Einige Inhalte dieser Anwendung sind momentan nicht verfügbar.
Wenn diese Situation weiterhin besteht, kontaktieren Sie uns bitte unterFeedback&Kontakt
1. (WO2018222711) COMPOSITIONS COMPRISING A COMBINATION OF AN ANTI-LAG-3 ANTIBODY, A PD-1 PATHWAY INHIBITOR, AND AN IMMUNOTHERAPEUTIC AGENT
Anmerkung: Text basiert auf automatischer optischer Zeichenerkennung (OCR). Verwenden Sie bitte aus rechtlichen Gründen die PDF-Version.

WHAT IS CLAIMED IS:

1. A method of treating a malignant tumor in a human patient comprising administering a therapeutically effective amount of:

a LAG-3 inhibitor;

a PD-1 pathway inhibitor; and

an immunotherapeutic agent.

2. The method of claim 1, wherein the LAG-3 inhibitor is an anti-LAG-3 antibody or an antigen binding fragment thereof.

3. The method of claim 1 or 2, wherein the anti-LAG-3 antibody is a bispecific antibody.

4. The method of any one of claims 1 to 3, wherein the anti-LAG-3 antibody or antigen binding fragment thereof comprises (a) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 7; (b) a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO:8; (c) a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO:9; (d) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO: 10; (e) a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO: 11; and (f) a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO: 12.

5. The method of any one of claims 1 to 4, wherein the anti-LAG-3 antibody or antigen binding fragment thereof comprises heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs:3 and 5, respectively.

6. The method of any one of claims 1 to 5, wherein the anti-LAG-3 antibody is BMS 986016, MK-4280 (28G-10), REGN3767, GSK2831781, IMP731 (H5L7BW), BAP050, IMP-701 (LAG-5250), IMP321, TSR-033, LAG525, BI 754111, or FS-118.

7. The method of claim 1, wherein the LAG-3 inhibitor is a soluble LAG-3 polypeptide.

8. The method of claim 7, wherein the soluble LAG-3 polypeptide is a fusion polypeptide.

9. The method of claim 7 or 8, wherein the soluble LAG-3 polypeptide comprises a ligand binding fragment of the LAG-3 extracellular domain.

10. The method of claim 9, wherein the ligand binding fragment of the LAG-3 extracellular domain comprises an amino acid sequence with at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to SEQ ID NO:44.

11. The method of any one of claims 7 to 10, wherein the soluble LAG-3 polypeptide further comprises an Fc domain.

12. The method of any one of claims 1 to 11, wherein the PD-1 pathway inhibitor is an anti- PD-1 antibody or antigen binding fragment thereof.

13. The method of claim 12, wherein the anti-PD-1 antibody is pembrolizumab (KEYTRUDA; MK-3475), pidilizumab (CT-011), nivolumab (OPDIVO; BMS-936558), PDR001, MEDI0680 (AMP-514), TSR-042, REGN2810, JS001, AMP-224 (GSK- 2661380), PF-06801591, BGB-A317, BI 754091, or SHR-1210.

14. The method of any one of claims 1 to 11, wherein the PD-1 pathway inhibitor is an anti- PD-L1 antibody or antigen binding fragment thereof.

15. The method of claim 14, wherein the anti-PD-Ll antibody is atezolizumab (TECENTRIQ; RG7446; MPDL3280A; R05541267), durvalumab (MEDI4736), BMS- 936559, avelumab (bavencio), LY3300054, CX-072 (Proclaim-CX-072), FAZ053, KN035, or MDX-1105.

16. The method of any one of claims 1 to 11, wherein the PD-1 pathway inhibitor is a small molecule drug.

17. The method of claim 16, wherein the PD-1 pathway inhibitor is CA-170.

18. The method of claim 16, wherein the PD-1 pathway inhibitor is a cell based therapy.

19. The method of claim 18, wherein the cell based therapy is a MiHA-loaded PD-L1/L2- silenced dendritic cell vaccine.

20. The method of claim 19, wherein the cell based therapy is an anti-programmed cell death protein 1 antibody expressing pluripotent killer T lymphocyte, an autologous PD-1- targeted chimeric switch receptor-modified T lymphocyte, or a PD-1 knockout autologous T lymphocyte.

