Use of tumor inflitrating lymphocytes for treating nsclc patients refractory for Anti-PD-1 antibody
Patent Information
- Application Number
- AU2026233995
- Authority / Receiving Office
- AU · AU
- Patent Type
- Applications
- Current Assignee / Owner
- Priority Date
- 2018-09-04
- Filing Date
- 2026-09-16
- Publication Date
- 2026-10-08
Smart Images
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Abstract
Claims
1. A method of treating non-small cell lung carcinoma (NSCLC) with a population of tumor infiltrating lymphocytes (TILs) comprising the steps of:(a) obtaining and / or receiving a first population of TILs from surgical resection, needle biopsy, core biopsy, small biopsy, or other means for obtaining a sample that contains a mixture of tumor and TIL cells from a NSCLC tumor in a patient, including from multiple tumor fragments or biopsies;(c) contacting the tumor fragments with a first cell culture medium;(d) performing an initial expansion of the first population of TILs in the first cell culture medium to obtain a second population of TILs, wherein the second population of TILs is at least 5-fold greater in number than the first population of TILs, wherein the first cell culture medium comprises IL-2;(e) performing a rapid expansion of the second population of TILs in a second cell culture medium to obtain a third population of TILs, wherein the third population of TILs is at least 50-fold greater in number than the second population of TILs after 7 days from the start of the rapid expansion; wherein the second cell culture medium comprises IL-2, OKT-3 (anti-CD3 antibody), and optionally irradiated allogeneic peripheral blood mononuclear cells (PBMCs); and wherein the rapid expansion is performed over a period of 14 days or less;(f) harvesting the third population of TILs; and(g) administering a therapeutically effective portion of the third population of TILs to a patient with the NSCLC;wherein the NSCLC is refractory to treatment with an anti-PD-1 antibody.
2. The method of Claim 1, wherein the obtaining the first population of TILs comprises a multilesional sampling method.
3. The method of Claim 1, wherein the refractory NSCLC has been previously treated with an anti-PD-1 and / or anti-PD-Ll and / or anti-PD-L2 antibody.
4. The method of Claim 1, wherein the refractory NSCLC has not been previously treated with an anti-PD-1 and / or anti-PD-Ll antibody.
5. The method of Claim 1, wherein the refractory NSCLC has been treated with a2026233995 16 Sep 2026chemotherapeutic agent.
6. The method of Claim 1, wherein the refractory NSCLC has been previously treated with an anti-PD-1 and / or anti-PD-Ll antibody and has been previously treated a chemotherapeutic agent.
7. The method of Claim 1, wherein the refractory NSCLC has not been previously treated with an anti-PD-1 and / or anti-PD-Ll antibody and has been previously treated a chemotherapeutic agent.
8. The method of Claims 5 to 7, wherein the refractory NSCLC has been treated with a chemotherapeutic agent but is not being currently treated with a chemotherapeutic agent.
9. The method of Claim 1, wherein the refractory NSCLC has low expression of PD-L1.
10. The method of Claim 1, wherein the refractory NSCLC has been previously treated with an anti-PD-1 and / or anti-PD-Ll antibody and has low expression of PD-L1.
11. The method of Claim 1, wherein the refractory NSCLC has not been previously treated with an anti-PD-1 and / or anti-PD-Ll antibody and has low expression of PD-L1.
12. The method of Claim 1, wherein the refractory NSCLC has been treated with a chemotherapeutic agent and has low expression of PD-L1.
13. The method of Claim 1, wherein the refractory NSCLC has been treated with a chemotherapeutic agent but is not being currently treated with a chemotherapeutic agent and has low expression of PD-L114. The method of Claim 1, wherein the refractory NSCLC has not been previously treated with an anti-PD-1 and / or anti-PD-Ll antibody and has bulky disease at baseline.
15. The method of Claim 1, wherein the refractory NSCLC has been previously treated with an anti-PD-1 and / or anti-PD-Ll antibody and has bulky disease at baseline.
16. The method of Claim 1, wherein the refractory NSCLC has been treated with a chemotherapeutic agent and has bulky disease at baseline.
