JPWO2020264398A5

JPWO2020264398A5 -

Info

Publication number: JPWO2020264398A5
Application number: JP2021577171A
Authority: JP
Publication date: 2023-07-14

Claims

Compounds of Formula (I)

(In the formula,

but,

is;
Z ¹ is CH or nitrogen;
Z ² is CH or nitrogen;
R ¹ is —CF ₃ or cyclopropyl;
R ² is —CF ₃ or cyclopropyl;
R ³ is hydrogen, C ₁ -C ₂ alkyl, or C ₁ -C ₂ haloalkyl;
R ⁴ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, 4- to 8-membered heterocyclyl, or C ₃ -C ₆ cycloalkyl;
wherein said heterocyclyl or cycloalkyl group is optionally substituted with 1 to 5 R ⁶ groups;
or R ³ and R ⁴ together with the carbon atom to which they are attached form a C ₃ -C ₅ cycloalkyl or 4- to 6-membered heterocyclyl, each of which has 1 to 5 R ⁶ groups optionally replaced by;
R ⁵ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₃ -C ₆ cycloalkyl;
each R ⁶ is independently C ₁ -C ₆ alkyl, halo, hydroxy, —O(C ₁ -C ₆ alkyl), —CN, C ₁ -C ₆ alkyl-CN, C ₁ -C ₆ alkyl- OH, or C ₁ -C ₆ haloalkyl;
or two ^R groups attached to the same carbon atom, together with the carbon atom to which they are attached, form a spiro _C3 - _C6 cycloalkyl or a spiro 4- to 6-membered heterocyclyl;
X is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkyl-OH, C ₁ -C ₆ alkyl-CN, optionally substituted with 1-5 R ⁸ groups C ₃ -C ₆ cycloalkyl, or

is;

is 4- to 7-membered heterocyclyl or 5- to 8-membered heteroaryl, wherein each heterocyclyl or heteroaryl has 1-2 additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur wherein each heterocyclyl or heteroaryl is optionally substituted with 1-5 R ⁸ groups;
each R ⁷ is independently hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl-OH, or C ₁ -C ₆ haloalkyl;
or two R ⁷ groups together with the carbon atom to which they are attached form a C ₃ -C ₅ cycloalkyl or 3- to 5-membered heterocyclyl;
Each R ⁸ is independently halo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl-CN, C ₁ -C ₆ alkyl-OH, C ₁ -C ₆ haloalkyl, —CN, oxo, or — O(C ₁ -C ₆ alkyl);
or two R ⁸ groups together with the carbon atom or atoms to which they are attached form a spiro or a fused C ₃ -C ₅ cycloalkyl or 3- to 5-membered heterocyclyl)
Or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

but,

is;
is Z ¹ CH;

but,

is;
is Z ¹ N;

but

is;

but,

is;
is Z ² is CH;

but,

is;
is Z ² is N;

but,

2. The compound of claim 1, which is

R ³ is hydrogen, C ₁ -C ₂ alkyl, or C ₁ -C ₂ haloalkyl;
R ⁴ is hydrogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl, 4-6 membered heterocyclyl, or C ₄ -C ₅ cycloalkyl;
wherein said heterocyclyl or cycloalkyl group is optionally substituted with 1 to 3 R ⁶ groups;
or R ³ and R ⁴ together with the carbon atom to which they are attached form a C ₄ -C ₅ cycloalkyl or 4- to 6-membered heterocyclyl, each of which has 1 to 3 R ⁶ groups optionally replaced by;
R ³ is hydrogen, —CH ₃ , or —CF ₃ ;
R ⁴ is hydrogen, —CH ₃ , —CF ₃ , cyclobutyl, or

is;
or R ³ and R ⁴ together with the carbon atom to which they are attached,

each of which is optionally substituted with 1 to 3 R ⁶ groups;
R ³ and R ⁴ together with the carbon atom to which they are attached,

2. The compound of claim 1, which forms:

each R ⁶ is independently C ₁ -C ₃ alkyl, halo, hydroxy, —O(C ₁ -C ₃ alkyl), —CN, C ₁ -C ₃ alkyl-CN, C ₁ -C ₃ alkyl- OH, or C ₁ -C ₃ haloalkyl;
or two R ⁶ groups attached to the same carbon atom together with the carbon atom to which they are attached form a spiro C ₃ -C ₆ cycloalkyl or a spiro 4- to 5-membered heterocyclyl;
each R ⁶ is independently —CH ₃ , fluoro, hydroxy, —OCH ₃ , —CN, —CH ₂ CN, —CH ₂ OH, or —CF ₃ ; or 2 attached to the same carbon atom 2. The compound of Claim 1, wherein the two ^R6 groups together with the carbon atom to which they are attached form a spirocyclopropyl.

whether R ⁵ is hydrogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl, or C ₃ -C ₄ cycloalkyl;
A compound according to any one of claims 1 to 4, wherein R ⁵ is hydrogen, -CH ₃ , -CHF ₂ or cyclopropyl.