21. The method of any one of claims 1 to 11, wherein the PD-1 pathway inhibitor is an anti- PD-L2 antibody or antigen binding fragment thereof.

22. The method of claim 21, wherein the anti-PD-L2 antibody is rHIgM12B7.

23. The method of claim 1 to 11, wherein the PD-1 pathway inhibitor is a soluble PD-1 polypeptide.

24. The method of claim 23, wherein the soluble PD-1 polypeptide is a fusion polypeptide.

25. The method of claim 23 or 24, wherein the soluble PD-1 polypeptide comprises a ligand binding fragment of the PD-1 extracellular domain.

26. The method of any one of claims 23 to 25, wherein the soluble PD-1 polypeptide comprises a ligand binding fragment of the PD-1 extracellular domain.

27. The method of claim 26, wherein the ligand binding fragment of the PD-1 extracellular domain comprises an amino acid sequence with at least 90%, at least 95%, .at least 98%, or at least 99% sequence identity to SEQ ID NO:45.

28. The method of any one of claims 23 to 27, wherein the soluble PD-1 polypeptide further comprises an Fc domain.

29. The method of any one of claims 1 to 28, wherein the immunotherapeutic agent is a modulator of CTLA-4 activity, a modulator of CD28 activity, a modulator of CD80 activity, a modulator of CD86 activity, a modulator of 4-lBB activity, an modulator of OX40 activity, a modulator of KIR activity, a modulator of Tim-3 activity, a modulator of CD27 activity, a modulator of CD40 activity, a modulator of GITR activity, a modulator of TIGIT activity, a modulator of CD20 activity, a modulator of CD96 activity, a modulator of IDOl activity, a modulator of STING activity, a modulator of GARP activity, a modulator of A2aR activity, a modulator of CEACAMl activity, a modulator of CEA activity, a modulator of CD47 activity, a modulator of PVRIG activity, a modulator of TDO activity, a modulator of VISTA activity, a cytokine, a chemokine, an interferon, an interleukin, a lymphokine, a member of the tumor necrosis factor (TNF) family, or an immunostimulatory oligonucleotide.

30. The method of any one of claims 1 to 28, wherein the immunotherapeutic agent is an immune checkpoint inhibitor.

31. The method of claim 30, wherein the immune checkpoint inhibitor is a CTLA-4 antagonist, a CD80 antagonist, a CD86 antagonist, a Tim-3 antagonist, a TIGIT antagonist, a CD20 antagonist, a CD96 antagonist, a IDOl antagonist, a STING antagonist, a GARP antagonist, a CD40 antagonist, A2aR antagonist, a CEACAMl (CD66a) antagonist, a CEA antagonist, a CD47 antagonist a PVRIG antagonist, a TDO antagonist, a VISTA antagonist, or a KIR antagonist.

32. The method of claim 31, wherein the immune checkpoint inhibitor is a CTLA-4 antagonist.

33. The method of claim 32, wherein the CTLA-4 antagonist is an anti-CTLA-4 antibody or antigen binding fragment thereof.

34. The method of claim 33, wherein the anti-CTLA-4 antibody is ipilimumab (YERVOY), tremelimumab (ticilimumab; CP-675,206), AGEN-1884, or ATOR-1015.

35. The method of claim 32, wherein the CTLA-4 antagonist is a soluble CTLA-4 polypeptide.

36. The method of claim 35, wherein the soluble CTLA-4 polypeptide is abatacept (Orencia), belatacept (Nulojix), RG2077, or RG-1046.