17. The method of Claim 1, wherein the refractory NSCLC has been treated with a chemotherapeutic agent but is not being currently treated with a chemotherapeutic agent and has bulky disease at baseline.
18. The method of Claims 14 to 17, wherein bulky disease is indicated where the maximal2026233995 16 Sep 2026tumor diameter is greater than 7 cm measured in either the transverse or coronal plane or swollen lymph nodes with a short-axis diameter of 20 mm or greater.
19. The method of Claim 1, wherein the refractory NSCLC is refractory to at least two prior systemic treatment courses, not including neo-adjuvant or adjuvant therapies.
20. The method of Claim 1, wherein the refractory NSCLC is refractory to an anti-PD-1 antibody selected from the group consisting of nivolumab, pembrolizumab, ipilimumab, JS001, TSR-042, pidilizumab, (BGB-A317, SHR-1210, REGN2810, MDX-1106, PDR001, anti-PD-1 from clone: RMP1-14; and an anti-PD-1 antibodies disclosed in U.S. Patent No. 8,008,449, durvalumab, atezolizumab, avelumab, and fragments, derivatives, variants, as well as biosimilars thereof.
21. The method of Claim 1, wherein the refractory NSCLC is refractory to pembrolizumab or a biosimilar thereof.
22. The method of Claim 1, wherein the refractory NSCLC is refractory to nivolumab or a biosimilar thereof.
23. The method of Claim 1, wherein the refractory NSCLC is refractory to ipilimumab or a biosimilar thereof.
24. The method of Claim 1, wherein the refractory NSCLC is refractory to ipilimumab or a biosimilar thereof and pembrolizumab or a biosimilar thereof.
25. The method of Claim 1, wherein the refractory NSCLC is refractory to ipilimumab or a biosimilar thereof and nivolumab or a biosimilar thereof.
26. The method of Claim 1, wherein the refractory NSCLC is refractory to durvalumab or a biosimilar thereof.
27. The method of Claim 1, wherein the refractory NSCLC is refractory to atezolizumab or a biosimilar thereof.
28. The method of Claim 1, wherein the refractory NSCLC is refractory to avelumab or a biosimilar thereof.
29. The method of any one of Claims 1 to 28, wherein the initial expansion is performed over a period of 21 days or less.
30. The method of any one of Claims 1 to 29, wherein the initial expansion is performed over a period of 14 days or less.2026233995 16 Sep 202631. The method of any one of Claims 1 to 30, wherein the initial expansion is performed over a period of about 11 days and the rapid expansion is performed over a period of about 11 days.
32. The method of any one of Claims 1 to 31, wherein the IL-2 is present at an initial concentration of between 1000 lU / mL and 6000 lU / mL in the first cell culture medium.
33. The method of any one of Claims 1 to 32, wherein the IL-2 is present at an initial concentration of between 1000 lU / mL and 6000 lU / mL and the OKT-3 antibody is present at an initial concentration of about 30 ng / mL in the second cell culture medium.
34. The method of any one of Claims 1 to 33, wherein the initial expansion is performed using a gas permeable container.
35. The method of any one of Claims 1 to 34, wherein the rapid expansion is performed using a gas permeable container.
36. The method of any one of Claims 1 to 35, wherein the first cell culture medium further comprises a cytokine selected from the group consisting of IL-4, IL-7, IL-15, IL-21, and combinations thereof.
37. The method of any one of Claims 1 to 36, wherein the second cell culture medium further comprises a cytokine selected from the group consisting of IL-4, IL-7, IL-15, IL-21, and combinations thereof.
38. The method of any one of Claims 1 to 37, further comprising the step of treating the patient with a non-myeloablative lymphodepletion regimen prior to administering the third population of TILs to the patient.
39. The method of Claim 38, wherein the non-myeloablative lymphodepletion regimen comprises the steps of administration of cyclophosphamide at a dose of 60 mg / m2 / day for two days followed by administration of fludarabine at a dose of 25 mg / m2 / day for five days.