X is optionally substituted with hydrogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ alkyl-OH, C ₁ -C ₃ alkyl-CN, or 1-3 R ⁸ groups; is C ₃ -C ₅ cycloalkyl;
whether X is hydrogen or —CH ₃ ;
X is

is;
X is

is;

is 4- to 6-membered heterocyclyl or 5- to 6-membered heteroaryl, wherein each heterocyclyl or heteroaryl has 1-2 additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur wherein each heterocyclyl or heteroaryl is optionally substituted with 1 to 5 R ⁸ groups; or

is a 4- to 5-membered heterocyclyl or 5- to 6-membered heteroaryl, each heterocyclyl or heteroaryl optionally containing one additional heteroatom selected from the group consisting of nitrogen and oxygen; or the heteroaryl is optionally substituted with 1-5 R ⁸ groups;
Y is oxygen;
2. The compound of claim 1, wherein Y is -CH ₂ -, -CHR ⁸ -, or -C(R ⁸ ) ₂ -.

each R ⁷ is independently hydrogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkyl-OH, or C ₁ -C ₃ haloalkyl;
or two R ⁷ groups together with the carbon atom to which they are attached form a C ₃ -C ₅ cycloalkyl or 3- to 5-membered heterocyclyl;
each R ⁷ is independently hydrogen, —CH ₃ , —CH ₂ OH, or —CF ₃ ;
or two ^R7 groups together with the carbon atom to which they are attached form cyclopropyl or oxetanyl;
Each R ⁸ is independently halo, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkyl-CN, C ₁ -C ₃ alkyl-OH, C ₁ -C ₃ haloalkyl, —CN, oxo, or — O(C ₁ -C ₃ alkyl);
or two R ⁸ groups together with the carbon atom or atoms to which they are attached form a spiro or fused C ₃ -C ₅ cycloalkyl or a spiro or fused 3- to 5-membered heterocyclyl ;
each R ⁸ is independently fluoro, —CH ₃ , —CH ₂ CH ₃ , —CH ₂ CN, —CH ₂ OH, —CF ₃ , —CN, oxo, or —OCH ₃ ;
or two ^R8 groups taken together with the carbon atom or atoms to which they are attached form a spiro or fused cyclopropyl or oxetanyl.

or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

comprising a compound of claim 1 and a pharmaceutically acceptable excipient;
A pharmaceutical composition comprising a Cbl -b inhibitor and one or both of an adjuvant and an antigen , wherein said Cbl-b inhibitor is a compound according to claim 1 .

A method of modulating the activity of an immune cell in vitro or ex vivo, comprising contacting said immune cell with an effective amount of a Cbl-b inhibitor to modulate the activity of said immune cell, said Cbl-b A method, wherein the inhibitor is a compound of claim 1.

whether said immune cells comprise T cells, B cells, or natural killer (NK) cells;
said immune cells were or are isolated from a blood sample from a mammalian subject;
whether said immune cells are tumor infiltrating lymphocytes (TILs) isolated or isolated from a tumor of a mammalian subject with cancer;
said immune cells comprise T cells, and modulating the activity of said T cells is one of increased T cell activation, increased T cell proliferation, decreased T cell exhaustion, and decreased T cell tolerance; contains one or more;
said immune cells comprise NK cells and modulating NK cell activity comprises increased NK cell activation;
said immune cells comprise B cells, wherein modulating B cell activity comprises increased B cell activation, optionally wherein increased B cell activation comprises increased expression of CD69;
whether said immune cells are human immune cells;
11. The method of claim 10, wherein said immune cells comprise recombinant chimeric receptors.

whether increased T cell activation includes increased production of cytokines;
12. The method of claim 11, wherein increased T cell activation comprises increased cell surface expression of one or more T cell activation markers.

13. The method of claim 12, wherein said cytokine comprises one or more selected from the group consisting of IL-2, IFN-γ, TNFα, and GM-CSF.

13. The method of claim 12, wherein said T cell activation markers comprise one or more selected from the group consisting of CD25, CD69, and CTLA4.

whether said T cells have been or have been contacted with an anti-CD3 antibody alone or in combination with an anti-CD28 antibody;
12. The method of claim 11, further comprising culturing said immune cells with IL-2 alone or in combination with anti-CD3 and/or anti-CD28 antibodies.

12. The method of claim 11, wherein increased NK cell activation comprises increased production of cytokines.

17. The method of claim 16, wherein said cytokine comprises one or more selected from the group consisting of IFN-γ, TNFα, and MIP1β.