37. The method of claim 32, wherein the CTLA-4 antagonist is a cell based therapy.

38. The method of claim 37, wherein the CTLA-4 antagonist is an anti-CTLA4 mAb RNA/GITRL RNA-transfected autologous dendritic cell vaccine or an anti-CTLA-4 mAb RNA-transfected autologous dendritic cell vaccine.

39. The method of claim 31, wherein the immune checkpoint inhibitor is a KIR antagonist

40. The method of claim 39, wherein the KIR antagonist is an anti-KIR antibody or antigen binding fragment thereof.

41. The method of claim 40, wherein the anti-KIR antibody is lirilumab (1-7F9, BMS- 986015, IPH 2101) or IPH4102.

42. The method of claim 31, wherein the immune checkpoint inhibitor is TIGIT antagonist.

43. The method of claim 42, wherein the TIGIT antagonist is an anti-TIGIT antibody or antigen binding fragment thereof.

44. The method of claim 43, wherein the anti-TIGIT antibody is BMS-986207, AB 154, COM902 (CGEN-15137), or OMP-313M32.

45. The method of claim 31, wherein the immune checkpoint inhibitor is Tim-3 antagonist.

46. The method of claim 45, wherein the Tim-3 antagonist is an anti-Tim-3 antibody or antigen binding fragment thereof.

47. The method of claim 46, wherein the anti-Tim-3 antibody is TSR-022 or LY3321367.

48. The method of claim 31, wherein the immune checkpoint inhibitor is a IDOl antagonist.

49. The method of claim 48, wherein the IDOl antagonist is indoximod (NLG8189; 1- methyl-D-TRP), epacadostat (INCB-024360, INCB-24360), KHK2455, PF-06840003, navoximod (RG6078, GDC-0919, NLG919), BMS-986205 (F001287), or pyrrolidine- 2,5-dione derivatives.

50. The method of claim 31, wherein the immune checkpoint inhibitor is a STING antagonist.

51. The method of claim 50, wherein the STING antagonist is 2' or 3'-mono-fluoro substituted cyclic-di-nucleotides; 2'3'-di-fluoro substituted mixed linkage 2', 5' - 3',5' cyclic-di-nucleotides; 2'-fluoro substituted, bis-3',5' cyclic-di-nucleotides; 2',2"-diF- Rp,Rp,bis-3',5' cyclic-di-nucleotides; or fluorinated cyclic-di-nucleotides.

52. The method of claim 31, wherein the immune checkpoint inhibitor is CD20 antagonist.

53. The method of claim 52, wherein the CD20 antagonist is an anti-CD20 antibody or antigen binding fragment thereof.

54. The method of claim 53, wherein the anti-CD20 antibody is rituximab (RITUXAN;

IDEC-102; IDEC-C2B8), ABP 798, ofatumumab, or obinutuzumab.

55. The method of claim 31, wherein the immune checkpoint inhibitor is CD80 antagonist.

56. The method of claim 55, wherein the CD80 antagonist is an anti-CD80 antibody or antigen binding fragment thereof.

57. The method of claim 56, wherein the anti-CD80 antibody is galiximab or AV 1142742.

58. The method of claim 31, wherein the immune checkpoint inhibitor is a GARP antagonist.

59. The method of claim 58, wherein the GARP antagonist is an anti-GARP antibody or antigen binding fragment thereof.

60. The method of claim 59, wherein the anti-GARP antibody is ARGX-115.

61. The method of claim 31, wherein the immune checkpoint inhibitor is a CD40 antagonist.

62. The method of claim 61, wherein the CD40 antagonist is an anti-CD40 antibody for antigen binding fragment thereof.

63. The method of claim 62, wherein the anti-CD40 antibody is BMS3h-56, lucatumumab (HCD122 and CHIR-12.12), CHIR-5.9, or dacetuzumab (huS2C6, PRO 64553, RG 3636, SGN 14, SGN-40).

