Treatment of nsclc patients with tumor infiltrating lymphocyte therapies

Abstract

The present invention provides improved and/or shortened processes and methods for preparing TILs in order to prepare therapeutic populations of TILs with increased therapeutic efficacy for the treatment of non-small cell lung carcinoma (NSCLC), wherein the NSCLC is refractory to treatment with an anti-PD-1 antibody and/or anti-PD-L1 antibody and/or VEGF inhibitor, or wherein the NSCLC has a predetermined tumor proportion score (TPS).

What is claimed is: 
     
         1 . A method of treating non-small cell lung carcinoma (NSCLC) by administering a population of tumor infiltrating lymphocytes (TILs) to a subject or patient in need thereof, wherein the subject or patient has at least one of:
 i. a predetermined tumor proportion score (TPS) of PD-L1 of <1%,   ii. a TPS score of PD-L1 of 1%-49%, or   iii. a predetermined absence of one or more driver mutations.   
     
     
         2 . A method of treating non-small cell lung carcinoma (NSCLC) by administering a population of tumor infiltrating lymphocytes (TILs) to a subject or patient in need thereof, wherein the subject or patient has at least one of:
 i. a predetermined tumor proportion score (TPS) of PD-L1 of <1%,   ii. a TPS score of PD-L1 of 1%-49%, or   iii. a predetermined absence of one or more driver mutations;   
       wherein the method comprises:
 (a) obtaining and/or receiving a first population of TILs from a tumor resected from the subject or patient by processing a tumor sample obtained from the subject into multiple tumor fragments; 
 (b) adding the first population of TILs 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, 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, 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 or patient. 
 
     
     
         3 . A method of treating non-small cell lung carcinoma (NSCLC), wherein the NSCLC is refractory or resistant to treatment with an anti-PD-1 and/or anti-PD-L1 antibody, by administering a population of tumor infiltrating lymphocytes (TILs) to a subject or patient in need thereof, wherein the subject or patient has at least one of:
 i. a predetermined tumor proportion score (TPS) of PD-L1 of <1%,   ii. a TPS score of PD-L1 of 1%-49%, or   iii. a predetermined absence of one or more driver mutations;   
       wherein the method comprises:
 (a) obtaining a first population of TILs from a tumor resected from a subject by processing a tumor sample 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 3-11 days to obtain the second 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 7-11 days to obtain the third 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 third population of TILs obtained from step (d), wherein the transition from step (d) to step (e) occurs without opening the system; 
 (f) transferring the harvested third TIL population from step (e) to an infusion bag, wherein the transfer from step (e) to (0 occurs without opening the system; 
 (g) cryopreserving the infusion bag comprising the harvested TIL population from step (0 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. 
 
     
     
         4 . A method of treating non-small cell lung carcinoma (NSCLC) by administering a population of tumor infiltrating lymphocytes (TILs) to a subject or patient in need thereof, wherein the subject or patient has at least one of:
 i. a predetermined tumor proportion score (TPS) of PD-L1 of <1%,   ii. a TPS score of PD-L1 of 1%-49%, or   iii. a predetermined absence of one or more driver mutations;   
       wherein the method comprises:
 (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 the subject or patient, 
 (b) adding the first population of TILs 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 3-11 days to obtain the second 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 7-11 days to obtain the third 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 third population of TILs obtained from step (d), wherein the transition from step (d) to step (e) occurs without opening the system; 
 (0 transferring the harvested third TIL population from step (e) to an infusion bag, wherein the transfer from step (e) to (0 occurs without opening the system; 
 (g) cryopreserving the infusion bag comprising the harvested TIL population from step (0 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 or patient. 
 