12. The method of claim 11, wherein said recombinant chimeric receptor is a chimeric antigen receptor.

1. A method of generating modified immune cells in vitro or ex vivo, comprising culturing a cell population containing immune cells in the presence of an effective amount of a Cbl-b inhibitor to modulate the activity of said immune cells, and wherein said Cbl-b inhibitor is the compound of claim 1.

further comprising culturing said immune cells with an anti-CD3 antibody alone or in combination with an anti-CD28 antibody;
further comprising culturing said immune cells with IL-2 alone or in combination with anti-CD3 and/or anti-CD28 antibodies;
20. The method of claim 19, further comprising recovering said modified immune cells.

Tumor-infiltrating lymphocytes, wherein said immune cells are isolated or isolated from a blood sample from a mammalian subject, or wherein said immune cells are isolated or isolated from a tumor of a mammalian subject with cancer ( TIL);
whether said immune cells are cells selected from the group consisting of hematopoietic cells, pluripotent stem cells, myeloid progenitor cells, lymphoid progenitor cells, T cells, B cells, and NK cells;
whether said immune cells are tumor infiltrating lymphocytes (TILs);
whether said immune cells are human immune cells;
21. The method of claim 20, wherein said immune cells or modified immune cells comprise recombinant chimeric receptors.

20. The method of claim 19, wherein said modified immune cells are cells selected from the group consisting of hematopoietic cells, pluripotent stem cells, myeloid progenitor cells, lymphoid progenitor cells, T cells, B cells, and NK cells.

22. The method of claim 21, wherein said recombinant chimeric receptor is a chimeric antigen receptor.

modified immune cells produced by the method of claim 19; or modified immune cells comprising a Cbl-b inhibitor, wherein said Cbl-b inhibitor is a compound of claim 1. or an isolated modified immune cell, said immune cell contacted or contacted with a Cbl-b inhibitor, said Cbl-b inhibitor being a compound of claim 1. Yes, modified immune cells.

25. The modified immune cells of claim 24, wherein said immune cells are or are isolated from a blood sample from a mammalian subject, or said immune cells are isolated from a tumor of a mammalian subject with cancer. modified immune cells that are isolated or isolated tumor infiltrating lymphocytes (TILs); Tumor infiltrating lymphocytes (TIL) isolated from the subject's tumor;
said modified immune cells are T cells, said T cells exhibiting one or more of increased T cell activation, increased T cell proliferation, decreased T cell exhaustion, and decreased T cell tolerance mosquito;
whether said modified immune cells are NK cells and said NK cells exhibit increased NK cell activation;
said modified immune cells are B cells, said B cells exhibit increased B cell activation, optionally wherein increased B cell activation comprises increased expression of CD69;
whether said modified immune cells are human immune cells;
A modified immune cell, wherein said modified immune cell comprises a recombinant chimeric receptor.

whether increased T cell activation includes increased production of cytokines;
26. The engineered immune cell of claim 25, wherein increased T cell activation comprises increased cell surface expression of one or more T cell activation markers.

27. The engineered immune cell of claim 26, wherein said cytokine comprises one or more selected from the group consisting of IL-2, IFN-γ, TNFα, and GM-CSF.

27. The engineered immune cell of Claim 26, wherein said T cell activation markers comprise one or more selected from the group consisting of CD25, CD69, and CTLA4.

whether said T cells have been or have been contacted with an anti-CD3 antibody alone or in combination with an anti-CD28 antibody;
26. The engineered immune cell of claim 25, wherein said T cell is or has been contacted with IL-2 alone or in combination with anti-CD3 and/or anti-CD28 antibodies.

26. The engineered immune cell of claim 25, wherein increased NK cell activation comprises increased production of cytokines.

31. The engineered immune cell of claim 30, wherein said cytokine comprises one or more selected from the group consisting of IFN-γ, TNFα, and MIP1β.

26. The engineered immune cell of claim 25, wherein said recombinant chimeric receptor is a chimeric antigen receptor.

25. A composition comprising a cell population containing the engineered immune cells of claim 24.

34. The composition of Claim 33, further comprising a pharmaceutically acceptable excipient.

the composition is in a culture vessel;
34. The composition of claim 33, wherein said composition is in a suitable container.

whether the culture vessel is a tube, dish, bag, multiwell plate, or flask;
36. The composition of Claim 35, wherein said suitable container is a bottle, vial, syringe, intravenous bag, or tube.

34. A method of modulating an immune response comprising administering an effective amount of the modified immune cells of claim 24 or an effective amount of the composition of claim 33.