64. The method of claim 61, wherein the CD40 antagonist is a soluble CD40 ligand (CD40- L).

65. The method of claim 64, wherein the soluble CD40 ligand is a fusion polypeptide.

66. The method of claim 64 or 65, wherein the soluble CD40 ligand is a CD40-L/FC2 or a monomelic CD40-L.

67. The method of claim 31, wherein the immune checkpoint inhibitor is an A2aR antagonist.

68. The method of claim 67, wherein the A2aR antagonist is a small molecule.

69. The method of claim 67 or 68, wherein the A2aR antagonist is CPI-444, PBF-509, istradefylline (KW-6002), preladenant (SCH420814), tozadenant (SYN115), vipadenant (BIIB014), HTL-1071, ST1535, SCH412348, SCH442416, SCH58261, ZM241385, or AZD4635.

70. The method of claim 31, wherein the immune checkpoint inhibitor is a CEACAM1 antagonist.

71. The method of claim 70, wherein the CEACAMl antagonist is an anti-CEACAMl antibody or antigen binding fragment thereof.

72. The method of claim 71 , wherein the anti-CEACAMl antibody is CM-24 (MK-6018).

73. The method of claim 31, wherein the immune checkpoint inhibitor is a CEA antagonist.

74. The method of claim 73, wherein the CEA antagonist is an anti-CEA antibody or antigen binding fragment thereof.

75. The method of claim 74, wherein the anti-CEA antibody is cergutuzumab amunaleukin (RG7813, RO-6895882) or RG7802 (R06958688).

76. The method of claim 31, wherein the immune checkpoint inhibitor is a CD47 antagonist.

77. The method of claim 76, wherein the CD47 antagonist is an anti-CD47 antibody or antigen binding fragment thereof.

78. The method of claim 77, wherein the anti-CD47 antibody is HuF9-G4, CC-90002, TTI- 621, ALX148, NI-1701, NI-1801, SRF231, or Effi-DEM.

79. The method of claim 31, wherein the immune checkpoint inhibitor is a PVRIG antagonist.

80. The method of claim 79, wherein the PVRIG antagonist is an anti-PVRIG antibody or antigen binding fragment thereof.

81. The method of claim 80, wherein the anti-PVRIG antibody is COM701 (CGEN- 15029).

82. The method of claim 31, wherein the immune checkpoint inhibitor is a TDO antagonist.

83. The method of claim 82, wherein the TDO antagonist is a 4-(indol-3-yl)-pyrazole derivative, a 3-indol substituted derivative, or a 3-(indol-3-yl)-pyridine derivative.

84. The method of claim 31, wherein the immune checkpoint inhibitor is a dual IDO and TDO antagonist.

85. The method of claim x84 wherein the dual IDO and TDO antagonist is a small molecule.

86. The method of claim 31, wherein the immune checkpoint inhibitor is a VISTA antagonist.

87. The method of claim 86, wherein the VISTA antagonist is CA-170 or JNJ-61610588.

88. The method of any one of claims 1-29, wherein the immunotherapeutic agent is an immune checkpoint enhancer or stimulator.

89. The method of claim 88, wherein the immune checkpoint enhancer or stimulator is a CD28 agonist, a 4-lBB agonist, an OX40 agonist, a CD27 agonist, a CD80 agonist, a CD86 agonist, a CD40 agonist, an ICOS agonist, a CD70 agonist, or a GITR agonist.

90. The method of claim 89, wherein the immune checkpoint enhancer or stimulator is an OX40 agonist.

91. The method of claim 90, wherein the OX40 agonist is an anti-OX40 antibody or antigen binding fragment thereof.

92. The method of claim 91, wherein the anti-OX40 antibody is tavolixizumab (MEDI-0562), pogalizumab (MOXR0916, RG7888), GSK3174998, ATOR-1015, MEDI-6383, MEDI- 6469, BMS 986178, PF-04518600, or RG7888 (MOXR0916). .