40. The method of any one of Claims 1 to 39, further comprising the step of treating the patient with an IL-2 regimen starting on the day after administration of the third population of TILs to the patient.
41. The method of Claim 40, wherein the IL-2 regimen is a high-dose IL-2 regimen comprising 600,000 or 720,000 lU / kg of aldesleukin, or a biosimilar or variant thereof, administered as a 15-minute bolus intravenous infusion every eight hours until tolerance.2026233995 16 Sep 202642. A method of treating non-small cell lung carcinoma (NSCLC) with a population of tumor infiltrating lymphocytes (TILs) comprising the steps of:(a) resecting one or more tumors from a patient, the one or more tumors comprising a first population of TILs;(b) fragmenting the one or more tumor into tumor fragments;(c) contacting the tumor fragments with a first cell culture medium;(d) performing an initial expansion of the first population of TILs in the first cell culture medium to obtain a second population of TILs, wherein the second population of TILs is at least 5-fold greater in number than the first population of TILs, wherein the first cell culture medium comprises IL-2;(e) performing a rapid expansion of the second population of TILs in a second cell culture medium to obtain a third population of TILs, wherein the third population of TILs is at least 50-fold greater in number than the second population of TILs after 7 days from the start of the rapid expansion; wherein the second cell culture medium comprises IL-2, OKT-3 (anti-CD3 antibody), and optionally irradiated allogeneic peripheral blood mononuclear cells (PBMCs); and wherein the rapid expansion is performed over a period of 14 days or less;(f) harvesting the third population of TILs; and(g) administering a therapeutically effective portion of the third population of TILs to a patient with the NSCLC;wherein the NSCLC is refractory to treatment with an anti-PD-1 antibody.
43. The method of Claim 42, wherein the tumor is resected from one or more tumor cites.
44. The method of Claim 42, wherein the refractory NSCLC has been previously treated with an anti-PD-1 and / or anti-PD-Ll and / or anti-PD-L2 antibody.
45. The method of Claim 42, wherein the refractory NSCLC has not been previously treated with an anti-PD-1 and / or anti-PD-Ll antibody.
46. The method of Claim 42, wherein the refractory NSCLC has been treated with a chemotherapeutic agent.
47. The method of Claim 42, wherein the refractory NSCLC has been previously treated with an anti-PD-1 and / or anti-PD-Ll antibody and has been previously treated a2026233995 16 Sep 2026chemotherapeutic agent.
48. The method of Claim 42, wherein the refractory NSCLC has not been previously treated with an anti-PD-1 and / or anti-PD-Ll antibody and has been previously treated a chemotherapeutic agent.
49. The method of Claims 46 to 48, wherein the refractory NSCLC has been treated with a chemotherapeutic agent but is not being currently treated with a chemotherapeutic agent.
50. The method of Claim 42, wherein the refractory NSCLC has low expression of PD-L1.
51. The method of Claim 42, wherein the refractory NSCLC has been previously treated with an anti-PD-1 and / or anti-PD-Ll antibody and has low expression of PD-L1.
52. The method of Claim 42, wherein the refractory NSCLC has not been previously treated with an anti-PD-1 and / or anti-PD-Ll antibody and has low expression of PD-L1.
53. The method of Claim 42, wherein the refractory NSCLC has been treated with a chemotherapeutic agent and has low expression of PD-L1.
54. The method of Claim 42, wherein the refractory NSCLC has been treated with a chemotherapeutic agent but is not being currently treated with a chemotherapeutic agent and has low expression of PD-L1.
55. The method of Claim 42, wherein the refractory NSCLC has not been previously treated with an anti-PD-1 and / or anti-PD-Ll antibody and has bulky disease at baseline.
56. The method of Claim 42, wherein the refractory NSCLC has been previously treated with an anti-PD-1 and / or anti-PD-Ll antibody and has bulky disease at baseline.
57. The method of Claim 42, wherein the refractory NSCLC has been treated with a chemotherapeutic agent and has bulky disease at baseline.
