  • TNFRSF agonist is added at a concentration sufficient to achieve a concentration in the cell culture medium of between 0.1 pg/mL and 100 pg/mL, and where at least one adenosine 2A receptor (A2aR) antagonist is added to achieve functional antagonism of the A2aR signaling pathway.
  • A2aR adenosine 2A receptor
  • the invention provides a method of treating a cancer with a population of tumor infiltrating lymphocytes (TILs) comprising the steps of:
  • A2aR adenosine 2A receptor
  • TNFRSF tumor necrosis factor receptor superfamily
  • the second cell culture medium comprises IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally the TNFRSF agonist, and wherein the rapid expansion is performed over a period of 14 days or less;
  • the invention provides a method of treating a cancer with a population of tumor infiltrating lymphocytes (TILs) comprising the steps of:
  • A2aR adenosine 2A receptor
  • TNFRSF tumor necrosis factor receptor superfamily
  • the second cell culture medium comprises IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally the TNFRSF agonist, and wherein the rapid expansion is performed over a period of 14 days or less;
  • the invention provides a method of treating a cancer with a population of tumor infiltrating lymphocytes (TILs) comprising the steps of:
  • A2aR adenosine 2A receptor
  • TNFRSF tumor necrosis factor receptor superfamily
  • the second cell culture medium comprises IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally the TNFRSF agonist, and wherein the rapid expansion is performed over a period of 14 days or less;
  • administering a therapeutically effective portion of the third population of TILs to a patient with cancer, wherein at least one adenosine 2A receptor (A2aR) antagonist is present in the first cell culture medium.
  • A2aR adenosine 2A receptor
  • the invention provides a method of treating a cancer with a population of tumor infiltrating lymphocytes (TILs) comprising the steps of:
  • A2aR adenosine 2A receptor
  • TNFRSF tumor necrosis factor receptor superfamily
  • the second cell culture medium comprises IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally the TNFRSF agonist, and wherein the rapid expansion is performed over a period of 14 days or less;
  • the invention provides a method of treating a cancer with a population of tumor infiltrating lymphocytes (TILs) comprising the steps of:
  • A2aR adenosine 2A receptor
  • TNFRSF tumor necrosis factor receptor superfamily
  • the second cell culture medium comprises IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally the TNFRSF agonist, and wherein the rapid expansion is performed over a period of 14 days or less;
  • the invention provides a method of treating a cancer with a population of tumor infiltrating lymphocytes (TILs) comprising the steps of:
  • A2aR adenosine 2A receptor
  • TNFRSF tumor necrosis factor receptor superfamily
  • the second cell culture medium comprises IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally the TNFRSF agonist, and wherein the rapid expansion is performed over a period of 14 days or less;
  • the invention provides a method of treating a cancer with a population of tumor infiltrating lymphocytes (TILs) comprising the steps of:
  • A2aR adenosine 2A receptor
  • TNFRSF tumor necrosis factor receptor superfamily
  • the second cell culture medium comprises IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally the TNFRSF agonist, and wherein the rapid expansion is performed over a period of 14 days or less;
  • the invention provides a method of treating a cancer with a population of tumor infiltrating lymphocytes (TILs) comprising the steps of:
  • A2aR adenosine 2A receptor
  • TNFRSF tumor necrosis factor receptor superfamily
  • the second cell culture medium comprises IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally the TNFRSF agonist, and wherein the rapid expansion is performed over a period of 14 days or less;
  • the invention provides a method of treating a cancer with a population of tumor infiltrating lymphocytes (TILs) comprising the steps of:
  • A2aR adenosine 2A receptor
  • TNFRSF tumor necrosis factor receptor superfamily
  • the second cell culture medium comprises IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally the TNFRSF agonist, and wherein the rapid expansion is performed over a period of 14 days or less;
  • IL-2 is present at an initial concentration of about 1000 IU/mL in the second cell culture medium and the A2aR antagonist is present at a concentration sufficient to attenuate signaling through the A2aR pathway.
  • the invention provides a method of treating a cancer with a population of tumor infiltrating lymphocytes (TILs) comprising the steps of:
  • A2aR adenosine 2A receptor
  • TNFRSF tumor necrosis factor receptor superfamily
  • the second cell culture medium comprises IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally the TNFRSF agonist, and wherein the rapid expansion is performed over a period of 14 days or less;
  • the invention provides a method of treating a cancer with a population of tumor infiltrating lymphocytes (TILs) comprising the steps of:
  • A2aR adenosine 2A receptor
  • TNFRSF tumor necrosis factor receptor superfamily
  • the second cell culture medium comprises IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally the TNFRSF agonist, and wherein the rapid expansion is performed over a period of 14 days or less;
  • the invention provides a method of treating a cancer with a population of tumor infiltrating lymphocytes (TILs) comprising the steps of:
  • A2aR adenosine 2A receptor
  • TNFRSF tumor necrosis factor receptor superfamily
  • the second cell culture medium comprises IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally the TNFRSF agonist, and wherein the rapid expansion is performed over a period of 14 days or less;
  • the invention provides a method of treating a cancer with a population of tumor infiltrating lymphocytes (TILs) comprising the steps of:
  • A2aR adenosine 2A receptor
  • TNFRSF tumor necrosis factor receptor superfamily
  • the second cell culture medium comprises IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally the TNFRSF agonist, and wherein the rapid expansion is performed over a period of 14 days or less;
  • the invention provides a method of treating a cancer with a population of tumor infiltrating lymphocytes (TILs) comprising the steps of:
  • A2aR adenosine 2A receptor
  • TNFRSF tumor necrosis factor receptor superfamily
  • the second cell culture medium comprises IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally the TNFRSF agonist, and wherein the rapid expansion is performed over a period of 14 days or less;
  • the invention provides a method of treating a cancer with a population of tumor infiltrating lymphocytes (TILs) comprising the steps of:
  • A2aR adenosine 2A receptor
  • TNFRSF tumor necrosis factor receptor superfamily
  • the second cell culture medium comprises IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally the TNFRSF agonist, and wherein the rapid expansion is performed over a period of 14 days or less;
  • the invention provides a method of treating a cancer with a population of tumor infiltrating lymphocytes (TILs) comprising the steps of:
  • A2aR adenosine 2A receptor
  • TNFRSF tumor necrosis factor receptor superfamily
  • the second cell culture medium comprises IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally the TNFRSF agonist, and wherein the rapid expansion is performed over a period of 14 days or less;
  • the invention provides a method of treating a cancer with a population of tumor infiltrating lymphocytes (TILs) comprising the steps of:
  • A2aR adenosine 2A receptor
  • TNFRSF tumor necrosis factor receptor superfamily
  • the second cell culture medium comprises IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally the TNFRSF agonist, and wherein the rapid expansion is performed over a period of 14 days or less;
  • the invention provides a method of treating a cancer with a population of tumor infiltrating lymphocytes (TILs) comprising the steps of:
  • A2aR adenosine 2A receptor
  • TNFRSF tumor necrosis factor receptor superfamily
  • the second cell culture medium comprises IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally the TNFRSF agonist, and wherein the rapid expansion is performed over a period of 14 days or less;
  • the invention provides a method of treating a cancer with a population of tumor infiltrating lymphocytes (TILs) comprising the steps of:
  • A2aR adenosine 2A receptor
  • TNFRSF tumor necrosis factor receptor superfamily
  • the second cell culture medium comprises IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally the TNFRSF agonist, and wherein the rapid expansion is performed over a period of 14 days or less; (e) harvesting the third population of TILs; and
  • the invention provides a method of treating a cancer with a population of tumor infiltrating lymphocytes (TILs) comprising the steps of:
  • A2aR adenosine 2A receptor
  • TNFRSF tumor necrosis factor receptor superfamily
  • the second cell culture medium comprises IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally the TNFRSF agonist, and wherein the rapid expansion is performed over a period of 14 days or less;
  • the invention provides a method of treating a cancer with a population of tumor infiltrating lymphocytes (TILs) comprising the steps of: (a) resecting a tumor from a patient;
  • A2aR adenosine 2A receptor
  • TNFRSF tumor necrosis factor receptor superfamily
  • the second cell culture medium comprises IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally the TNFRSF agonist, and wherein the rapid expansion is performed over a period of 14 days or less;
  • the invention provides a method of treating a cancer with a population of tumor infiltrating lymphocytes (TILs) comprising the steps of:
  • A2aR adenosine 2A receptor
  • TNFRSF tumor necrosis factor receptor superfamily
  • the second cell culture medium comprises IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally the TNFRSF agonist, and wherein the rapid expansion is performed over a period of 14 days or less;
  • the invention provides a method of treating a cancer with a population of tumor infiltrating lymphocytes (TILs) comprising the steps of:
  • A2aR adenosine 2A receptor
  • TNFRSF tumor necrosis factor receptor superfamily
  • the second cell culture medium comprises IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally the TNFRSF agonist, and wherein the rapid expansion is performed over a period of 14 days or less;
  • the invention provides a method of treating a cancer with a population of tumor infiltrating lymphocytes (TILs) comprising the steps of:
  • A2aR adenosine 2A receptor
  • TNFRSF tumor necrosis factor receptor superfamily
  • the second cell culture medium comprises IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally the TNFRSF agonist, and wherein the rapid expansion is performed over a period of 14 days or less; (e) harvesting the third population of TILs; and
  • the invention provides a method of treating a cancer with a population of tumor infiltrating lymphocytes (TILs) comprising the steps of:
  • A2aR adenosine 2A receptor
  • TNFRSF tumor necrosis factor receptor superfamily
  • the second cell culture medium comprises IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally the TNFRSF agonist, and wherein the rapid expansion is performed over a period of 14 days or less;
  • the invention provides a method of treating a cancer with a population of tumor infiltrating lymphocytes (TILs) comprising the steps of:
  • A2aR adenosine 2A receptor
  • TNFRSF tumor necrosis factor receptor superfamily
  • the second cell culture medium comprises IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally the TNFRSF agonist, and wherein the rapid expansion is performed over a period of 14 days or less;
  • the invention provides a method of treating a cancer with a population of tumor infiltrating lymphocytes (TILs) comprising the steps of:
  • the second cell culture medium comprises IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally the TNFRSF agonist, and wherein the rapid expansion is performed over a period of 14 days or less;
  • the invention provides a method of treating a cancer with a population of tumor infiltrating lymphocytes (TILs) comprising the steps of:
  • A2aR adenosine 2A receptor
  • TNFRSF tumor necrosis factor receptor superfamily
  • the second cell culture medium comprises IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally the TNFRSF agonist, and wherein the rapid expansion is performed over a period of 14 days or less;
  • cancer selected from the group consisting of melanoma, ovarian cancer, cervical cancer, lung cancer, bladder cancer, breast cancer, head and neck cancer, renal cell carcinoma, acute myeloid leukemia, colorectal cancer, cholangiocarcinoma, and sarcoma.