93. The method of claim 90, wherein the OX40 agonist is a cell based therapy.

94. The method of claim 93, wherein the OX40 agonist is a GINAKIT cell.

95. The method of claim 89, wherein the immune checkpoint enhancer or stimulator is a CD40 agonist.

96. The method of claim 95 wherein the CD40 agonist is an anti-CD40 antibody or antigen binding fragment thereof.

97. The method of claim 96, wherein the anti-CD40 antibody is ADC-1013 (JNJ-64457107), RG7876 (RO-7009789), HuCD40-M2, APX005M (EPI-0050), or Chi Lob 7/4.

98. The method of claim 95, wherein the CD40 agonist is a soluble CD40 ligand (CD40-L).

99. The method of claim 98, wherein the soluble CD40 ligand is a fusion polypeptide.

100. The method of claim 98 or 99, wherein the soluble CD40 ligand is a trimeric CD40-L (AVRE D).

101. The method of claim 89, wherein the immune checkpoint enhancer or stimulator is a GITR agonist.

102. The method of claim 101, wherein the GITR agonist is an anti-GITR antibody or antigen binding fragment thereof.

103. The method of claim 102, wherein the anti-GITR antibody is BMS-986156, TRX518, GWN323, INCAGN01876, or MEDI1873.

104. The method of claim 101, wherein the GITR agonist is a soluble GITR ligand (GITRL).

105. The method of claim 104, wherein the soluble GITR ligand is a fusion polypeptide.

106. The method of claim 101, wherein the GITR agonist is a cell based therapy.

107. The method of claim 106, wherein the cell based therapy is an anti-CTLA4 mAb RNA/GITRL RNA-transfected autologous dendritic cell vaccine or a GITRL RNA- transfected autologous dendritic cell vaccine.

108. The method of claim 89, wherein the immune checkpoint enhancer or stimulator a 4-1BB agonist.

109. The method of claim 108, wherein the 4- IBB agonist is an anti-4-lBB antibody or antigen binding fragment thereof.

110. The method of claim 109, wherein the anti-4-lBB antibody is urelumab or PF-05082566.

111. The method of claim 89, wherein the immune checkpoint enhancer or stimulator is a CD80 agonist or a CD86 agonist.

112. The method of claim 111, wherein the CD80 agonist or the CD86 agonist is a soluble CD80 or CD86 ligand (CTLA-4).

113. The method of claim 112, wherein the soluble CD80 or CD86 ligand is a fusion polypeptide.

114. The method of claim 112 or 113, wherein the CD80 or CD86 ligand is CTLA4-Ig (CTLA4-IgG4m, RG2077, or RG1046) or abatacept (ORENCIA, BMS-188667).

115. The method of claim 111, wherein the CD80 agonist or the CD86 agonist is a cell based therapy.

116. The method of claim 115, wherein the cell based therapy is MGN1601.

117. The method of claim 89, wherein the immune checkpoint enhancer or stimulator is a CD28 agonist.

118. The method of claim 117, wherein the CD28 agonist is an anti-CD28 antibody or antigen binding fragment thereof.

119. The method of claim 118, wherein the anti-CD28 antibody is TGN1412.

120. The method of claim 117, wherein the CD28 agonist is a cell based therapy.

121. The method of claim 120, wherein the cell based therapy is JCAR015 (anti-CD 19-CD28- zeta modified CAR CD3+ T lymphocyte); CD28CAR/CD137CAR-expressing T lymphocyte; allogeneic CD4+ memory Thl-like T cells/microparticle-bound anti- CD3/anti-CD28; anti-CD 19/CD28/CD3zeta CAR gammaretroviral vector-transduced autologous T lymphocytes KTE-C19; anti-CEA IgCD28TCR-transduced autologous T lymphocytes; anti-EGFRvIII CAR-transduced allogeneic T lymphocytes; autologous CD123CAR-CD28-CD3zeta-EGFRt-expressing T lymphocytes; autologous CD171- specific CAR-CD28 zeta-4-l-BB-EGFRt-expressing T lymphocytes; autologous CD19CAR-CD28-CD3zeta-EGFRt-expressing Tcm-enriched T cells; autologous PD-1- targeted chimeric switch receptor-modified T lymphocytes (chimera with CD28); CD19CAR-CD28-CD3zeta-EGFRt-expressing Tcm-enriched T lymphocytes;