58. The method of Claim 42, wherein the refractory NSCLC has been treated with a chemotherapeutic agent but is not being currently treated with a chemotherapeutic agent and has bulky disease at baseline.
59. The method of Claims 55 to 58, wherein said bulky disease is indicated where the maximal tumor diameter is greater than 7 cm measured in either the transverse or coronal plane or swollen lymph nodes with a short-axis diameter of 20 mm or greater.
60. The method of Claim 42, wherein the refractory NSCLC is refractory to at least two prior2026233995 16 Sep 2026systemic treatment courses, not including neo-adjuvant or adjuvant therapies.
61. The method of Claim 42, wherein the refractory NSCLC is refractory to an anti-PD-1 antibody selected from the group consisting of nivolumab, pembrolizumab, ipilimumab, JS001, TSR-042, pidilizumab, (BGB-A317, SHR-1210, REGN2810, MDX-1106, PDR001, anti-PD-1 from clone: RMP1-14; and an anti-PD-1 antibodies disclosed in U.S. Patent No. 8,008,449, durvalumab, atezolizumab, avelumab, and fragments, derivatives, variants, as well as biosimilars thereof.
62. The method of Claim 42, wherein the refractory NSCLC is refractory to pembrolizumab or a biosimilar thereof.
63. The method of Claim 42, wherein the refractory NSCLC is refractory to nivolumab or a biosimilar thereof.
64. The method of Claim 42, wherein the refractory NSCLC is refractory to ipilimumab or a biosimilar thereof.
65. The method of Claim 42, wherein the refractory NSCLC is refractory to ipilimumab or a biosimilar thereof and pembrolizumab or a biosimilar thereof.
66. The method of Claim 42, wherein the refractory NSCLC is refractory to ipilimumab or a biosimilar thereof and nivolumab or a biosimilar thereof.
67. The method of Claim 42, wherein the refractory NSCLC is refractory to durvalumab or a biosimilar thereof.
68. The method of Claim 42, wherein the refractory NSCLC is refractory to atezolizumab or a biosimilar thereof.
69. The method of Claim 42, wherein the refractory NSCLC is refractory to avelumab or a biosimilar thereof.
70. The method of any one of Claims 42 to 69, wherein the initial expansion is performed over a period of 21 days or less.
71. The method of any one of Claims 42 to 70, wherein the initial expansion is performed over a period of 14 days or less.
72. The method of any one of Claims 42 to 71, wherein the initial expansion is performed over a period of about 11 days and the rapid expansion is performed over a period of about 11 days.2026233995 16 Sep 202673. The method of any one of Claims 42 to 72, wherein the IL-2 is present at an initial concentration of between 1000 lU / mL and 6000 lU / mL in the first cell culture medium.
74. The method of any one of Claims 42 to 73, wherein the IL-2 is present at an initial concentration of between 1000 lU / mL and 6000 lU / mL and the OKT-3 antibody is present at an initial concentration of about 30 ng / mL in the second cell culture medium.
75. The method of any one of Claims 42 to 74, wherein the initial expansion is performed using a gas permeable container.
76. The method of any one of Claims 42 to 75, wherein the rapid expansion is performed using a gas permeable container.
77. The method of any one of Claims 42 to 76, wherein the first cell culture medium further comprises a cytokine selected from the group consisting of IL-4, IL-7, IL-15, IL-21, and combinations thereof.
78. The method of any one of Claims 42 to 77, wherein the second cell culture medium further comprises a cytokine selected from the group consisting of IL-4, IL-7, IL-15, IL-21, and combinations thereof.
79. The method of any one of Claims 42 to 78, further comprising the step of treating the patient with a non-myeloablative lymphodepletion regimen prior to administering the third population of TILs to the patient.
80. The method of Claim 79, wherein the non-myeloablative lymphodepletion regimen comprises the steps of administration of cyclophosphamide at a dose of 60 mg / m2 / day for two days followed by administration of fludarabine at a dose of 25 mg / m2 / day for five days.
81. The method of any one of Claims 42 to 80, further comprising the step of treating the patient with an IL-2 regimen starting on the day after administration of the third population of TILs to the patient.