  • the invention provides a method of treating a cancer with a population of tumor infiltrating lymphocytes (TILs) comprising the steps of:
  • A2aR adenosine 2A receptor
  • TNFRSF tumor necrosis factor receptor superfamily
  • the second cell culture medium comprises IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally the TNFRSF agonist, and wherein the rapid expansion is performed over a period of 14 days or less;
  • NSCLC non-small cell lung cancer
  • TILs triple negative breast cancer
  • double-refractory melanoma double-refractory melanoma
  • uveal (ocular) melanoma uveal (ocular) melanoma
  • the invention provides a method of treating a cancer with a population of tumor infiltrating lymphocytes (TILs) comprising the steps of:
  • A2aR adenosine 2A receptor
  • TNFRSF tumor necrosis factor receptor superfamily
  • the second cell culture medium comprises IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally the TNFRSF agonist, and wherein the rapid expansion is performed over a period of 14 days or less;
  • the invention provides a method of treating a cancer with a population of tumor infiltrating lymphocytes (TILs) comprising the steps of:
  • A2aR adenosine 2A receptor
  • TNFRSF tumor necrosis factor receptor superfamily
  • the second cell culture medium comprises IL-2, OKT-3 (anti-CD3 antibody), peripheral blood mononuclear cells (PBMCs), and optionally the TNFRSF agonist, and wherein the rapid expansion is performed over a period of 14 days or less;
  • PD-l inhibitor or PD-L1 inhibitor is selected from the group consisting of nivolumab, pembrolizumab, durvalumab, atezolizumab, avelumab, and fragments, derivatives, variants, biosimilars, and combinations thereof.
  • the invention provides a method of treating a cancer with a population of tumor infiltrating lymphocytes (TILs) comprising the steps of: (a) resecting a tumor from a patient;
  • A2aR adenosine 2A receptor
  • TNFRSF tumor necrosis factor receptor superfamily
  • the second cell culture medium comprises IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally the TNFRSF agonist, and wherein the rapid expansion is performed over a period of 14 days or less;
  • the invention provides a method of treating a cancer with a population of tumor infiltrating lymphocytes (TILs) comprising the steps of:
  • A2aR adenosine 2A receptor
  • TNFRSF tumor necrosis factor receptor superfamily
  • the second cell culture medium comprises IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally the TNFRSF agonist, and wherein the rapid expansion is performed over a period of 14 days or less;
  • the invention provides a method of treating a cancer with a population of tumor infiltrating lymphocytes (TILs) comprising the steps of:
  • A2aR adenosine 2A receptor
  • TNFRSF tumor necrosis factor receptor superfamily
  • the second cell culture medium comprises IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally the TNFRSF agonist, and wherein the rapid expansion is performed over a period of 14 days or less;
  • PD-l inhibitor or PD-L1 inhibitor is selected from the group consisting of nivolumab, pembrolizumab, durvalumab, atezolizumab, avelumab, and fragments, derivatives, variants, biosimilars, and combinations thereof.
  • the invention provides a method of treating a cancer with a population of tumor infiltrating lymphocytes (TILs) comprising the steps of:
  • A2aR adenosine 2A receptor
  • TNFRSF tumor necrosis factor receptor superfamily
  • the second cell culture medium comprises IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally the TNFRSF agonist, and wherein the rapid expansion is performed over a period of 14 days or less;
  • the invention provides a method of treating a cancer with a population of tumor infiltrating lymphocytes (TILs) comprising the steps of:
  • A2aR adenosine 2A receptor
  • TNFRSF tumor necrosis factor receptor superfamily
  • the second cell culture medium comprises IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally the TNFRSF agonist, and wherein the rapid expansion is performed over a period of 14 days or less;
  • the invention provides a process for the preparation of a population of tumor infiltrating lymphocytes (TILs) comprising the steps of:
  • A2aR adenosine 2A receptor
  • TNFRSF tumor necrosis factor receptor superfamily
  • the second cell culture medium comprises IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally the TNFRSF agonist, and wherein the rapid expansion is performed over a period of 14 days or less; and
  • the invention provides a population of tumor infiltrating lymphocytes (TILs) obtainable from a process comprising the steps of:
  • A2aR adenosine 2A receptor
  • TNFRSF tumor necrosis factor receptor superfamily
  • the second cell culture medium comprises IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally the TNFRSF agonist, and wherein the rapid expansion is performed over a period of 14 days or less; and
  • the invention provides a population of TILs is for use in the treatment of cancer.
  • the invention provides a pharmaceutical composition comprising a population of tumor infiltrating lymphocytes (TILs) for use in treating a cancer wherein the population of tumor infiltrating lymphocytes (TILs) is obtainable by a process comprising the steps of:
  • A2aR adenosine 2A receptor
  • TNFRSF tumor necrosis factor receptor superfamily
  • the second cell culture medium comprises IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally the TNFRSF agonist, and wherein the rapid expansion is performed over a period of 14 days or less; and
  • the first population of TILs is obtained from a tumor.
  • the tumor is firstly resected from a patient.
  • the first population of TILs is obtained from the tumor which has been resected from a patient.
  • the population of TILs is for administration in a therapeutically effective amount to a patient with cancer.
  • the invention provides a method of expanding a population of tumor infiltrating lymphocytes (TILs) comprising the steps of:
  • the second cell culture medium comprises IL-2, OKT-3 (anti-CD3) antibody, at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and a TNFRSF agonist, and wherein the rapid expansion is performed over a period of 11 days or less;
  • the invention provides a method of treating a cancer with a population of tumor infiltrating lymphocytes (TILs) comprising the steps of:
  • the second cell culture medium comprises IL-2, OKT-3 (anti-CD3) antibody, at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and a TNFRSF agonist, and wherein the rapid expansion is performed over a period of 11 days or less;
  • the invention provides a method of treating a cancer with a population of tumor infiltrating lymphocytes (TILs) comprising the steps of:
  • TNFRSF agonist is selected from the group consisting of a 4-1BB agonist, an 0X40 agonist, and a combination thereof.
  • the invention provides a method of treating a cancer with a population of tumor infiltrating lymphocytes (TILs) comprising the steps of:
  • the second cell culture medium comprises IL-2, OKT-3 (anti-CD3) antibody, at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and a TNFRSF agonist, and wherein the rapid expansion is performed over a period of 11 days or less;
  • TNFRSF agonist is selected from the group consisting of a 4-1BB agonist, an 0X40 agonist, and a combination thereof, and
  • the TNFRSF agonist is a 4-1BB agonist
  • the 4-1BB agonist is selected from the group consisting of urelumab, utomilumab, EU-101, a fusion protein, and fragments, derivatives, variants, biosimilars, and combinations thereof.
  • the invention provides a method of treating a cancer with a population of tumor infiltrating lymphocytes (TILs) comprising the steps of:
  • the second cell culture medium comprises IL-2, OKT-3 (anti-CD3) antibody, at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and a TNFRSF agonist, and wherein the rapid expansion is performed over a period of 11 days or less;
  • the rapid expansion is performed over a period of 11 days or less;
  • TNFRSF agonist is selected from the group consisting of a 4-1BB agonist, an 0X40 agonist, and a combination thereof, and
  • the TNFRSF agonist is a 0X40 agonist
  • the 0X40 agonist is selected from the group consisting of tavolixizumab, GSK3174998, MEDI6469, MEDI6383, MOXR0916, PF-04518600, Creative Biolabs MOM-18455, and fragments, derivatives, variants, biosimilars, and combinations thereof.
  • step (d) wherein the 0X4 agonist is present at the start of step (d) at a concentration between 1 pg/mL and 30 pg/mL.
  • the invention provides a method of any of the foregoing embodiments, wherein the TNFRSF agonist is present at the start of step (d) at a concentration between 5 pg/mL and 20 pg/mL.
  • the invention provides a method of any of the foregoing embodiments, wherein the TNFRSF agonist is present at the start of step (d) at a concentration of about 10 pg/mL.
  • the invention provides a method of any of the foregoing embodiments, wherein the TNFRSF agonist is maintained throughout step (d) at a concentration between 1 pg/mL and 30 pg/mL.
  • the invention provides a method of any of the foregoing embodiments, wherein the TNFRSF agonist is maintained throughout step (d) at a concentration between 5 pg/mL and 20 pg/mL.
  • the invention provides a method of any of the foregoing embodiments, wherein the TNFRSF agonist is maintained throughout step (d) at a concentration of about 10 pg/mL.
  • the invention provides a method of any of the foregoing embodiments, wherein the one adenosine 2A receptor (A2aR) antagonist is maintained throughout step (d) at a concentration at least lnM, about 10 nM, about 50 nM, about 60 nM, about 70 nM, about 80 nM, about 85 nM, about 90 nM, about 95 nM, about lOOnM, about luM, about lOuM, about 25uM, about 50 uM, about 75 uM, about 80 uM, about 90 uM, about lOOuM, about l25uM, about 150 uM, about 175 uM, about 200 uM, about 225 uM, about 250 uM, about 280 uM, about 275 uM, about 290 uM, about 300 uM, less than 500 uM, less than 1000 uM, less than 2000 uM, about the
  • the invention provides a method of any of the foregoing embodiments, wherein the third population of TILs exhibits an increased ratio of CD8 + TILs to CD4 + TILs in comparison to the reference ratio of CD8 + TILs to CD4 + TILs in the second population of TILs.
  • the increased ratio is selected from the group consisting of at least 1% greater than the reference ratio, at least 2% greater than the reference ratio, at least 5% greater than the reference ratio, at least 10% greater than the reference ratio, at least 15% greater than the reference ratio, at least 20% greater than the reference ratio, at least 25% greater than the reference ratio, at least 30% greater than the reference ratio, at least 35% greater than the reference ratio, at least 40% greater than the reference ratio, at least 45% greater than the reference ratio, and at least 50% greater than the reference ratio.
  • the increased ratio is between 5% and 80% greater than the reference ratio.
  • the increased ratio is between 10% and 70% greater than the reference ratio.
  • the increased ratio is between 15% and 60% greater than the reference ratio.
  • the reference ratio is obtained from a third TIL population that is a responder to the TNFRSF agonist.
  • the invention provides a method of any of the foregoing embodiments, wherein the cancer is selected from the group consisting of melanoma, uveal (ocular) melanoma, ovarian cancer, cervical cancer, lung cancer, bladder cancer, breast cancer, head and neck cancer (head and neck squamous cell cancer), renal cell carcinoma, colorectal cancer, pancreatic cancer, glioblastoma, cholangiocarcinoma, and sarcoma.
  • the cancer is selected from the group consisting of melanoma, uveal (ocular) melanoma, ovarian cancer, cervical cancer, lung cancer, bladder cancer, breast cancer, head and neck cancer (head and neck squamous cell cancer), renal cell carcinoma, colorectal cancer, pancreatic cancer, glioblastoma, cholangiocarcinoma, and sarcoma.
  • the invention provides a method of any of the foregoing embodiments, wherein the cancer is selected from the group consisting of cutaneous melanoma, uveal (ocular) melanoma, platinum- resistant ovarian cancer, pancreatic ductal adenocarcinoma, osteosarcoma, triple-negative breast cancer, and non-small-cell lung cancer.
  • the cancer is selected from the group consisting of cutaneous melanoma, uveal (ocular) melanoma, platinum- resistant ovarian cancer, pancreatic ductal adenocarcinoma, osteosarcoma, triple-negative breast cancer, and non-small-cell lung cancer.
  • any of the foregoing embodiments may be combined with any of the following embodiments.
  • the process is an in vitro or an ex vivo process.
  • the TNFRSF agonist is selected from the group consisting of a 4- 1BB agonist, an 0X40 agonist, a CD27 agonist, a GITR agonist, a HVEM agonist, a CD95 agonist, and combinations thereof.
  • the TNFRSF agonist is a 4-1BB agonist.
  • the TNFRSF agonist is a 4-1BB agonist
  • the 4-1BB agonist is selected from the group consisting of urelumab, utomilumab, EU-101 and fragments, derivatives, variants, biosimilars, and combinations thereof.
  • the TNFRSF agonist is a 4-1BB agonist
  • the 4-1BB agonist is a 4-1BB agonist fusion protein.