A method of treating a cancer responsive to inhibition of Cbl-b activity in vitro or ex vivo, comprising administering an effective amount of the modified immune cells of claim 24 or an effective amount of a composition of claim 33. wherein said cancer is responsive to inhibition of Cbl-b activity.

whether said cancer is a blood cancer;
39. The method of claim 38, wherein said cancer is a non-hematologic cancer.

whether said hematologic cancer is lymphoma, leukemia, or myeloma;
40. The method of claim 39, wherein said non-hematologic cancer is sarcoma, carcinoma, or melanoma.

34. A method of inhibiting abnormal cell proliferation in vitro or ex vivo, comprising administering an effective amount of the modified immune cells of claim 24 or an effective amount of the composition of claim 33.

42. The method of claim 41, wherein said abnormal cell proliferation is hyperplasia or cancer cell proliferation.

whether said cancer cells are derived from a hematological cancer;
43. The method of claim 42, wherein said cancer cells are derived from a non-hematologic cancer.

whether said hematologic cancer is lymphoma, leukemia, or myeloma;
44. The method of claim 43, wherein the non-hematologic cancer is sarcoma, carcinoma, or melanoma.

2. A method of modulating an immune response in vitro or ex vivo, comprising administering an effective amount of a Cbl-b inhibitor to modulate an immune response, wherein the Cbl-b inhibitor is according to claim 1. A method, which is a compound of

A method of inhibiting Cbl-b activity in vitro or ex vivo comprising administering an effective amount of a Cbl-b inhibitor to inhibit Cbl-b activity, wherein said Cbl-b inhibitor comprises: Item 2. A method, which is the compound of Item 1.

A method of treating a cancer responsive to inhibition of Cbl-b activity in vitro or ex vivo, comprising administering an effective amount of a Cbl-b inhibitor to treat said cancer responsive to inhibition of Cbl-b activity. wherein said Cbl-b inhibitor is the compound of claim 1.

said cancer is a hematologic cancer, optionally said hematologic cancer is lymphoma, leukemia, or myeloma;
48. The method of claim 47, wherein said cancer is a non-hematologic cancer, optionally said non-hematologic cancer is sarcoma, carcinoma, or melanoma.

said Cbl-b inhibitor is administered by enteral administration, optionally said enteral administration is oral administration;
said Cbl-b inhibitor is administered by parenteral administration, optionally said parenteral administration is intratumoral administration;
46. The method of claim 45, further comprising administering to said individual an effective amount of the engineered immune cells of claim 24 or an effective amount of the composition of claim 33 to treat said cancer. .

A method of inhibiting aberrant cell proliferation in vitro or ex vivo comprising administering an effective amount of a Cbl-b inhibitor to inhibit aberrant cell proliferation, said Cbl-b inhibitor comprising: Item 2. A method, which is the compound of Item 1.

51. The method of claim 50, wherein said abnormal cell proliferation is hyperplasia or cancer cell proliferation.

said cancer cells are derived from a hematologic cancer, optionally said hematologic cancer is lymphoma, leukemia, or myeloma;
52. The method of claim 51, wherein said cancer cells are derived from a non-hematologic cancer, optionally said non-hematologic cancer is sarcoma, carcinoma, or melanoma.

said Cbl-b inhibitor is administered by enteral administration, optionally said enteral administration is oral administration;
said Cbl-b inhibitor is administered by parenteral administration, optionally said parenteral administration is intratumoral injection or said parenteral administration is selected from the group consisting of intravenous, intraperitoneal and subcutaneous 51. The method of claim 50, according to the route taken.

modulation of said immune response is one or more of increased T cell activation, increased T cell proliferation, decreased T cell exhaustion, and decreased T cell tolerance after administration of said Cbl-b inhibitor contains;
comprising increased NK cell activation following administration of said Cbl-b inhibitor;
46. The method of claim 45, having increased B cell activation after administration of said Cbl-b inhibitor, optionally wherein increased B cell activation comprises increased expression of CD69.

whether increased T cell activation includes increased production of cytokines;
55. The method of claim 54, wherein increased T cell activation comprises increased cell surface expression of one or more T cell activation markers.

56. The method of claim 55, wherein said cytokine comprises one or more selected from the group consisting of IL-2, IFN-γ, TNFα, and GM-CSF.

56. The method of claim 55, wherein said T cell activation markers comprise one or more selected from the group consisting of CD25, CD69, and CTLA4.

55. The method of claim 54, wherein increased NK cell activation comprises increased production of cytokines.

59. The method of claim 58, wherein said cytokine comprises one or more selected from the group consisting of IFN-γ, TNFα, and MIP1β.

A cell culture composition comprising a cell population containing immune cells and a Cbl-b inhibitor, wherein said Cbl-b inhibitor is the compound of claim 1.

whether said immune cells are cells selected from the group consisting of hematopoietic cells, pluripotent stem cells, myeloid progenitor cells, lymphoid progenitor cells, T cells, B cells, and NK cells;
whether said immune cell is an engineered immune cell comprising a recombinant chimeric receptor;
61. The cell culture composition of claim 60, further comprising an anti-CD3 antibody alone or in combination with an anti-CD28 antibody.