82. The method of Claim 81, wherein the IL-2 regimen is a high-dose IL-2 regimen comprising 600,000 or 720,000 lU / kg of aldesleukin, or a biosimilar or variant thereof, administered as a 15-minute bolus intravenous infusion every eight hours until tolerance.
83. A method for treating a subject with non-small cell lung carcinoma (NSCLC), wherein the cancer is refractory to treatment with an anti-PD-1 antibody, the method comprising administering expanded tumor infiltrating lymphocytes (TILs) comprising:2026233995 16 Sep 2026(a) obtaining and / or receiving a first population of TILs from one or more tumors resected from a subject by processing the one or more tumors obtained from the subject into multiple tumor fragments;(b) adding the tumor fragments into a closed system;(c) performing a first expansion by culturing the first population of TILs in a cell culture medium comprising IL-2 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;(d) performing a second expansion by supplementing the cell culture medium of the second population of TILs with additional IL-2, OKT-3, 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 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;(g) cryopreserving the infusion bag comprising the harvested TIL population from step (f) using a cryopreservation process; and(h) administering a therapeutically effective dosage of the third population of TILs from the infusion bag in step (g) to the subject.
84. The method of Claim 83, wherein the tumor sample is derived from a multilesional sampling method.
85. The method of Claim 83, wherein the refractory NSCLC has been previously treated with an anti-PD-1 and / or anti-PD-Ll antibody.2026233995 16 Sep 202686. The method of Claim 83, wherein the refractory NSCLC has not been previously treated with an anti-PD-1 and / or anti-PD-Ll antibody.
87. The method of Claim 83, wherein the refractory NSCLC has been treated with a chemotherapeutic agent.
88. The method of Claim 83, wherein the refractory NSCLC has been previously treated with an anti-PD-1 and / or anti-PD-Ll antibody and has been previously treated a chemotherapeutic agent.
89. The method of Claim 83, wherein the refractory NSCLC has not been previously treated with an anti-PD-1 and / or anti-PD-Ll antibody and has been previously treated a chemotherapeutic agent.
90. The method of Claims 87 to 89, wherein the refractory NSCLC has been treated with a chemotherapeutic agent but is not being currently treated with a chemotherapeutic agent.
91. The method of Claim 83, wherein the refractory NSCLC has low expression of PD-L1.
92. The method of Claim 83, wherein the refractory NSCLC has been previously treated with an anti-PD-1 and / or anti-PD-Ll antibody and has low expression of PD-L1.
93. The method of Claim 83, wherein the refractory NSCLC has not been previously treated with an anti-PD-1 and / or anti-PD-Ll antibody and has low expression of PD-L1.
94. The method of Claim 83, wherein the refractory NSCLC has been treated with a chemotherapeutic agent and has low expression of PD-L1.
95. The method of Claim 83, wherein the refractory NSCLC has been treated with a chemotherapeutic agent but is not being currently treated with a chemotherapeutic agent and has low expression of PD-L196. The method of Claim 83, wherein the refractory NSCLC has not been previously treated with an anti-PD-1 and / or anti-PD-Ll antibody and has bulky disease at baseline.
97. The method of Claim 83, wherein the refractory NSCLC has been previously treated with an anti-PD-1 and / or anti-PD-Ll antibody and has bulky disease at baseline.
98. The method of Claim 83, wherein the refractory NSCLC has been treated with a chemotherapeutic agent and has bulky disease at baseline.
99. The method of Claim 83, wherein the refractory NSCLC has been treated with a2026233995 16 Sep 2026chemotherapeutic agent but is not being currently treated with a chemotherapeutic agent and has bulky disease at baseline.
100. The method of Claims 96 to 99, wherein bulky disease is indicated where the maximal tumor diameter is greater than 7 cm measured in either the transverse or coronal plane or swollen lymph nodes with a short-axis diameter of 20 mm or greater.
101. The method of Claim 83, wherein the refractory NSCLC is refractory to at least two prior systemic treatment courses, not including neo-adjuvant or adjuvant therapies.