  • the TNFRSF agonist is a 4-1BB agonist fusion protein
  • the 4- 1BB agonist fusion protein comprises (i) a first soluble 4-1BB binding domain, (ii) a first peptide linker, (iii) a second soluble 4-1BB binding domain, (iv) a second peptide linker, and (v) a third soluble 4-1BB binding domain, further comprising an additional domain at the N-terminal and/or C-terminal end, and wherein the additional domain comprises a Fc fragment domain and hinge domain, and wherein the fusion protein is a dimeric structure according to structure I-A or structure I-B.
  • the TNFRSF agonist is a 0X40 agonist.
  • the TNFRSF agonist is a 0X40 agonist
  • the 0X40 agonist is selected from the group consisting of tavolixizumab, GSK3174998, MEDI6469, MEDI6383, MOXR0916, PF-04518600, Creative Biolabs MOM-18455, and fragments, derivatives, variants, biosimilars, and combinations thereof.
  • the TNFRSF agonist is an 0X40 agonist
  • the 0X40 agonist is an 0X40 agonist fusion protein.
  • the TNFRSF agonist is an 0X40 agonist fusion protein
  • the 0X40 agonist fusion protein comprises (i) a first soluble 0X40 binding domain, (ii) a first peptide linker, (iii) a second soluble 0X40 binding domain, (iv) a second peptide linker, and (v) a third soluble 0X40 binding domain, further comprising an additional domain at the N-terminal and/or C-terminal end, and wherein the additional domain comprises a Fc fragment domain and hinge domain, and wherein the fusion protein is a dimeric structure according to structure I-A or structure I-B.
  • the TNFRSF agonist is a CD27 agonist.
  • the TNFRSF agonist is a CD27 agonist
  • the CD27 agonist is varlilumab, or a fragment, derivative, variant, or biosimilar thereof.
  • the TNFRSF agonist is a CD27 agonist, and wherein the CD27 agonist is an CD27 agonist fusion protein.
  • the TNFRSF agonist is a CD27 agonist
  • the CD27 agonist fusion protein comprises (i) a first soluble CD27 binding domain, (ii) a first peptide linker, (iii) a second soluble CD27 binding domain, (iv) a second peptide linker, and (v) a third soluble CD27 binding domain, further comprising an additional domain at the N-terminal and/or C-terminal end, and wherein the additional domain comprises a Fc fragment domain and hinge domain, and wherein the fusion protein is a dimeric structure according to structure I-A or structure I-B.
  • the TNFRSF agonist is a GITR agonist.
  • the TNFRSF agonist is a GITR agonist
  • the GITR agonist is selected from the group consisting of TRX518, 6C8, 36E5, 3D6, 61G6, 6H6, 61F6, 1D8, 17F10, 35D8, 49A1, 9E5, 31H6, 2155, 698, 706, 827, 1649, 1718, 1D7, 33C9, 33F6, 34G4, 35B10, 41E11, 41G5, 42A11, 44C1, 45A8, 46E11, 48H12, 48H7, 49D9, 49E2, 48A9, 5H7, 7A10, 9H6, and fragments, derivatives, variants, biosimilars, and combinations thereof.
  • the TNFRSF agonist is an GITR agonist
  • the GITR agonist is a GITR agonist fusion protein.
  • the TNFRSF agonist is a GITR agonist fusion protein
  • the GITR agonist fusion protein comprises (i) a first soluble GITR binding domain, (ii) a first peptide linker, (iii) a second soluble GITR binding domain, (iv) a second peptide linker, and (v) a third soluble GITR binding domain, further comprising an additional domain at the N-terminal and/or C-terminal end, and wherein the additional domain comprises a Fc fragment domain and hinge domain, and wherein the fusion protein is a dimeric structure according to structure I-A or structure I-B.
  • the TNFRSF agonist is a HVEM agonist.
  • the TNFRSF agonist is an HVEM agonist
  • the HVEM agonist is a HVEM agonist fusion protein.
  • the TNFRSF agonist is a HVEM agonist fusion protein
  • the HVEM agonist fusion protein comprises (i) a first soluble HVEM binding domain, (ii) a first peptide linker, (iii) a second soluble HVEM binding domain, (iv) a second peptide linker, and (v) a third soluble HVEM binding domain, further comprising an additional domain at the N-terminal and/or C-terminal end, and wherein the additional domain comprises a Fc fragment domain and hinge domain, and wherein the fusion protein is a dimeric structure according to structure I-A or structure I-B.
  • the TNFRSF agonist is selected from the group consisting of urelumab, utomilumab, EET-101, tavolixizumab, Creative Biolabs MOM-18455, and fragments, derivatives, variants, biosimilars, and combinations thereof.
  • the first cell culture medium comprises a second TNFRSF agonist.
  • the TNFRSF agonist is added to the first cell culture medium during the initial expansion at an interval selected from the group consisting of every day, every two days, every three days, every four days, every five days, every six days, every seven days, and every two weeks.
  • the TNFRSF agonist is added to the second cell culture medium during the rapid expansion at an interval selected from the group consisting of every day, every two days, every three days, every four days, every five days, every six days, every seven days, and every two weeks.
  • the TNFRSF agonist is added at a concentration sufficient to achieve a concentration in the cell culture medium of between 0.1 pg/mL and 100 pg/mL.
  • the TNFRSF agonist is added at a concentration sufficient to achieve a concentration in the cell culture medium of between 20 pg/mL and 40 pg/mL. [00184] Further details of the TNFRSF agonists are provided herein.
  • IL-2 is present at an initial concentration of about 10 to about 6000 IU/mL in the first cell culture medium.
  • IL-2 is present at an initial concentration of about 3000 IU/mL in the first cell culture medium.
  • IL-2 is present at an initial concentration of about 800 to about 1100 IU/mL in the first cell culture medium.
  • IL-2 is present at an initial concentration of about 1000 IU/mL in the first cell culture medium.
  • IL-2 is present at an initial concentration of about 10 to about 6000 IU/mL in the second cell culture medium.
  • IL-2 is present at an initial concentration of about 3000 IU/mL in the second cell culture medium.
  • IL-2 is present at an initial concentration of about 800 to about 1100 IU/mL in the second cell culture medium.
  • IL-2 is present at an initial concentration of about 1000 IU/mL in the second cell culture medium.
  • IL-15 is present in the first cell culture medium.
  • IL-15 is present at an initial concentration of about 5 ng/mL to about 20 ng/mL in the first cell culture medium.
  • IL-15 is present in the second cell culture medium.
  • IL-15 is present at an initial concentration of about 5 ng/mL to about 20 ng/mL in the second cell culture medium.
  • IL-21 is present in the first cell culture medium.
  • IL-21 is present at an initial concentration of about 5 ng/mL to about 20 ng/mL in the first cell culture medium.
  • IL-21 is present in the second cell culture medium.
  • IL-21 is present at an initial concentration of about 5 ng/mL to about 20 ng/mL in the second cell culture medium.
  • OKT-3 antibody is present at an initial concentration of about 10 ng/mL to about 60 ng/mL in the second cell culture medium.
  • OKT-3 antibody is present at an initial concentration of about 30 ng/mL in the second cell culture medium.
  • the initial expansion is performed using a gas permeable container.
  • the rapid expansion is performed using a gas permeable container.
  • the invention provides a population of tumor infiltrating lymphocytes (TILs) for use in treating a cancer wherein the population of tumor infiltrating lymphocytes (TILs) is obtainable by a process of the invention as described herein.
  • TILs tumor infiltrating lymphocytes
  • the invention provides a pharmaceutical composition comprising a population of tumor infiltrating lymphocytes (TILs) for use in a method of treating a cancer wherein the population of tumor infiltrating lymphocytes (TILs) is obtainable by a process of the invention as described herein.
  • TILs tumor infiltrating lymphocytes
  • the population of TILs and/or the pharmaceutical composition is for use in treating cancer in combination with a TNFRSF.
  • the invention provides a combination of a population of TILs obtainable by a process of the invention as described herein and a TNFRSF for use in the treatment of cancer.
  • the population of TILs and/or the pharmaceutical composition is for use in treating cancer in combination with a TNFRSF agonist wherein the TNFRSF agonist is for administration on the day after administration of the third population of TILs to the patient, and wherein the TNFRSF agonist is administered intravenously at a dose of between 0.1 mg/kg and 50 mg/kg every four weeks for up to eight cycles.
  • the population of TILs and/or the pharmaceutical composition is for use in treating cancer in combination with a TNFRSF agonist wherein the TNFRSF agonist is for administration prior to the step of resecting of a tumor from the patient, and wherein the TNFRSF agonist for administration intravenously at a dose of between 0.1 mg/kg and 50 mg/kg every four weeks for up to eight cycles.
  • the population of TILs and/or the pharmaceutical composition is for use in treating cancer in combination with a non-myeloablative lymphodepletion regimen.
  • the population of TILs and/or the pharmaceutical composition is for use in treating cancer in combination with a non-myeloablative lymphodepletion regimen prior to administering the third population of TILs and/or a pharmaceutical composition comprising the third population of TILs to the patient.
  • the population of TILs and/or the pharmaceutical composition is for use in treating cancer in combination with a non-myeloablative lymphodepletion regimen prior to administering the third population of TILs and/or a pharmaceutical composition comprising the third population of TILs to the patient, wherein the non-myeloablative lymphodepletion regimen comprises the steps of administration of cyclophosphamide at a dose of 60 mg/m 2 /day for two days followed by administration of fludarabine at a dose of 25 mg/m 2 /day for five days. Further details of the non-myeloablative lymphodepletion regimen are provided herein, e.g., under the Heading“Non-Myeloablative Lymphodepletion with
  • the population of TILs and/or the pharmaceutical composition is for use in treating cancer in combination with a IL-2 regimen.
  • the IL-2 regimen is a decrescendo IL-2 regimen.
  • the population of TILs and/or the pharmaceutical composition is for use in treating cancer in combination with a decrescendo IL-2 regimen starting on the day after administration of the third population of TILs and/or a pharmaceutical composition comprising the third population of TILs to the patient, wherein the decrescendo IL-2 regimen comprises aldesleukin administered intravenously at a dose of 18,000,000 IU/m 2 on day 1, 9,000,000 IU/m 2 on day 2, and 4,500,000 IU/m 2 on days 3 and 4.
  • the population of TILs and/or the pharmaceutical composition is for use in treating cancer in combination with pegylated IL-2.
  • the population of TILs and/or the pharmaceutical composition is for use in a method of treating cancer in combination with pegylated IL-2 administered after administration of the third population of TILs and/or a pharmaceutical composition comprising the third population of TILs to the patient at a dose of 0.10 mg/day to 50 mg/day.
  • the population of TILs and/or the pharmaceutical composition is for use in a method of treating cancer in combination with a high-dose IL-2 regimen.
  • the population of TILs and/or the pharmaceutical composition is for use in a method of treating cancer in combination with a high-dose IL-2 regimen starting on the day after administration of the third population of TILs and/or a pharmaceutical composition comprising the third population of TILs to the patient.
  • the population of TILs and/or the pharmaceutical composition is for use in treating cancer in combination with a high-dose IL-2 regimen starting on the day after administration of the third population of TILs and/or a pharmaceutical composition comprising the third population of TILs to the patient, wherein the high-dose IL-2 regimen comprises 600,000 or 720,000 IU/kg of aldesleukin, or a biosimilar or variant thereof, administered as a 15- minute bolus intravenous infusion every eight hours until tolerance.