CD19CAR-CD28-CD3zeta-EGFRt-expressing Tn/mem-enriched T lymphocytes; CD19CAR-CD28zeta-4-lBB-expressing allogeneic T lymphocytes; CD19CAR-CD3zeta- 4-lBB-CD28-expressing autologous T lymphocytes; CD28CAR/CD137CAR-expressing T lymphocytes; CD3/CD28 costimulated vaccine-primed autologous T lymphocytes; or iC9-GD2-CD28-OX40-expressing T lymphocytes.

122. The method of claim 89, wherein the immune checkpoint enhancer or stimulator is a CD27 agonist.

123. The method of claim 122, wherein the CD27 agonist is an anti-CD27 antibody or antigen binding fragment thereof.

124. The method of claim 123, wherein the anti-CD27 antibody is varlilumab (CDX-1127).

125. The method of claim 89, wherein the immune checkpoint enhancer or stimulator is a CD70 agonist.

126. The method of claim 125, wherein the CD70 agonist is an anti-CD70 antibody or antigen binding fragment thereof.

127. The method of claim 126, wherein the anti-CD70 antibody is ARGX-110.

128. The method of claim 89, wherein the immune checkpoint enhancer or stimulator is an ICOS agonist.

129. The method of claim 128, wherein the ICOS agonist is an anti-ICOS antibody or antigen binding fragment thereof.

130. The method of claim 129, wherein the anti-ICOS antibody is BMS986226, MEDI-570, GSK3359609, or JTX-2011.

1. The method of claim 128, wherein the ICOS agonist is a soluble ICOS ligand.

The method of claim 131, wherein the soluble ICOS ligand is a fusion polypeptide.

The method of claim 131 or 132, wherein the soluble ICOS ligand is AMG 750.

The method of claim 89, wherein the immunotherapeutic agent is an anti-CD73 antibody or antigen binding fragment thereof.

The method of claim 134, wherein the anti-CD73 antibody is MEDI9447.

The method of any one of claims 1-28, wherein the immunotherapeutic agent is a TLR9 agonist.

The method of claim 136, wherein the TLR9 agonist is agatolimod sodium.

The method of any one of claims 1-28, wherein the immunotherapeutic agent is a cytokine.

The method of claim 138, wherein the cytokine is a chemokine, an interferon, an interleukin, lymphokine, or a member of the tumor necrosis factor family.

The method of claim 138 or 139, wherein the cytokine is IL-2, IL-15, or interferon- gamma.

The method of any one of claims 1-28, wherein the immunotherapeutic agent is a TGF-β antagonist.

The method of claim 141, wherein the TGF-β antagonist is fresolimumab (GC-1008), NIS793, IMC-TRl (LY3022859), ISTH0036, trabedersen (AP 12009), recombinant

transforming growth factor-beta-2, autologous HPV-16/18 E6/E7-specific TGF -beta- resistant T lymphocytes, or TGF-beta-resistant LMP-specific cytotoxic T-lymphocytes.

143. The method of any one of claims 1-28, wherein the immunotherapeutic agent is an iNOS antagonist.

144. The method of claim 143, wherein the iNOS antagonist is N-Acetyle-cysteine (NAC), aminoguanidine, L-nitroarginine methyl ester, or S,S-l,4-phenylene-bis(l,2- ethanediyl)bi s-i sothiourea) .