102. The method of Claim 83, wherein the refractory NSCLC is refractory to an anti-PD-1 antibody selected from the group consisting of nivolumab, pembrolizumab, ipilimumab, JS001, TSR-042, pidilizumab, (BGB-A317, SHR-1210, REGN2810, MDX-1106, PDR001, anti-PD-1 from clone: RMP1-14; and an anti-PD-1 antibodies disclosed in U.S. Patent No. 8,008,449, durvalumab, atezolizumab, avelumab, and fragments, derivatives, variants, as well as biosimilars thereof.
103. The method of Claim 83, wherein the refractory NSCLC is refractory to pembrolizumab or a biosimilar thereof.
104. The method of Claim 83, wherein the refractory NSCLC is refractory to nivolumab or a biosimilar thereof.
105. The method of Claim 83, wherein the refractory NSCLC is refractory to ipilimumab or a biosimilar thereof.
106. The method of Claim 83, wherein the refractory NSCLC is refractory to ipilimumab or a biosimilar thereof and pembrolizumab or a biosimilar thereof.
107. The method of Claim 83, wherein the refractory NSCLC is refractory to ipilimumab or a biosimilar thereof and nivolumab or a biosimilar thereof.
108. The method of Claim 83, wherein the refractory NSCLC is refractory to durvalumab or a biosimilar thereof.
109. The method of Claim 83, wherein the refractory NSCLC is refractory to atezolizumab or a biosimilar thereof.
110. The method of Claim 83, wherein the refractory NSCLC is refractory to avelumab or a biosimilar thereof.
111. The method of any one of Claims 83 to 110, wherein the initial expansion is2026233995 16 Sep 2026performed over a period of 21 days or less.
112. The method of any one of Claims 83 to 111, wherein the initial expansion is performed over a period of 14 days or less.
113. The method of any one of Claims 83 to 112, wherein the initial expansion is performed over a period of about 3-11 days and the second expansion is performed over a period of about 7-11 days.
114. The method of any one of Claims 83 to 113, wherein the initial expansion is performed over a period of about 11 days and the rapid expansion is performed over a period of about 11 days.
115. The method of any one of Claims 83 to 114, wherein the IL-2 is present at an initial concentration of between 1000 lU / mL and 6000 lU / mL in the first cell culture medium.
116. The method of any one of Claims 83 to 115, wherein the IL-2 is present at an initial concentration of between 1000 lU / mL and 6000 lU / mL and the OKT-3 antibody is present at an initial concentration of about 30 ng / mL in the second cell culture medium.
117. The method of any one of Claims 83 to 116, wherein the initial expansion is performed using a gas permeable container.
118. The method of any one of Claims 83 to 117, wherein the rapid expansion is performed using a gas permeable container.
119. The method of any one of Claims 83 to 118, wherein the first cell culture medium further comprises a cytokine selected from the group consisting of IL-4, IL-7, IL-15, IL-21, and combinations thereof.
120. The method of any one of Claims 83 to 119, wherein the second cell culture medium further comprises a cytokine selected from the group consisting of IL-4, IL-7, IL-15, IL-21, and combinations thereof.
121. The method of any one of Claims 83 to 120, further comprising the step of treating the patient with a non-myeloablative lymphodepletion regimen prior to administering the third population of TILs to the patient.
122. The method of Claim 121, wherein the non-myeloablative lymphodepletion regimen comprises the steps of administration of cyclophosphamide at a dose of 60 mg / m2 / day for two days followed by administration of fludarabine at a dose of 25 mg / m2 / day for2026233995 16 Sep 2026five days.
123. The method of any one of Claims 83 to 122, further comprising the step of treating the patient with an IL-2 regimen starting on the day after administration of the third population of TILs to the patient.
124. The method of Claim 123, wherein the IL-2 regimen is a high-dose IL-2 regimen comprising 600,000 or 720,000 lU / kg of aldesleukin, or a biosimilar or variant thereof, administered as a 15-minute bolus intravenous infusion every eight hours until tolerance.