  • the population of TILs and/or the pharmaceutical composition is for use in treating cancer, wherein the cancer is selected from the group consisting of melanoma, ovarian cancer, cervical cancer, lung cancer, bladder cancer, breast cancer, head and neck cancer, renal cell carcinoma, acute myeloid leukemia, colorectal cancer, cholangiocarcinoma, and sarcoma.
  • the cancer is selected from the group consisting of melanoma, ovarian cancer, cervical cancer, lung cancer, bladder cancer, breast cancer, head and neck cancer, renal cell carcinoma, acute myeloid leukemia, colorectal cancer, cholangiocarcinoma, and sarcoma.
  • the population of TILs and/or the pharmaceutical composition is for use in treating cancer, wherein the cancer is selected from the group consisting of non-small cell lung cancer (NSCLC), triple negative breast cancer, double-refractory melanoma, and uveal (ocular) melanoma.
  • NSCLC non-small cell lung cancer
  • triple negative breast cancer double-refractory melanoma
  • uveal (ocular) melanoma uveal (ocular) melanoma.
  • the population of TILs and/or the pharmaceutical composition is for use in treating cancer in combination with a PD-l inhibitor or PD-L1 inhibitor.
  • the population of TILs and/or the pharmaceutical composition is for use in treating cancer in combination with a PD-l inhibitor or PD-L1 inhibitor, wherein the PD-l inhibitor or PD-L1 inhibitor is selected from the group consisting of nivolumab, pembrolizumab, durvalumab, atezolizumab, avelumab, and fragments, derivatives, variants, biosimilars, and combinations thereof.
  • the population of TILs and/or the pharmaceutical composition is for use in treating cancer in combination with a PD-l inhibitor or PD-L1 inhibitor, wherein the PD-l inhibitor or PD-L1 inhibitor is for administration prior to resecting the tumor from the patient.
  • the population of TILs and/or the pharmaceutical composition is for use in treating cancer in combination with a PD-l inhibitor or PD-L1 inhibitor prior to resecting the tumor from the patient, wherein the PD-l inhibitor or PD-L1 inhibitor is selected from the group consisting of nivolumab, pembrolizumab, durvalumab, atezolizumab, avelumab, and fragments, derivatives, variants, biosimilars, and combinations thereof.
  • the population of TILs and/or the pharmaceutical composition is for use in method of treating cancer in combination with a PD-l inhibitor or PD-L1 inhibitor.
  • the population of TILs and/or the pharmaceutical composition is for use in treating cancer in combination with a PD-l inhibitor or PD-L1 inhibitor, wherein the PD-l inhibitor or PD-L1 inhibitor is selected from the group consisting of nivolumab, pembrolizumab, durvalumab, atezolizumab, avelumab, and fragments, derivatives, variants, biosimilars, and combinations thereof.
  • the population of TILs and/or the pharmaceutical composition is for use in a method of treating cancer in combination with a PD-l inhibitor or PD-L1 inhibitor after resecting the tumor from the patient.
  • the population of TILs and/or the pharmaceutical composition is for use in treating cancer in combination with a PD-l inhibitor or PD-L1 inhibitor after resecting the tumor from the patient, wherein the PD-l inhibitor or PD-L1 inhibitor is selected from the group consisting of nivolumab, pembrolizumab, durvalumab, atezolizumab, avelumab, and fragments, derivatives, variants, biosimilars, and combinations thereof.
  • the population of TILs and/or the pharmaceutical composition is for use in treating cancer in combination with a PD-l inhibitor or PD-L1 inhibitor, wherein the PD-l or PD-L1 inhibitor is for administration after administering the third population of TILs and/or a pharmaceutical composition comprising the third population of TILs to the patient.
  • the population of TILs and/or the pharmaceutical composition is for use in treating cancer in combination with a PD-l inhibitor or PD-L1 inhibitor which is for administration after administering the third population of TILs to the patient, wherein the PD-l inhibitor or PD-L1 inhibitor is selected from the group consisting of nivolumab, pembrolizumab, durvalumab, atezolizumab, avelumab, and fragments, derivatives, variants, biosimilars, and combinations thereof. Further details of the PD-l inhibitor and the PD-L1 inhibitor are described herein e.g. under the heading“Combinations with PD-l and PD-L1 Inhibitors”.
  • the population of TILs and/ or the pharmaceutical composition comprising a population of TILs further comprise one or more features as described herein, for example, under the headings“Pharmaceutical Compositions, Dosages, and Dosing Regimens for TILs” and “Pharmaceutical Compositions, Dosages, and Dosing Regimens for TNFRSF Agonists”.
  • FIG. 1 illustrates a TIL expansion and treatment process.
  • A2AR antagonists (denoted as“A2AR” in FIG. 1) or TNFRSF agonists of the present disclosure may be used in both the pre- REP stage (top half of figure) or REP stage (bottom half of figure) and may be added when IL-2 is added to each cell culture.
  • Step 1 refers to the addition of about 4 tumor fragments into 10 G- Rex 10 flasks.
  • approximately 40 c 10 6 TILs or greater are obtained.
  • a split occurs into 36 G-Rex 100 flasks for REP.
  • TILs are harvested by centrifugation at step 4.
  • Fresh TIL product is obtained at step 5 after a total process time of approximate 43 days, at which point TILs may be infused into a patient.
  • FIG. 2 illustrates a treatment protocol for use with TILs expanded with the A2AR antagonists of the present disclosure.
  • TNFRSF agonists of the present disclosure may also be used during therapy as described herein after administration of TILs or during the expansion processes.
  • FIG. 3 illustrates an exemplary TIL expansion and manufacturing protocol (Process 2A).
  • FIG. 4 illustrates exemplary method steps undertaken in Process 2A.
  • FIG. 5 illustrates an exemplary TIL expansion protocol.
  • FIG. 6 illustrates binding affinity for Creative Biolabs (CB) and BPS Biosciences (BPS) 4-1BB agonist antibodies as assessed by percentage of 4-1BB+ cells by flow cytometry.
  • CB 4-1BB agonist exhibited the highest binding affinity.
  • FIG. 7 illustrates binding affinity for Creative Biolabs (CB) and BPS Biosciences (BPS) 4-1BB agonist antibodies as assessed by mean fluorescence intensity (MFI).
  • CB 4-1BB agonist exhibited the highest binding affinity.
  • FIG. 8 illustrates the results of an assessment of NF-kB pathway activation of anti -4- 1BB agonistic antibodies.
  • FIG. 9 illustrates binding affinity for Creative Biolabs 0X40 agonist antibody as assessed by percentage of OX40 + cells by flow cytometry.
  • FIG. 10 illustrates binding affinity for Creative Biolabs 0X40 agonist antibodies as assessed by mean fluorescence intensity (MFI).
  • FIG. 11 illustrates comparable binding affinity between Creative Biolabs anti-OX40 agonist antibody (at five concentrations shown) and a commercial anti-OX40 (clone Ber- ACT35) agonist.
  • FIG. 12 illustrates the results of an assessment of NF-kB pathway activation of anti- 0X40 agonist antibody.
  • 0X40 reporter cells were treated with either anti-OX40 alone or Isotype control at the concentrations of 1, 2, 4, 8, and 16 pg/mL with or without PBMC feeder cells for 24 hours. The cells were lysed using One-Step Luciferase reagent, and luciferase activity was measured by luminometer.
  • FIG. 13 illustrates the experimental design for 4-1BB and 0X40 agonist experiments during pre-REP.
  • FIG. 14 illustrates the tumor histologies used in the experimental design of FIG. 23.
  • FIG. 15 illustrates the data analysis strategy used to assess the impact of 4-1BB and anti-OX40 agonists used during pre-REP on TIL performance and properties.
  • FIG. 25 illustrates the experimental scheme for REP propagation of pre-REP TILs expanded in the presence of 4-1BB or 0X40 agonists.
  • FIG. 26 illustrates fold expansion of TILs expanded in REP from pre-REP TILs expanded in the presence of CB 4-1BB agonist versus TILs not treated in the pre-REP (NT).
  • FIG. 27 illustrates fold expansion of TILs expanded in REP from pre-REP TILs expanded in the presence of CB 0X40 agonist versus TILs not treated in the pre-REP (NT).
  • FIG. 28 illustrates fold expansion of TILs expanded in REP from pre-REP TILs expanded in the presence of CB 4-1BB agonist and CB 0X40 agonist versus TILs not treated in the pre-REP (NT).
  • FIG. 29 illustrates the histologies of twenty-one TIL lines used for assessment of CB 0X40 agonist during the REP phase.
  • FIG. 30 illustrates the experimental scheme for assessment of CB 0X40 agonist during the REP phase.
  • FIG. 31 illustrates that the presence of an 0X40 agonistic antibody preferentially expands CD8 + TIL during REP (shown as a percentage of CD3 + CD4 + cells).
  • FIG. 32 illustrates that the presence of an 0X40 agonistic antibody preferentially expands CD8 + TIL during REP (shown as a percentage of CD3 + CD8 + cells).
  • FIG. 33 illustrates that in non-responder TIL lines, down-regulation of 0X40 was not observed in CD4 + subset following anti-OX40 treatment.
  • FIG. 34 illustrates experimental details for CB 0X40 agonist dose titration in non responder and responder TIL lines.
  • FIG. 35 illustrates the results of CB 0X40 agonist dose titration in responder TIL lines.
  • FIG. 36 illustrates the results of CB 0X40 agonist dose titration in non-responder TIL lines.
  • FIG. 37 illustrates comparable TCRvb repertoire profiles for responder L4005.
  • FIG. 38 illustrates comparable TCRvb repertoire profiles for responder H3005.
  • FIG. 39 illustrates comparable TCRvb repertoire profiles for responder M1022.
  • FIG. 40 illustrates the cell count results for melanoma TILs obtained after the addition of an A2AR antagonist to pre-REP and REP cultures under various conditions.
  • FIG. 41 illustrates the cell count results for lung TILs (first tumor) obtained after the addition of an A2AR antagonist to pre-REP and REP cultures under various conditions.
  • FIG. 42 illustrates the cell count results for lung TILs (second tumor) obtained after the addition of an A2AR antagonist to pre-REP and REP cultures under various conditions.
  • FIG. 43 illustrates flow cytometry analysis of CD8 + and CD4 + subsets for melanoma TILs obtained after the addition of an A2AR antagonist to pre-REP and REP cultures under various conditions.
  • FIG. 44 illustrates flow cytometry analysis of CD8 + and CD4 + subsets for lung TILs (first tumor) obtained after the addition of an A2AR antagonist to pre-REP and REP cultures under various conditions.
  • FIG. 45 illustrates flow cytometry analysis of CD8 + and CD4 + subsets for lung TILs (second tumor) obtained after the addition of an A2AR antagonist to pre-REP and REP cultures under various conditions.
  • FIG. 46 illustrates ELISA and ELIspot results obtained from melanoma TILs after the addition of an A2AR antagonist to pre-REP and REP cultures under various conditions.
  • FIG. 47 illustrates ELISA and ELIspot results obtained from lung TILs (first tumor) after the addition of an A2AR antagonist to pre-REP and REP cultures under various conditions.
  • FIG. 48 illustrates ELISA and ELIspot results obtained from lung TILs (second tumor) after the addition of an A2AR antagonist to pre-REP and REP cultures under various conditions.
  • FIG. 49 illustrates a treatment protocol for use with TILs expanded with the A2AR antagonists of the present disclosure.
  • TNFRSF agonists of the present disclosure may also be used during therapy as described herein after administration of TILs or during the expansion processes.