62. The cell culture composition of claim 61, wherein said recombinant chimeric receptor is a chimeric antigen receptor.

10. The pharmaceutical composition according to claim 9, wherein said antigen is a cancer antigen.

10. A product comprising the engineered immune cells of claim 24, the composition of claim 33, the cell culture composition of claim 60, or the pharmaceutical composition of claim 9.

whether said modified immune cell or cell culture composition is in a tube, dish, bag, multiwell plate, or flask;
65. The article of manufacture of claim 64, wherein said engineered immune cells or pharmaceutical composition is in a bottle, vial, syringe, intravenous bag, or tube.

34. A kit comprising the modified immune cells of claim 24 or the composition of claim 33.

whether said modified immune cells are in a tube, dish, bag, multiwell plate, or flask;
whether the modified immune cells are in a bottle, vial, syringe, intravenous bag, or tube;
67. The kit of claim 66, wherein said kit comprises instructions for administering said modified immune cells or composition to an individual according to the method of claim 37.

a kit comprising the pharmaceutical composition of claim 9; or
46. A kit, said kit comprising instructions for administering said pharmaceutical composition to an individual according to the method of claim 45.

a kit comprising the cell culture composition of claim 60; or
20. A kit, wherein the kit comprises instructions for generating modified immune cells according to the method of claim 19.

A method for treating or preventing a disease or condition associated with Cbl-b activity in vitro or ex vivo , comprising administering a Cbl -b inhibitor , said Cbl-b inhibitor comprising: Item 2. A method, which is the compound of Item 1 .

Use of a Cbl-b inhibitor in the manufacture of a medicament for treating or preventing a disease or condition associated with Cbl-b activity, said Cbl-b inhibitor being a compound according to claim 1, use; or
Use of a Cbl-b inhibitor in the manufacture of a medicament for treating cancer, wherein said Cbl-b inhibitor is a compound according to claim 1.

A Cbl-b inhibitor for use in the treatment or prevention of a disease or condition associated with Cbl-b activity, wherein said Cbl-b inhibitor is a compound according to claim 1. agent; or
A Cbl-b inhibitor for use in treating cancer, wherein said Cbl-b inhibitor is a compound according to claim 1.

A method of treating cancer in vitro or ex vivo, comprising:
administering to the cancer an effective amount of a C bl-b inhibitor; and administering an effective amount of a further treatment agent;
wherein said Cbl-b inhibitor is the compound of claim 1 .

whether said Cbl-b inhibitor and said further treatment are administered sequentially in any order;
whether said Cbl-b inhibitor and said further treatment are administered at the same time;
said Cbl-b inhibitor is administered by enteral administration, optionally said enteral administration is oral administration;
said Cbl-b inhibitor is administered by parenteral administration, optionally said parenteral administration is intratumoral injection or said parenteral administration is selected from the group consisting of intravenous, intraperitoneal and subcutaneous by the route taken;
74. The method of claim 73, further comprising administering to said individual an effective amount of radiation therapy.

whether said further treatment comprises an immune checkpoint inhibitor;
74. The method of claim 73, wherein said additional treatment agent comprises an anti-neoplastic agent.

The immune checkpoint inhibitor is PD-1 (CD279), PD-L1 (CD274), CTLA-4 (CD125), LAG3 (CD223), PVR (CD155), PVRL2 (CD112), PVRL3 (CD113), TIGIT is an antagonist of at least one inhibitory checkpoint molecule selected from the group consisting of: , TIM3 (CD366), and VISTA;
said immune checkpoint inhibitor is an antagonist of at least one inhibitory checkpoint molecule selected from the group consisting of PD-1 (CD279), PD-L1 (CD274), and CTLA-4 (CD152);
said at least one inhibitory checkpoint molecule comprises PD-1 and optionally said immune checkpoint inhibitor is selected from the group consisting of pembrolizumab, nivolumab, semiplimab, and biosimilars thereof;
said at least one inhibitory checkpoint molecule comprises PD-L1, and optionally said immune checkpoint inhibitor is selected from the group consisting of atezolizumab, avelumab, durvalumab, and biosimilars thereof;
said at least one inhibitory checkpoint molecule comprises CTLA-4, and optionally said immune checkpoint inhibitor is selected from the group consisting of ipilimumab, tremelimumab, and biosimilars thereof;
76. The method of claim 75, wherein said immune checkpoint inhibitor comprises an antibody or antigen binding fragment thereof, optionally said antibody or fragment is a human or humanized antibody or fragment.