145. The method of any one of claims 1-28, wherein the immunotherapeutic agent is a SHP-1 antagonist.

146. The method of any one of claims 1-28, wherein the immunotherapeutic agent is a CSFIR (colony stimulating factor 1 receptor) antagonist.

147. The method of claim 146, wherein the CSFIR antagonist is an anti-CSFIR antibody or antigen binding fragment thereof.

148. The method of claim 147, wherein the anti-CSFIR antibody is emactuzumab.

149. The method of any one of claims 1-28, wherein the immunotherapeutic agent is an agonist of a TNF family member.

150. The method of claim 149, wherein the agonist of the TNF family member is ATOR 1016, ABBV-621, or Adalimumab.

151. The method of any one of claims 1-28, wherein the immunotherapeutic agent is aldesleukin, tocilizumab, or MEDI5083.

152. The method of any one of claims 1-28, wherein the immunotherapeutic agent is a CD 160 (NK1) agonist.

153. The method of claim 152, wherein the CD160 ( K1) agonist is an anti-CD160 antibody or antigen binding fragment thereof.

154. The method of claim 152 or 153, wherein the anti-CD160 antibody is BY55.

155. The method of any one of claims 1-154, wherein the LAG-3 inhibitor, PD-1 pathway inhibitor, and the immunotherapeutic agent are formulated for intravenous administration.

156. The method of any one of claims 1-155, wherein the LAG-3 inhibitor, PD-1 pathway inhibitor, and the immunotherapeutic agent are formulated together.

157. The method of any one of claims 1-155, wherein the LAG-3 inhibitor, PD-1 pathway inhibitor, and the immunotherapeutic agent are formulated separately.

158. The method of any one of claims 1-157, wherein the malignant tumor is selected from the group consisting of a liver cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, breast cancer, lung cancer, cutaneous or intraocular malignant melanoma, renal cancer, uterine cancer, ovarian cancer, colorectal cancer, colon cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, non-Hodgkin's lymphoma, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, cancers of the childhood, lymphocytic lymphoma, cancer of the bladder, cancer of the kidney or ureter, carcinoma of the renal pelvis, neoplasm of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid cancer, squamous cell cancer, environmentally induced cancers including those induced by asbestos, hematologic malignancies including, for

example, multiple myeloma, B-cell lymphoma, Hodgkin lymphoma/primary mediastinal B-cell lymphoma, non-Hodgkin's lymphomas, acute myeloid lymphoma, chronic myelogenous leukemia, chronic lymphoid leukemia, follicular lymphoma, diffuse large B-cell lymphoma, Burkitt's lymphoma, immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, mantle cell lymphoma, acute lymphoblastic leukemia, mycosis fungoides, anaplastic large cell lymphoma, T-cell lymphoma, and precursor T-lymphoblastic lymphoma, and any combination thereof.

The method of claim 158, wherein the malignant tumor is non-small cell lung cancer (NSCLC), a virally-related cancer related tumor, or gastric adenocarcinoma.

The method of any one of claims 1-157, wherein the malignant tumor is melanoma, gastric cancer, gastroesophageal junction cancer, non-small cell lung cancer, bladder cancer, head and neck squamous cell carcinoma, or renal cell cancer.

The method of any one of claims 1-157, wherein the tumor is lung cancer, melanoma, squamous cell carcinoma of the head and neck, renal cancer, gastric cancer, or hepatocellular carcinoma.

The method of any one of claims 1-161, wherein the anti-LAG-3 antibody or antigen binding fragment thereof and the immunotherapeutic agent are administered as a first line of treatment.

The method of any one of claims 1-161, wherein the LAG-3 inhibitor, PD-1 pathway inhibitor, and the immunotherapeutic agent are administered as a second line of treatment.

The method of any one of claims 1-163, wherein the malignant tumor is refractory to first line treatment.

The method of any one of claims 1-164, further comprising the administration of at least one additional therapeutic agent.

166. The method of claim 165, wherein the at least one additional therapeutic agent is a chemotherapeutic agent.