  • SEQ ID NO: 1 is the amino acid sequence of the heavy chain of muromonab.
  • SEQ ID NO:2 is the amino acid sequence of the light chain of muromonab.
  • SEQ ID NO:3 is the amino acid sequence of a recombinant human IL-2 protein.
  • SEQ ID NO:4 is the amino acid sequence of aldesleukin.
  • SEQ ID NO: 5 is the amino acid sequence of a recombinant human IL-4 protein.
  • SEQ ID NO:6 is the amino acid sequence of a recombinant human IL-7 protein.
  • SEQ ID NO:7 is the amino acid sequence of a recombinant human IL-15 protein.
  • SEQ ID NO: 8 is the amino acid sequence of a recombinant human IL-21 protein.
  • SEQ ID NO:9 is the amino acid sequence of human 4-1BB.
  • SEQ ID NO: 10 is the amino acid sequence of murine 4-1BB.
  • SEQ ID NO: 11 is the heavy chain for the 4-1BB agonist monoclonal antibody utomilumab (PF-05082566).
  • SEQ ID NO: 12 is the light chain for the 4-1BB agonist monoclonal antibody utomilumab (PF-05082566).
  • SEQ ID NO: 13 is the heavy chain variable region (VH) for the 4-1BB agonist monoclonal antibody utomilumab (PF-05082566).
  • SEQ ID NO: 14 is the light chain variable region (VL) for the 4-1BB agonist monoclonal antibody utomilumab (PF-05082566).
  • SEQ ID NO: 15 is the heavy chain CDR1 for the 4-1BB agonist monoclonal antibody utomilumab (PF-05082566).
  • SEQ ID NO: 16 is the heavy chain CDR2 for the 4-1BB agonist monoclonal antibody utomilumab (PF-05082566).
  • SEQ ID NO: 17 is the heavy chain CDR3 for the 4-1BB agonist monoclonal antibody utomilumab (PF-05082566).
  • SEQ ID NO: 18 is the light chain CDR1 for the 4-1BB agonist monoclonal antibody utomilumab (PF-05082566).
  • SEQ ID NO: 19 is the light chain CDR2 for the 4-1BB agonist monoclonal antibody utomilumab (PF-05082566).
  • SEQ ID NO:20 is the light chain CDR3 for the 4-1BB agonist monoclonal antibody utomilumab (PF-05082566).
  • SEQ ID NO:2l is the heavy chain for the 4-1BB agonist monoclonal antibody urelumab (BMS-663513).
  • SEQ ID NO:22 is the light chain for the 4-1BB agonist monoclonal antibody urelumab (BMS-663513).
  • SEQ ID NO:23 is the heavy chain variable region (VH) for the 4-1BB agonist monoclonal antibody urelumab (BMS-663513).
  • SEQ ID NO:24 is the light chain variable region (VL) for the 4-1BB agonist monoclonal antibody urelumab (BMS-663513).
  • SEQ ID NO:25 is the heavy chain CDR1 for the 4-1BB agonist monoclonal antibody urelumab (BMS-663513).
  • SEQ ID NO:26 is the heavy chain CDR2 for the 4-1BB agonist monoclonal antibody urelumab (BMS-663513).
  • SEQ ID NO:27 is the heavy chain CDR3 for the 4-1BB agonist monoclonal antibody urelumab (BMS-663513).
  • SEQ ID NO:28 is the light chain CDR1 for the 4-1BB agonist monoclonal antibody urelumab (BMS-663513).
  • SEQ ID NO:29 is the light chain CDR2 for the 4-1BB agonist monoclonal antibody urelumab (BMS-663513).
  • SEQ ID NO:30 is the light chain CDR3 for the 4-1BB agonist monoclonal antibody urelumab (BMS-663513).
  • SEQ ID NO:31 is an Fc domain for a TNFRSF agonist fusion protein.
  • SEQ ID NO:32 is a linker for a TNFRSF agonist fusion protein.
  • SEQ ID NO:33 is a linker for a TNFRSF agonist fusion protein.
  • SEQ ID NO:34 is a linker for a TNFRSF agonist fusion protein.
  • SEQ ID NO:35 is a linker for a TNFRSF agonist fusion protein.
  • SEQ ID NO:36 is a linker for a TNFRSF agonist fusion protein.
  • SEQ ID NO:37 is a linker for a TNFRSF agonist fusion protein.
  • SEQ ID NO:38 is a linker for a TNFRSF agonist fusion protein
  • SEQ ID NO:39 is a linker for a TNFRSF agonist fusion protein
  • SEQ ID NO:40 is a linker for a TNFRSF agonist fusion protein
  • SEQ ID N0:4l is a linker for a TNFRSF agonist fusion protein
  • SEQ ID NO:42 is an Fc domain for a TNFRSF agonist fusion protein
  • SEQ ID NO:43 is a linker for a TNFRSF agonist fusion protein
  • SEQ ID NO:44 is a linker for a TNFRSF agonist fusion protein
  • SEQ ID NO:45 is a linker for a TNFRSF agonist fusion protein
  • SEQ ID NO:46 is a 4-1BB ligand (4-1BBL) amino acid sequence
  • SEQ ID NO:47 is a soluble portion of 4-1BBL polypeptide.
  • SEQ ID NO:48 is a heavy chain variable region (VH) for the 4-1BB agonist antibody
  • SEQ ID NO:49 is a light chain variable region (VL) for the 4-1BB agonist antibody
  • SEQ ID NO:50 is a heavy chain variable region (VH) for the 4-1BB agonist antibody
  • SEQ ID NO:5l is a light chain variable region (VL) for the 4-1BB agonist antibody
  • SEQ ID NO:52 is a heavy chain variable region (VH) for the 4-1BB agonist antibody
  • SEQ ID NO:53 is a light chain variable region (VL) for the 4-1BB agonist antibody
  • SEQ ID NO:54 is the amino acid sequence of human 0X40.
  • SEQ ID NO:55 is the amino acid sequence of murine 0X40.
  • SEQ ID NO:56 is the heavy chain for the 0X40 agonist monoclonal antibody tavolixizumab (MEDI-0562).
  • SEQ ID NO:57 is the light chain for the 0X40 agonist monoclonal antibody tavolixizumab (MEDI-0562).
  • SEQ ID NO:58 is the heavy chain variable region (VH) for the 0X40 agonist monoclonal antibody tavolixizumab (MEDI-0562).
  • SEQ ID NO:59 is the light chain variable region (VL) for the 0X40 agonist monoclonal antibody tavolixizumab (MEDI-0562).
  • SEQ ID NO:60 is the heavy chain CDR1 for the 0X40 agonist monoclonal antibody tavolixizumab (MEDI-0562).
  • SEQ ID NO:6l is the heavy chain CDR2 for the 0X40 agonist monoclonal antibody tavolixizumab (MEDI-0562).
  • SEQ ID NO:62 is the heavy chain CDR3 for the 0X40 agonist monoclonal antibody tavolixizumab (MEDI-0562).
  • SEQ ID NO:63 is the light chain CDR1 for the 0X40 agonist monoclonal antibody tavolixizumab (MEDI-0562).
  • SEQ ID NO:64 is the light chain CDR2 for the 0X40 agonist monoclonal antibody tavolixizumab (MEDI-0562).
  • SEQ ID NO:65 is the light chain CDR3 for the 0X40 agonist monoclonal antibody tavolixizumab (MEDI-0562).
  • SEQ ID NO:66 is the heavy chain for the 0X40 agonist monoclonal antibody 11D4.
  • SEQ ID NO:67 is the light chain for the 0X40 agonist monoclonal antibody 11D4.
  • SEQ ID NO:68 is the heavy chain variable region (VH) for the 0X40 agonist monoclonal antibody 11D4.
  • SEQ ID NO:69 is the light chain variable region (VL) for the 0X40 agonist monoclonal antibody 11D4.
  • SEQ ID NO:70 is the heavy chain CDR1 for the 0X40 agonist monoclonal antibody 11D4.
  • SEQ ID NO:7l is the heavy chain CDR2 for the 0X40 agonist monoclonal antibody 11D4.
  • SEQ ID NO:72 is the heavy chain CDR3 for the 0X40 agonist monoclonal antibody 11D4.
  • SEQ ID NO:73 is the light chain CDR1 for the 0X40 agonist monoclonal antibody 11D4.
  • SEQ ID NO:74 is the light chain CDR2 for the 0X40 agonist monoclonal antibody 11D4.
  • SEQ ID NO:75 is the light chain CDR3 for the 0X40 agonist monoclonal antibody 11D4.
  • SEQ ID NO:76 is the heavy chain for the 0X40 agonist monoclonal antibody 18D8.
  • SEQ ID NO:77 is the light chain for the 0X40 agonist monoclonal antibody 18D8.
  • SEQ ID NO:78 is the heavy chain variable region (VH) for the 0X40 agonist monoclonal antibody 18D8.
  • SEQ ID NO:79 is the light chain variable region (VL) for the 0X40 agonist monoclonal antibody 18D8.
  • SEQ ID NO:80 is the heavy chain CDR1 for the 0X40 agonist monoclonal antibody 18D8.
  • SEQ ID NO:8l is the heavy chain CDR2 for the 0X40 agonist monoclonal antibody 18D8.
  • SEQ ID NO:82 is the heavy chain CDR3 for the 0X40 agonist monoclonal antibody 18D8.
  • SEQ ID NO:83 is the light chain CDR1 for the 0X40 agonist monoclonal antibody 18D8.
  • SEQ ID NO:84 is the light chain CDR2 for the 0X40 agonist monoclonal antibody 18D8.
  • SEQ ID NO:85 is the light chain CDR3 for the 0X40 agonist monoclonal antibody 18D8.
  • SEQ ID NO:86 is the heavy chain variable region (VH) for the 0X40 agonist monoclonal antibody Hul 19-122.
  • SEQ ID NO:87 is the light chain variable region (VL) for the 0X40 agonist monoclonal antibody Hul 19-122.
  • SEQ ID NO:88 is the heavy chain CDR1 for the 0X40 agonist monoclonal antibody Hul 19-122.
  • SEQ ID NO:89 is the heavy chain CDR2 for the 0X40 agonist monoclonal antibody Hul 19-122.
  • SEQ ID NO:90 is the heavy chain CDR3 for the 0X40 agonist monoclonal antibody Hul 19-122.
  • SEQ ID NO:9l is the light chain CDR1 for the 0X40 agonist monoclonal antibody Hul 19-122.
  • SEQ ID NO:92 is the light chain CDR2 for the 0X40 agonist monoclonal antibody Hul 19-122.
  • SEQ ID NO:93 is the light chain CDR3 for the 0X40 agonist monoclonal antibody Hul 19-122.
  • SEQ ID NO:94 is the heavy chain variable region (VH) for the 0X40 agonist monoclonal antibody Hul06-222.
  • SEQ ID NO:95 is the light chain variable region (VL) for the 0X40 agonist monoclonal antibody Hul06-222.
  • SEQ ID NO:96 is the heavy chain CDR1 for the 0X40 agonist monoclonal antibody Hu 106-222.
  • SEQ ID NO:97 is the heavy chain CDR2 for the 0X40 agonist monoclonal antibody Hu 106-222.
  • SEQ ID NO:98 is the heavy chain CDR3 for the 0X40 agonist monoclonal antibody Hu 106-222.
  • SEQ ID NO:99 is the light chain CDR1 for the 0X40 agonist monoclonal antibody Hu 106-222.
  • SEQ ID NO: 100 is the light chain CDR2 for the 0X40 agonist monoclonal antibody Hu 106-222.