whether said antineoplastic agent is classified as one of the group consisting of cytotoxic antibiotics, plant alkaloids, antimetabolites, alkylating agents, and other antineoplastic agents;
the anti-tumor agent comprises a cytotoxic antibiotic, optionally wherein the cytotoxic antibiotic is ixabepilone, mitomycin, plicamycin, bleomycin, pixantrone, amrubicin, valrubicin, pirarubicin, mitoxantrone, idarubicin, zorubicin, is selected from the group consisting of aclarubicin, epirubicin, daunorubicin, doxorubicin, and dactinomycin;
The antitumor agent comprises a plant alkaloid, optionally wherein the plant alkaloid is trabectedin, cabazitaxel, polyglutamate paclitaxel, docetaxel, paclitaxel, demecolcine, teniposide, etoposide, bintaforide, vinflunine, vinorelbine, vindesine, vincristine, and vinblastine;
The anti-neoplastic agent comprises an antimetabolite, optionally the antimetabolite is a pyrimidine analogue, a purine analogue, or a folic acid analogue, optionally the antimetabolite is floxuridine, trifluridine, tegafur , fluorouracil, decitabine, azacitidine, capecitabine, gemcitabine, carmofur, tegafur, fluorouracil, cytarabine, nelarabine, clofarabine, fludarabine, cladribine, thioguanine, mercaptopurine, pralatrexate, pemetrexed, raltitrexed, and methotrexate ;
The anti-tumor agent comprises an alkylating agent, optionally wherein the alkylating agent is dacarbazine, temozolomide, pipobroman, mitobronitol, etogluside, uracil mustard, lanimustine, nimustine, fotemustine, streptozocin, semustine, lomustine, carmustine, carbocone , triaziquone, thiotepa, mannosulphan, treosulfan, busulfan, bendamustine, prednimustine, trofosfamide, ifosfamide, mechlorethamine, melphalan, chlorambucil, and cyclophosphamide;
whether the anti-tumor agent comprises other anti-tumor agents selected from the group consisting of platinum compounds, protein kinase inhibitors, and other agents;
said anti-tumor agent comprises a platinum compound, optionally said platinum compound is selected from the group consisting of cisplatin, carboplatin, oxaliplatin, satraplatin, and polyplatylene;
whether the anti-tumor agent comprises a protein kinase inhibitor;
76. The method of claim 75, wherein said anti-tumor agent comprises other agents.

whether said radiotherapy is external beam radiotherapy;
75. The method of claim 74 , wherein said radiotherapy is internal radiotherapy.

whether said cancer is a blood cancer;
79. The method of any one of claims 73, 74, 75, 76, 77, or 78, wherein said cancer is a non-hematologic cancer.

whether said hematologic cancer is lymphoma, leukemia, or myeloma;
80. The method of claim 79, wherein said non-hematologic cancer is carcinoma, sarcoma, or melanoma.

A method of generating an expanded population of tumor-infiltrating lymphocytes (TILs), comprising:
(a) obtaining in vitro or ex vivo a biological sample comprising TILs according to the method of claim 73; and (b) culturing said TILs in a cell culture medium comprising at least one T cell growth factor. and generating said expanded population of TILs.

whether said at least one T cell growth factor comprises IL-2;
whether the cell culture medium further comprises an anti-CD3 antibody or both an anti-CD3 antibody and an anti-CD28 antibody;
whether said cell culture medium further comprises said Cbl-b inhibitor;
82. The method of claim 81, wherein said cell culture medium further comprises irradiated feeder cells.

82. A composition comprising an expanded population of TILs produced by the method of claim 81 and a physiologically acceptable buffer.

84. A method of treating cancer in vitro or ex vivo, comprising administering to the cancer an effective amount of the composition of claim 83.

85. The method of claim 84, further comprising continuing to administer an effective amount of a Cbl-b inhibitor to said cancer.

A method of generating an expanded population of tumor-infiltrating lymphocytes (TILs), comprising:
(a ) obtaining, in vitro or ex vivo, a biological sample comprising a Cbl-b inhibitor and TILs from cancer; and (b) culturing said TILs in a cell culture medium comprising at least one T cell growth factor. wherein said Cbl-b inhibitor is the compound of claim 1, comprising generating said expanded population of TILs.

whether said at least one T cell growth factor comprises IL-2;
whether the cell culture medium further comprises an anti-CD3 antibody or both an anti-CD3 antibody and an anti-CD28 antibody;
87. The method of claim 86, wherein said cell culture medium further comprises said Cbl-b inhibitor.

87. The method of claim 86, wherein said cancer is a non-hematologic cancer, optionally said non-hematologic cancer is sarcoma, carcinoma, or melanoma.

87. A composition comprising an expanded population of TILs produced by the method of claim 86 and a physiologically acceptable buffer.