  • SEQ ID NO: 101 is the light chain CDR3 for the 0X40 agonist monoclonal antibody Hu 106-222.
  • SEQ ID NO: 102 is an 0X40 ligand (OX40L) amino acid sequence.
  • SEQ ID NO: 103 is a soluble portion of OX40L polypeptide.
  • SEQ ID NO: 104 is an alternative soluble portion of OX40L polypeptide.
  • SEQ ID NO: 105 is the heavy chain variable region (VH) for the 0X40 agonist monoclonal antibody 008.
  • SEQ ID NO: 106 is the light chain variable region (VL) for the 0X40 agonist monoclonal antibody 008.
  • SEQ ID NO: 107 is the heavy chain variable region (VH) for the 0X40 agonist monoclonal antibody 011.
  • SEQ ID NO: 108 is the light chain variable region (VL) for the 0X40 agonist monoclonal antibody 011.
  • SEQ ID NO: 109 is the heavy chain variable region (VH) for the 0X40 agonist monoclonal antibody 021.
  • SEQ ID NO: 110 is the light chain variable region (VL) for the 0X40 agonist monoclonal antibody 021.
  • SEQ ID NO: 111 is the heavy chain variable region (VH) for the 0X40 agonist monoclonal antibody 023.
  • SEQ ID NO: 112 is the light chain variable region (VL) for the 0X40 agonist monoclonal antibody 023.
  • SEQ ID NO: 113 is the heavy chain variable region (VH) for an 0X40 agonist monoclonal antibody.
  • SEQ ID NO: 114 is the light chain variable region (VL) for an 0X40 agonist monoclonal antibody.
  • SEQ ID NO: 115 is the heavy chain variable region (VH) for an 0X40 agonist monoclonal antibody.
  • SEQ ID NO: 116 is the light chain variable region (VL) for an 0X40 agonist monoclonal antibody.
  • SEQ ID NO: 117 is the heavy chain variable region (VH) for a humanized 0X40 agonist monoclonal antibody.
  • SEQ ID NO: 118 is the heavy chain variable region (VH) for a humanized 0X40 agonist monoclonal antibody.
  • SEQ ID NO: 119 is the light chain variable region (VL) for a humanized 0X40 agonist monoclonal antibody.
  • SEQ ID NO: 120 is the light chain variable region (VL) for a humanized 0X40 agonist monoclonal antibody.
  • SEQ ID NO: 121 is the heavy chain variable region (VH) for a humanized 0X40 agonist monoclonal antibody.
  • SEQ ID NO: 122 is the heavy chain variable region (VH) for a humanized 0X40 agonist monoclonal antibody.
  • SEQ ID NO: 123 is the light chain variable region (VL) for a humanized 0X40 agonist monoclonal antibody.
  • SEQ ID NO: 124 is the light chain variable region (VL) for a humanized 0X40 agonist monoclonal antibody.
  • SEQ ID NO: 125 is the heavy chain variable region (VH) for an 0X40 agonist monoclonal antibody.
  • SEQ ID NO: 126 is the light chain variable region (VL) for an 0X40 agonist monoclonal antibody.
  • SEQ ID NO: 127 is the amino acid sequence of human CD27.
  • SEQ ID NO: 128 is the amino acid sequence of macaque CD27.
  • SEQ ID NO: 129 is the heavy chain for the CD27 agonist monoclonal antibody varlilumab (CDX-1127).
  • SEQ ID NO: 130 is the light chain for the CD27 agonist monoclonal antibody varlilumab (CDX-1127).
  • SEQ ID NO: 131 is the heavy chain variable region (VH) for the CD27 agonist monoclonal antibody varlilumab (CDX-1127).
  • SEQ ID NO: 132 is the light chain variable region (VL) for the CD27 agonist monoclonal antibody varlilumab (CDX-1127).
  • SEQ ID NO: 133 is the heavy chain CDR1 for the CD27 agonist monoclonal antibody varlilumab (CDX-1127).
  • SEQ ID NO: 134 is the heavy chain CDR2 for the CD27 agonist monoclonal antibody varlilumab (CDX-1127).
  • SEQ ID NO: 135 is the heavy chain CDR3 for the CD27 agonist monoclonal antibody varlilumab (CDX-1127).
  • SEQ ID NO: 136 is the light chain CDR1 for the CD27 agonist monoclonal antibody varlilumab (CDX-1127).
  • SEQ ID NO: 137 is the light chain CDR2 for the CD27 agonist monoclonal antibody varlilumab (CDX-1127).
  • SEQ ID NO: 138 is the light chain CDR3 for the CD27 agonist monoclonal antibody varlilumab (CDX-1127).
  • SEQ ID NO: 139 is an CD27 ligand (CD70) amino acid sequence.
  • SEQ ID NO: 140 is a soluble portion of CD70 polypeptide.
  • SEQ ID NO: 141 is an alternative soluble portion of CD70 polypeptide.
  • SEQ ID NO: 142 is the amino acid sequence of human GITR (human tumor necrosis factor receptor superfamily member 18 (TNFRSF18) protein).
  • SEQ ID NO: 143 is the amino acid sequence of murine GITR (murine tumor necrosis factor receptor superfamily member 18 (TNFRSF18) protein).
  • SEQ ID NO: 144 is the amino acid sequence of the heavy chain variant HuN6C8 (glycosylated) of the 6C8 humanized GITR agonist monoclonal antibody, with an N (asparagine) in CDR2, corresponding to SEQ ID NO: 60 in ET.S. Patent No. 7,812,135.
  • SEQ ID NO: 145 is the amino acid sequence of the heavy chain variant HuN6C8 (aglycosylated) of the 6C8 humanized GITR agonist monoclonal antibody, with an N
  • SEQ ID NO: 146 is the amino acid sequence of the heavy chain variant HuQ6C8 (glycosylated) of the 6C8 humanized GITR agonist monoclonal antibody, with an Q (glutamine) in CDR2, corresponding to SEQ ID NO: 62 in U.S. Patent No. 7,812,135.
  • SEQ ID NO: 147 is the amino acid sequence of the heavy chain variant HuQ6C8 (aglycosylated) of the 6C8 humanized GITR agonist monoclonal antibody, with an Q
  • SEQ ID NO: 148 is the amino acid sequence of the light chain of the 6C8 humanized GITR agonist monoclonal antibody, corresponding to SEQ ID NO:58 in U.S. Patent No.
  • SEQ ID NO: 149 is the amino acid sequence of the leader sequence that may optionally be included with the amino acid sequences of SEQ ID NO: 144, SEQ ID NO: 145, SEQ ID NO: 146, or SEQ ID NO: 147 in GITR agonist monoclonal antibodies.
  • SEQ ID NO: 150 is the amino acid sequence of the leader sequence that may optionally be included with the amino acid sequence of SEQ ID NO: 148 in GITR agonist monoclonal antibodies.
  • SEQ ID NO: 151 is the amino acid sequence of the heavy chain variable region of the 6C8 humanized GITR agonist monoclonal antibody, corresponding to SEQ ID NO: l in U.S. Patent No. 7,812, 135.
  • SEQ ID NO: 152 is the amino acid sequence of the heavy chain variable region of the 6C8 humanized GITR agonist monoclonal antibody, corresponding to SEQ ID NO:66 in U.S. Patent No. 7,812, 135.
  • SEQ ID NO: 153 is the amino acid sequence of the light chain variable region of the 6C8 humanized GITR agonist monoclonal antibody, corresponding to SEQ ID NO:2 in U.S. Patent No. 7,812,135.
  • SEQ ID NO: 154 is the amino acid sequence of the heavy chain CDR1 region of the 6C8 humanized GITR agonist monoclonal antibody, corresponding to SEQ ID NO:3 in ET.S. Patent No. 7,812,135.
  • SEQ ID NO: 155 is the amino acid sequence of the heavy chain CDR2 region of the 6C8 humanized GITR agonist monoclonal antibody, corresponding to SEQ ID NO:4 in ET.S. Patent No. 7,812,135.
  • SEQ ID NO: 156 is the amino acid sequence of the heavy chain CDR2 region of the 6C8 humanized GITR agonist monoclonal antibody, corresponding to SEQ ID NO:l9 in U.S. Patent No. 7,812,135.
  • SEQ ID NO: 157 is the amino acid sequence of the heavy chain CDR3 region of the 6C8 humanized GITR agonist monoclonal antibody, corresponding to SEQ ID NO:5 in U.S. Patent No. 7,812,135.
  • SEQ ID NO: 158 is the amino acid sequence of the heavy chain CDR1 region of the 6C8 humanized GITR agonist monoclonal antibody, corresponding to SEQ ID NO:6 in U.S. Patent No. 7,812,135.
  • SEQ ID NO: 159 is the amino acid sequence of the heavy chain CDR2 region of the 6C8 humanized GITR agonist monoclonal antibody, corresponding to SEQ ID NO:7 in U.S. Patent No. 7,812,135.
  • SEQ ID NO: 160 is the amino acid sequence of the heavy chain CDR3 region of the 6C8 humanized GITR agonist monoclonal antibody, corresponding to SEQ ID NO:8 in U.S. Patent No. 7,812,135.
  • SEQ ID NO: 161 is the amino acid sequence of the heavy chain variant HuN6C8 (glycosylated) of the 6C8 chimeric GITR agonist monoclonal antibody, with an N (asparagine) in CDR2, corresponding to SEQ ID NO:23 in U.S. Patent No. 7,812,135.
  • SEQ ID NO: 162 is the amino acid sequence of the heavy chain variant HuQ6C8 (aglycosylated) of the 6C8 chimeric GITR agonist monoclonal antibody, with an Q (glutamine) in CDR2, corresponding to SEQ ID NO:24 in U.S. Patent No. 7,812,135.
  • SEQ ID NO: 163 is the amino acid sequence of the light chain of the 6C8 chimeric GITR agonist monoclonal antibody, corresponding to SEQ ID NO:22 in ET.S. Patent No. 7,812,135.
  • SEQ ID NO: 164 is the amino acid sequence of the GITR agonist 36E5 heavy chain variable region from ET.S. Patent No. 8,709,424.
  • SEQ ID NO: 165 is the amino acid sequence of the GITR agonist 36E5 light chain variable region from U.S. Patent No. 8,709,424.
  • SEQ ID NO: 166 is the amino acid sequence of the GITR agonist 3D6 heavy chain variable region from U.S. Patent No. 8,709,424.
  • SEQ ID NO: 167 is the amino acid sequence of the GITR agonist 3D6 light chain variable region from U.S. Patent No. 8,709,424.
  • SEQ ID NO: 168 is the amino acid sequence of the GITR agonist 61G6 heavy chain variable region from U.S. Patent No. 8,709,424.
  • SEQ ID NO: 169 is the amino acid sequence of the GITR agonist 61G6 light chain variable region from U.S. Patent No. 8,709,424.
  • SEQ ID NO: 170 is the amino acid sequence of the GITR agonist 6H6 heavy chain variable region from U.S. Patent No. 8,709,424.
  • SEQ ID NO: 171 is the amino acid sequence of the GITR agonist 6H6 light chain variable region from U.S. Patent No. 8,709,424.
  • SEQ ID NO: 172 is the amino acid sequence of the GITR agonist 61F6 heavy chain variable region from U.S. Patent No. 8,709,424.
  • SEQ ID NO: 173 is the amino acid sequence of the GITR agonist 61F6 light chain variable region from U.S. Patent No. 8,709,424.
  • SEQ ID NO: 174 is the amino acid sequence of the GITR agonist 1D8 heavy chain variable region from U.S. Patent No. 8,709,424.
  • SEQ ID NO: 175 is the amino acid sequence of the GITR agonist 1D8 light chain variable region from U.S. Patent No. 8,709,424.
  • SEQ ID NO: 176 is the amino acid sequence of the GITR agonist 17F10 heavy chain variable region from ET.S. Patent No. 8,709,424.
  • SEQ ID NO: 177 is the amino acid sequence of the GITR agonist 17F10 light chain variable region from ET.S. Patent No. 8,709,424.
  • SEQ ID NO: 178 is the amino acid sequence of the GITR agonist 35D8 heavy chain variable region from U.S. Patent No. 8,709,424.
  • SEQ ID NO: 179 is the amino acid sequence of the GITR agonist 35D8 light chain variable region from U.S. Patent No. 8,709,424.
  • SEQ ID NO: 180 is the amino acid sequence of the GITR agonist 49 A 1 heavy chain variable region from U.S. Patent No. 8,709,424.
  • SEQ ID NO: 181 is the amino acid sequence of the GITR agonist 49 A 1 light chain variable region from U.S. Patent No. 8,709,424.
  • SEQ ID NO: 182 is the amino acid sequence of the GITR agonist 9E5 heavy chain variable region from U.S. Patent No. 8,709,424.
  • SEQ ID NO: 183 is the amino acid sequence of the GITR agonist 9E5 light chain variable region from U.S. Patent No. 8,709,424.
  • SEQ ID NO: 184 is the amino acid sequence of the GITR agonist 31H6 heavy chain variable region from U.S. Patent No. 8,709,424.
  • SEQ ID NO: 185 is the amino acid sequence of the GITR agonist 31H6 light chain variable region from U.S. Patent No. 8,709,424.
  • SEQ ID NO: 186 is the amino acid sequence of the humanized GITR agonist 36E5 heavy chain variable region from U.S. Patent No. 8,709,424.
  • SEQ ID NO: 187 is the amino acid sequence of the humanized GITR agonist 36E5 light chain variable region from U.S. Patent No. 8,709,424.
  • SEQ ID NO: 188 is the amino acid sequence of the humanized GITR agonist 3D6 heavy chain variable region from U.S. Patent No. 8,709,424.
  • SEQ ID NO: 189 is the amino acid sequence of the humanized GITR agonist 3D6 light chain variable region from U.S. Patent No. 8,709,424.
  • SEQ ID NO: 190 is the amino acid sequence of the humanized GITR agonist 61G6 heavy chain variable region from U.S. Patent No. 8,709,424.
  • SEQ ID NO: 191 is the amino acid sequence of the humanized GITR agonist 61G6 light chain variable region from U.S. Patent No. 8,709,424.
  • SEQ ID NO: 192 is the amino acid sequence of the humanized GITR agonist 6H6 heavy chain variable region from U.S. Patent No. 8,709,424.
  • SEQ ID NO: 193 is the amino acid sequence of the humanized GITR agonist 6H6 light chain variable region from U.S. Patent No. 8,709,424.
  • SEQ ID NO: 194 is the amino acid sequence of the humanized GITR agonist 61F6 heavy chain variable region from U.S. Patent No. 8,709,424.
  • SEQ ID NO: 195 is the amino acid sequence of the humanized GITR agonist 61F6 light chain variable region from U.S. Patent No. 8,709,424.
  • SEQ ID NO: 196 is the amino acid sequence of the humanized GITR agonist 1D8 heavy chain variable region from U.S. Patent No. 8,709,424.
  • SEQ ID NO: 197 is the amino acid sequence of the humanized GITR agonist 1D8 light chain variable region from U.S. Patent No. 8,709,424.
  • SEQ ID NO: 198 is the amino acid sequence of the humanized GITR agonist 17F10 heavy chain variable region from U.S. Patent No. 8,709,424.
  • SEQ ID NO: 199 is the amino acid sequence of the humanized GITR agonist 17F10 light chain variable region from U.S. Patent No. 8,709,424.
  • SEQ ID NO:200 is the amino acid sequence of the humanized GITR agonist 35D8 heavy chain variable region from U.S. Patent No. 8,709,424.
  • SEQ ID NO:20l is the amino acid sequence of the humanized GITR agonist 35D8 light chain variable region from U.S. Patent No. 8,709,424.
  • SEQ ID NO:202 is the amino acid sequence of the humanized GITR agonist 49 A 1 heavy chain variable region from U.S. Patent No. 8,709,424.
  • SEQ ID NO:203 is the amino acid sequence of the humanized GITR agonist 49A1 light chain variable region from U.S. Patent No. 8,709,424.
  • SEQ ID NO:204 is the amino acid sequence of the humanized GITR agonist 9E5 heavy chain variable region from ET.S. Patent No. 8,709,424.
  • SEQ ID NO:205 is the amino acid sequence of the humanized GITR agonist 9E5 light chain variable region from ET.S. Patent No. 8,709,424.
  • SEQ ID NO:206 is the amino acid sequence of the humanized GITR agonist 31H6 heavy chain variable region from U.S. Patent No. 8,709,424.
  • SEQ ID NO:207 is the amino acid sequence of the humanized GITR agonist 31H6 light chain variable region from U.S. Patent No. 8,709,424.
  • SEQ ID NO:208 is the amino acid sequence of the GITR agonist 2155 variable heavy chain from U.S. Patent Application Publication No. US 2013/0108641 Al.
  • SEQ ID NO:209 is the amino acid sequence of the GITR agonist 2155 variable light chain from U.S. Patent Application Publication No. US 2013/0108641 Al.
  • SEQ ID NO:2lO is the amino acid sequence of the GITR agonist 2155 humanized (HC1) heavy chain from U.S. Patent Application Publication No. US 2013/0108641 Al.
  • SEQ ID NO:2l 1 is the amino acid sequence of the GITR agonist 2155 humanized (HC2) heavy chain from U.S. Patent Application Publication No. US 2013/0108641 Al.
  • SEQ ID NO:2l2 is the amino acid sequence of the GITR agonist 2155 humanized (HC3a) heavy chain from U.S. Patent Application Publication No. US 2013/0108641 Al.
  • SEQ ID NO:2l3 is the amino acid sequence of the humanized (HC3b) GITR agonist heavy chain from U.S. Patent Application Publication No. US 2013/0108641 Al.
  • SEQ ID NO:2l4 is the amino acid sequence of the humanized (HC4) GITR agonist heavy chain from U.S. Patent Application Publication No. US 2013/0108641 Al.
  • SEQ ID NO:2l5 is the amino acid sequence of the 2155 humanized (LC1) GITR agonist light chain from U.S. Patent Application Publication No. US 2013/0108641 Al.
  • SEQ ID NO:2l6 is the amino acid sequence of the 2155 humanized (LC2a) GITR agonist light chain from U.S. Patent Application Publication No. US 2013/0108641 Al.
  • SEQ ID NO:2l7 is the amino acid sequence of the 2155 humanized (LC2b) GITR agonist light chain from U.S. Patent Application Publication No. US 2013/0108641 Al.
  • SEQ ID NO:2l8 is the amino acid sequence of the 2155 humanized (LC3) GITR agonist light chain from U.S. Patent Application Publication No. US 2013/0108641 Al.
  • SEQ ID NO:2l9 is the amino acid sequence of the GITR agonist 698 variable heavy chain from U.S. Patent Application Publication No. US 2013/0108641 Al.
  • SEQ ID NO:220 is the amino acid sequence of the GITR agonist 698 variable light chain from U.S. Patent Application Publication No. US 2013/0108641 Al.
  • SEQ ID NO:22l is the amino acid sequence of the GITR agonist 706 variable heavy chain from U.S. Patent Application Publication No. US 2013/0108641 Al.
  • SEQ ID NO:222 is the amino acid sequence of the GITR agonist 706 variable light chain from U.S. Patent Application Publication No. US 2013/0108641 Al.
  • SEQ ID NO:223 is the amino acid sequence of the GITR agonist 827 variable heavy chain from U.S. Patent Application Publication No. US 2013/0108641 Al.
  • SEQ ID NO:224 is the amino acid sequence of the GITR agonist 827 variable light chain from U.S. Patent Application Publication No. US 2013/0108641 Al.
  • SEQ ID NO:225 is the amino acid sequence of the GITR agonist 1718 variable heavy chain from U.S. Patent Application Publication No. US 2013/0108641 Al.
  • SEQ ID NO:226 is the amino acid sequence of the GITR agonist 1718 variable light chain from U.S. Patent Application Publication No. US 2013/0108641 Al.
  • SEQ ID NO:227 is the amino acid sequence of the GITR agonist 2155 heavy chain CDR3 from U.S. Patent Application Publication No. US 2013/0108641 Al.
  • SEQ ID NO:228 is the amino acid sequence of the GITR agonist 2155 heavy chain CDR2 from U.S. Patent Application Publication No. US 2013/0108641 Al.
  • SEQ ID NO:229 is the amino acid sequence of the GITR agonist 2155 heavy chain CDR1 from U.S. Patent Application Publication No. US 2013/0108641 Al.
  • SEQ ID NO:230 is the amino acid sequence of the GITR agonist 2155 light chain CDR3 from U.S. Patent Application Publication No. US 2013/0108641 Al.
  • SEQ ID NO:231 is the amino acid sequence of the GITR agonist 2155 light chain CDR2 from U.S. Patent Application Publication No. US 2013/0108641 Al.
  • SEQ ID NO:232 is the amino acid sequence of the GITR agonist 2155 light chain CDR1 from U.S. Patent Application Publication No. US 2013/0108641 Al.
  • SEQ ID NO:233 is the amino acid sequence of the GITR agonists 698 and 706 heavy chain CDR3 from U.S. Patent Application Publication No. US 2013/0108641 Al.
  • SEQ ID NO:234 is the amino acid sequence of the GITR agonists 698 and 706 heavy chain CDR2 from U.S. Patent Application Publication No. US 2013/0108641 Al.
  • SEQ ID NO:235 is the amino acid sequence of the GITR agonists 698 and 706 heavy chain CDR1 from U.S. Patent Application Publication No. US 2013/0108641 Al.
  • SEQ ID NO:236 is the amino acid sequence of the GITR agonist 698 light chain CDR3 from U.S. Patent Application Publication No. US 2013/0108641 Al.
  • SEQ ID NO:237 is the amino acid sequence of the GITR agonists 698, 706, 827, and 1649 light chain CDR2 from U.S. Patent Application Publication No. US 2013/0108641 Al.
  • SEQ ID NO:238 is the amino acid sequence of the GITR agonists 698, 706, 827, and 1649 light chain CDR1 from U.S. Patent Application Publication No. US 2013/0108641 Al.
  • SEQ ID NO:239 is the amino acid sequence of the GITR agonists 706, 827, and 1649 light chain CDR3 from U.S. Patent Application Publication No. US 2013/0108641 Al.
  • SEQ ID NO:240 is the amino acid sequence of the GITR agonists 827 and 1649 heavy chain CDR3 from U.S. Patent Application Publication No. US 2013/0108641 Al.
  • SEQ ID NO:24l is the amino acid sequence of the GITR agonist 827 heavy chain CDR2 from U.S. Patent Application Publication No. US 2013/0108641 Al.
  • SEQ ID NO:242 is the amino acid sequence of the GITR agonist 1649 heavy chain CDR2 from U.S. Patent Application Publication No. US 2013/0108641 Al.
  • SEQ ID NO:243 is the amino acid sequence of the GITR agonist 1718 heavy chain CDR3 from U.S. Patent Application Publication No. US 2013/0108641 Al.