90. A method of treating cancer in vitro or ex vivo, comprising administering to the cancer an effective amount of the composition of claim 89.

91. The method of claim 90, further comprising continuing to administer an effective amount of said Cbl-b inhibitor.

A method of immunization in vitro or ex vivo, comprising:
A method comprising administering an effective amount of a small molecule Cbl-b inhibitor; and administering an effective amount of a vaccine.

the immunization is
93. The method of claim 92, which is a method of treating cancer comprising administering to the cancer an effective amount of a small molecule Cbl-b inhibitor; and administering an effective amount of a treatment cancer vaccine.

whether the Cbl-b inhibitor and the cancer vaccine are administered sequentially;
94. The method of claim 93, wherein said Cbl-b inhibitor and said cancer vaccine are administered simultaneously.

whether said cancer vaccine is an immunogenic composition comprising at least one tumor antigen and a pharmaceutically acceptable excipient;
said cancer vaccine comprises a microbial vector, optionally said microbial vector is TICE-BCG;
94. The method of claim 93, wherein said cancer vaccine comprises killed cancer cells or cancer cell lysates.

whether said at least one tumor antigen comprises at least one synthetic peptide or recombinant protein;
96. The method of claim 95, wherein said immunogenic composition further comprises an adjuvant.

whether the adjuvant comprises one or more components of the group consisting of aluminum salts, squalene, and saponins;
97. The method of claim 96, wherein said immunogenic composition further comprises antigen presenting cells (APCs), optionally said APCs are dendritic cells, optionally said cancer vaccine is PROVENGE. .

96. The method of claim 95, wherein said microbial vector is a recombinant viral vector or a recombinant bacterial vector.

A method of treating cancer in vitro or ex vivo, comprising:
A method comprising: administering to the cancer an effective amount of a small molecule Cbl-b inhibitor; and administering an effective amount of an oncolytic virus.

whether the Cbl-b inhibitor and the oncolytic virus are administered sequentially;
whether the Cbl-b inhibitor and the oncolytic virus are administered simultaneously;
The oncolytic virus is adenovirus, coxsackievirus, echovirus, fowlpox virus, herpes simplex virus, maraba virus, measles virus, myxoma virus, Newcastle disease virus, parvovirus, poliovirus, retrovirus, reovirus, Seneca is a virus selected from the group consisting of Valley virus, Semliki Forest virus, vaccinia virus, and vesicular stomatitis virus;
whether said oncolytic virus is a recombinant virus comprising one or both of functional deletion of at least one viral gene and insertion of at least one transgene;
whether said oncolytic virus is a transgenic serotype 5 adenovirus;
said oncolytic virus is transgenic herpes simplex virus type 1 (HSV-1), optionally said transgenic HSV-1 is talimodin laherparepvec;
said oncolytic virus is a transgenic vaccinia virus, optionally said transgenic vaccinia virus is pexastimodin devacirepvec;
wherein said oncolytic virus is a non-recombinant oncolytic virus, optionally wherein said non-recombinant oncolytic virus is the group consisting of echovirus, Newcastle disease virus, parvovirus, reovirus, and seneca valley virus 100. The method of claim 99, wherein the virus is selected from

whether said recombinant virus comprises a functional deletion of at least one viral gene and an insertion of at least one transgene;
101. The method of claim 100, wherein said transgene encodes human granulocyte-macrophage colony-stimulating factor (GM-CSF).

whether said cancer is a blood cancer;
94. The method of claim 93, wherein said cancer is a non-hematologic cancer.

whether said hematologic cancer is lymphoma, leukemia, or myeloma;
103. The method of claim 102, wherein the non-hematologic cancer is carcinoma, sarcoma, or melanoma.

93. The method of claim 92, wherein said small molecule Cbl-b inhibitor is a compound of claim 1.

93. The small molecule Cbl-b inhibitor is a compound selected from the compounds in Table 1, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof according to claim 92. the method of.

A method of treating cancer in vitro or ex vivo, comprising:
administering to cancer an effective amount of an agent capable of lowering the activation threshold of immune cells; and administering an effective amount of a therapeutic cancer vaccine; or administering an effective amount of an oncolytic virus. method involving

whether the agent is further capable of reducing the need for co-stimulation of immune cells;
whether the agent is further capable of promoting tumor immune surveillance;
107. The method of claim 106, wherein said agent is a small molecule, Cbl-b inhibitor.

A pharmaceutical composition comprising a cancer vaccine and a small molecule Cbl-b inhibitor, optionally further comprising a pharmaceutically acceptable excipient.

A kit for treating cancer in vitro or ex vivo, comprising:
(a) small molecule Cbl-b inhibitors;
(b) a cancer vaccine for treatment;
(c) a kit comprising instructions for administration of an effective amount of said Cbl-b inhibitor and said cancer vaccine for treating cancer.