  • SEQ ID NO:244 is the amino acid sequence of the GITR agonist 1718 heavy chain CDR2 from U.S. Patent Application Publication No. US 2013/0108641 Al.
  • SEQ ID NO:245 is the amino acid sequence of the GITR agonist 1718 heavy chain CDR1 from U.S. Patent Application Publication No. US 2013/0108641 Al.
  • SEQ ID NO:246 is the amino acid sequence of the GITR agonist 1718 light chain CDR3 from U.S. Patent Application Publication No. US 2013/0108641 Al.
  • SEQ ID NO:247 is the amino acid sequence of the GITR agonist 1718 light chain CDR2 from U.S. Patent Application Publication No. US 2013/0108641 Al.
  • SEQ ID NO:248 is the amino acid sequence of the GITR agonist 1718 light chain CDR1 from U.S. Patent Application Publication No. US 2013/0108641 Al.
  • SEQ ID NO:249 is the amino acid sequence of the GITR agonists 827 and 1649 heavy chain CDR1 from U.S. Patent Application Publication No. US 2013/0108641 Al.
  • SEQ ID NO:250 is the amino acid sequence of the GITR agonist 1D7 heavy chain from U.S. Patent Application Publication No. US 2015/0064204 Al.
  • SEQ ID NO:25l is the amino acid sequence of the GITR agonist 1D7 light chain from U.S. Patent Application Publication No. US 2015/0064204 Al.
  • SEQ ID NO:252 is the amino acid sequence of the GITR agonist 1D7 variable heavy chain from U.S. Patent Application Publication No. US 2015/0064204 Al.
  • SEQ ID NO:253 is the amino acid sequence of the GITR agonist 1D7 variable light chain from U.S. Patent Application Publication No. US 2015/0064204 Al.
  • SEQ ID NO:254 is the amino acid sequence of the GITR agonist 1D7 heavy chain CDR1 from U.S. Patent Application Publication No. US 2015/0064204 Al.
  • SEQ ID NO:255 is the amino acid sequence of the GITR agonist 1D7 heavy chain CDR2 from U.S. Patent Application Publication No. US 2015/0064204 Al.
  • SEQ ID NO:256 is the amino acid sequence of the GITR agonist 1D7 heavy chain CDR3 from U.S. Patent Application Publication No. US 2015/0064204 Al.
  • SEQ ID NO:257 is the amino acid sequence of the GITR agonist 1D7 light chain CDR1 from U.S. Patent Application Publication No. US 2015/0064204 Al.
  • SEQ ID NO:258 is the amino acid sequence of the GITR agonist 1D7 light chain CDR2 from U.S. Patent Application Publication No. US 2015/0064204 Al.
  • SEQ ID NO:259 is the amino acid sequence of the GITR agonist 1D7 light chain CDR3 from U.S. Patent Application Publication No. US 2015/0064204 Al.
  • SEQ ID NO:260 is the amino acid sequence of the GITR agonist 33C9 heavy chain from U.S. Patent Application Publication No. US 2015/0064204 Al.
  • SEQ ID NO:26l is the amino acid sequence of the GITR agonist 33C9 light chain from U.S. Patent Application Publication No. US 2015/0064204 Al.
  • SEQ ID NO:262 is the amino acid sequence of the GITR agonist 33C9 variable heavy chain from U.S. Patent Application Publication No. US 2015/0064204 Al.
  • SEQ ID NO:263 is the amino acid sequence of the GITR agonist 33C9 variable light chain from U.S. Patent Application Publication No. US 2015/0064204 Al.
  • SEQ ID NO:264 is the amino acid sequence of the GITR agonist 33C9 heavy chain CDR1 from U.S. Patent Application Publication No. US 2015/0064204 Al.
  • SEQ ID NO:265 is the amino acid sequence of the GITR agonist 33C9 heavy chain CDR2 from U.S. Patent Application Publication No. US 2015/0064204 Al.
  • SEQ ID NO:266 is the amino acid sequence of the GITR agonist 33C9 heavy chain CDR3 from U.S. Patent Application Publication No. US 2015/0064204 Al.
  • SEQ ID NO:267 is the amino acid sequence of the GITR agonist 33C9 light chain CDR1 from U.S. Patent Application Publication No. US 2015/0064204 Al.
  • SEQ ID NO:268 is the amino acid sequence of the GITR agonist 33C9 light chain CDR2 from U.S. Patent Application Publication No. US 2015/0064204 Al.
  • SEQ ID NO:269 is the amino acid sequence of the GITR agonist 33C9 light chain CDR3 from U.S. Patent Application Publication No. US 2015/0064204 Al.
  • SEQ ID NO:270 is the amino acid sequence of the GITR agonist 33F6 heavy chain from U.S. Patent Application Publication No. US 2015/0064204 Al.
  • SEQ ID NO:27l is the amino acid sequence of the GITR agonist 33F6 light chain from U.S. Patent Application Publication No. US 2015/0064204 Al.
  • SEQ ID NO:272 is the amino acid sequence of the GITR agonist 33F6 variable heavy chain from U.S. Patent Application Publication No. US 2015/0064204 Al.
  • SEQ ID NO:273 is the amino acid sequence of the GITR agonist 33F6 variable light chain from U.S. Patent Application Publication No. US 2015/0064204 Al.
  • SEQ ID NO:274 is the amino acid sequence of the GITR agonist 33F6 heavy chain CDR1 from U.S. Patent Application Publication No. US 2015/0064204 Al.
  • SEQ ID NO:275 is the amino acid sequence of the GITR agonist 33F6 heavy chain CDR2 from U.S. Patent Application Publication No. US 2015/0064204 Al.
  • SEQ ID NO:276 is the amino acid sequence of the GITR agonist 33F6 heavy chain CDR3 from U.S. Patent Application Publication No. US 2015/0064204 Al.
  • SEQ ID NO:277 is the amino acid sequence of the GITR agonist 33F6 light chain CDR1 from U.S. Patent Application Publication No. US 2015/0064204 Al.
  • SEQ ID NO:278 is the amino acid sequence of the GITR agonist 33F6 light chain CDR2 from U.S. Patent Application Publication No. US 2015/0064204 Al.
  • SEQ ID NO:279 is the amino acid sequence of the GITR agonist 33F6 light chain CDR3 from U.S. Patent Application Publication No. US 2015/0064204 Al.
  • SEQ ID NO:280 is the amino acid sequence of the GITR agonist 34G4 heavy chain from U.S. Patent Application Publication No. US 2015/0064204 Al.
  • SEQ ID NO:28l is the amino acid sequence of the GITR agonist 34G4 light chain from U.S. Patent Application Publication No. US 2015/0064204 Al.
  • SEQ ID NO:282 is the amino acid sequence of the GITR agonist 34G4 variable heavy chain from U.S. Patent Application Publication No. US 2015/0064204 Al.
  • SEQ ID NO:283 is the amino acid sequence of the GITR agonist 34G4 variable light chain from U.S. Patent Application Publication No. US 2015/0064204 Al.
  • SEQ ID NO:284 is the amino acid sequence of the GITR agonist 34G4 heavy chain CDR1 from U.S. Patent Application Publication No. US 2015/0064204 Al.
  • SEQ ID NO:285 is the amino acid sequence of the GITR agonist 34G4 heavy chain CDR2 from U.S. Patent Application Publication No. US 2015/0064204 Al.
  • SEQ ID NO:286 is the amino acid sequence of the GITR agonist 34G4 heavy chain CDR3 from U.S. Patent Application Publication No. US 2015/0064204 Al.
  • SEQ ID NO:287 is the amino acid sequence of the GITR agonist 34G4 light chain CDR1 from U.S. Patent Application Publication No. US 2015/0064204 Al.
  • SEQ ID NO:288 is the amino acid sequence of the GITR agonist 34G4 light chain CDR2 from U.S. Patent Application Publication No. US 2015/0064204 Al.
  • SEQ ID NO:289 is the amino acid sequence of the GITR agonist 34G4 light chain CDR3 from U.S. Patent Application Publication No. US 2015/0064204 Al.
  • SEQ ID NO:290 is the amino acid sequence of the GITR agonist 35B 10 heavy chain from U.S. Patent Application Publication No. US 2015/0064204 Al.
  • SEQ ID NO:29l is the amino acid sequence of the GITR agonist 35B 10 light chain from U.S. Patent Application Publication No. US 2015/0064204 Al.
  • SEQ ID NO:292 is the amino acid sequence of the GITR agonist 35B 10 variable heavy chain from U.S. Patent Application Publication No. US 2015/0064204 Al.
  • SEQ ID NO:293 is the amino acid sequence of the GITR agonist 35B 10 variable light chain from U.S. Patent Application Publication No. US 2015/0064204 Al.
  • SEQ ID NO:294 is the amino acid sequence of the GITR agonist 35B 10 heavy chain CDR1 from U.S. Patent Application Publication No. US 2015/0064204 Al.
  • SEQ ID NO:295 is the amino acid sequence of the GITR agonist 35B 10 heavy chain CDR2 from U.S. Patent Application Publication No. US 2015/0064204 Al.
  • SEQ ID NO:296 is the amino acid sequence of the GITR agonist 35B 10 heavy chain CDR3 from U.S. Patent Application Publication No. US 2015/0064204 Al.
  • SEQ ID NO:297 is the amino acid sequence of the GITR agonist 35B 10 light chain CDR1 from U.S. Patent Application Publication No. US 2015/0064204 Al.
  • SEQ ID NO:298 is the amino acid sequence of the GITR agonist 35B 10 light chain CDR2 from U.S. Patent Application Publication No. US 2015/0064204 Al.
  • SEQ ID NO:299 is the amino acid sequence of the GITR agonist 35B 10 light chain CDR3 from U.S. Patent Application Publication No. US 2015/0064204 Al.
  • SEQ ID NO:300 is the amino acid sequence of the GITR agonist 41E11 heavy chain from U.S. Patent Application Publication No. US 2015/0064204 Al.
  • SEQ ID NO:30l is the amino acid sequence of the GITR agonist 41E11 light chain from U.S. Patent Application Publication No. US 2015/0064204 Al.
  • SEQ ID NO:302 is the amino acid sequence of the GITR agonist 41E11 variable heavy chain from U.S. Patent Application Publication No. US 2015/0064204 Al.
  • SEQ ID NO:303 is the amino acid sequence of the GITR agonist 41E11 variable light chain from U.S. Patent Application Publication No. US 2015/0064204 Al.
  • SEQ ID NO:304 is the amino acid sequence of the GITR agonist 41E11 heavy chain CDR1 from U.S. Patent Application Publication No. US 2015/0064204 Al.
  • SEQ ID NO:305 is the amino acid sequence of the GITR agonist 41E11 heavy chain CDR2 from U.S. Patent Application Publication No. US 2015/0064204 Al.
  • SEQ ID NO:306 is the amino acid sequence of the GITR agonist 41E11 heavy chain CDR3 from U.S. Patent Application Publication No. US 2015/0064204 Al.
  • SEQ ID NO:307 is the amino acid sequence of the GITR agonist 41E11 light chain CDR1 from U.S. Patent Application Publication No. US 2015/0064204 Al.
  • SEQ ID NO:308 is the amino acid sequence of the GITR agonist 41E11 light chain CDR2 from U.S. Patent Application Publication No. US 2015/0064204 Al.
  • SEQ ID NO:309 is the amino acid sequence of the GITR agonist 41E11 light chain CDR3 from U.S. Patent Application Publication No. US 2015/0064204 Al.
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