A kit for treating cancer in vitro or ex vivo, comprising:
(a) a pharmaceutical composition comprising a small molecule Cbl-b inhibitor and a therapeutic cancer vaccine; and (b) an effective amount of said Cbl-b inhibitor and said therapeutic cancer vaccine for treating said cancer. A kit comprising instructions for administration of said pharmaceutical composition comprising.

whether said cancer vaccine is an immunogenic composition comprising at least one tumor antigen and a pharmaceutically acceptable excipient;
said cancer vaccine comprises a microbial vector, optionally said microbial vector is TICE-BCG;
111. The method of claim 106, the composition of claim 108, or the kit of claim 110, wherein said cancer vaccine comprises killed cancer cells or cancer cell lysates.

whether said at least one tumor antigen comprises at least one synthetic peptide or recombinant protein;
whether said immunogenic composition further comprises an adjuvant;
112. The method of claim 111, wherein said immunogenic composition further comprises antigen presenting cells (APCs), optionally said APCs are dendritic cells, optionally said cancer vaccine is PROVENGE. , composition or kit.

113. The method, composition, or kit of Claim 112, wherein said adjuvant comprises one or more components of the group consisting of aluminum salts, squalene, and saponins.

112. The method, composition, or kit of claim 111, wherein said microbial vector is a recombinant viral vector or a recombinant bacterial vector.

A pharmaceutical composition comprising an oncolytic virus and a small molecule Cbl-b inhibitor, optionally further comprising a pharmaceutically acceptable excipient.

A kit for treating cancer in vitro or ex vivo, comprising:
(a) small molecule Cbl-b inhibitors;
(b) an oncolytic virus;
(c) a kit comprising instructions for administration of an effective amount of said Cbl-b inhibitor and said oncolytic virus to treat cancer.

A kit for treating cancer in vitro or ex vivo, comprising:
(a) a pharmaceutical composition comprising a small molecule Cbl-b inhibitor and an oncolytic virus; and (b) an effective amount of said small molecule Cbl-b inhibitor and said oncolytic virus for treating cancer. A kit comprising instructions for administration of said pharmaceutical composition comprising

The oncolytic virus is adenovirus, coxsackievirus, echovirus, fowlpox virus, herpes simplex virus, maraba virus, measles virus, myxoma virus, Newcastle disease virus, parvovirus, poliovirus, retrovirus, reovirus, Seneca is a virus selected from the group consisting of Valley virus, Semliki Forest virus, vaccinia virus, and vesicular stomatitis virus;
whether said oncolytic virus is a recombinant virus comprising one or both of functional deletion of at least one viral gene and insertion of at least one transgene;
whether said oncolytic virus is a transgenic serotype 5 adenovirus;
said oncolytic virus is transgenic herpes simplex virus type 1 (HSV-1), optionally said transgenic HSV-1 is talimodin laherparepvec;
said oncolytic virus is a transgenic vaccinia virus, optionally said transgenic vaccinia virus is pexastimodin devacirepvec;
wherein said oncolytic virus is a non-recombinant oncolytic virus, optionally wherein said non-recombinant oncolytic virus is the group consisting of echovirus, Newcastle disease virus, parvovirus, reovirus, and seneca valley virus 118. The method of claim 106, the composition of claim 115, or the kit of claim 116 or claim 117, wherein the virus is selected from:

whether said recombinant virus comprises a functional deletion of at least one viral gene and an insertion of at least one transgene;
119. The method, composition, or kit of claim 118 , wherein said transgene encodes human granulocyte-macrophage colony-stimulating factor (GM-CSF).

whether said cancer is a blood cancer;
The method of claim 106, the composition of claim 108 or claim 115, or the kit of claim 109, 110, 116 or 117, wherein said cancer is a non-hematologic cancer. .

whether said hematologic cancer is lymphoma, leukemia, or myeloma;
121. The method, composition, or kit of claim 120, wherein said non-hematologic cancer is carcinoma, sarcoma, or melanoma.

The method of claim 106, the composition of claim 108 or claim 115, or claim 109, claim 110, claim, wherein said small molecule Cbl-b inhibitor is a compound of claim 1. 117. The kit of Claim 115 or Claim 116.

107. of claim 106, wherein said small molecule Cbl-b inhibitor is a compound selected from the compounds in Table 1, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof 116. The composition of claim 108 or claim 115, or the kit of claim 109, 110, 115 or 116.

A method of treating disease by cell therapy in vitro or ex vivo, comprising:
administering an effective amount of one or more treating cells to treat said disease; and administering an effective amount of a Cbl-b inhibitor, said Cbl-b inhibitor comprising: 2. The method of claim 1, wherein treatment with said treating cells is enhanced by combination with said Cbl-b inhibitor.