     
     
         5 . A method of treating non-small cell lung carcinoma (NSCLC) by administering a population of tumor infiltrating lymphocytes (TILs) to a subject or patient in need thereof, wherein the subject or patient has at least one of:
 i. a predetermined tumor proportion score (TPS) of PD-L1 of <1%,   ii. a TPS score of PD-L1 of 1%-49%, or   iii. a predetermined absence of one or more driver mutations;   
       wherein the method comprises:
 (a) resecting a NSCLC tumor from the subject or patient, the tumor comprising a first population of TILs, optionally 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; 
 (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 3-11 days to obtain the second 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 7-11 days to obtain the third 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 third population of TILs obtained from step (d), wherein the transition from step (d) to step (e) occurs without opening the system; 
 (f) transferring the harvested third 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. 
 
     
     
         6 . The method of any one of  claims 2  to  5 , wherein the second population of TILs is at least 50-fold greater in number than the first population of TILs. 
     
     
         7 . A method of treating non-small cell lung carcinoma (NSCLC) by administering a population of tumor infiltrating lymphocytes (TILs) to a subject or patient in need thereof, wherein the subject or patient has at least one of:
 i. a predetermined tumor proportion score (TPS) of PD-L1 of <1%,   ii. a TPS score of PD-L1 of 1%-49%, or   iii. a predetermined absence of one or more driver mutations;   
       wherein the method comprises:
 (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 the subject or patient; 
 (c) contacting the first population of TILs with a first cell culture medium; 
 (d) performing an initial expansion (or priming first 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, optionally, where the priming first expansion occurs for a period of 1 to 8 days; 
 (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 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, optionally the rapid expansion can proceed for 1 day, 2 days, 3 days, 4, days, 5 days, 6 days, 7 days, 8 days, 9 days or 10 days after initiation of the rapid expansion; 
 (f) harvesting the third population of TILs; and 
 (g) administering a therapeutically effective portion of the third population of TILs to the subject or patient with the NSCLC. 
 
     
     
         8 . A method of treating non-small cell lung carcinoma (NSCLC) by administering a population of tumor infiltrating lymphocytes (TILs) to a subject or patient in need thereof, wherein the subject or patient has at least one of:
 i. a predetermined tumor proportion score (TPS) of PD-L1 of <1%,   ii. a TPS score of PD-L1 of 1%-49%, or   iii. a predetermined absence of one or more driver mutations;   
       wherein the method comprises:
 (a) resecting a NSCLC tumor from the subject or patient, the tumor comprising a first population of TILs, optionally 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; 
 (b) fragmenting the tumor into tumor fragments; 
 (c) contacting the tumor fragments with a first cell culture medium; 
 (d) performing an initial expansion (or priming first 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, optionally, where the priming first expansion occurs for a period of 1 to 8 days; 
 (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 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, optionally the rapid expansion can proceed for 1 day, 2 days, 3 days, 4, days, 5 days, 6 days, 7 days, 8 days, 9 days or 10 days after initiation of the rapid expansion; 
 (f) harvesting the third population of TILs; and 
 (g) administering a therapeutically effective portion of the third population of TILs to the subject or patient with the NSCLC. 
 
     
     
         9 . A method of treating non-small cell lung carcinoma (NSCLC), wherein the NSCLC is refractory or resistant to treatment with an anti-PD-1 and/or anti-PD-L1 antibody, by administering a population of tumor infiltrating lymphocytes (TILs) to a subject or patient in need thereof, wherein the subject or patient has at least one of:
 i. a predetermined tumor proportion score (TPS) of PD-L1 of <1%,   ii. a TPS score of PD-L1 of 1%-49%, or   iii. a predetermined absence of one or more driver mutations;   
       wherein the method comprises:
 (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 the subject or patient; 
 (c) contacting the first population of TILs with a first cell culture medium; 
 (d) performing an initial expansion (or priming first 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, optionally, where the priming first expansion occurs for a period of 1 to 8 days; 
 (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 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, optionally the rapid expansion can proceed for 1 day, 2 days, 3 days, 4, days, 5 days, 6 days, 7 days, 8 days, 9 days or 10 days after initiation of the rapid expansion; 
 (f) harvesting the third population of TILs; and 
 (g) administering a therapeutically effective portion of the third population of TILs to the subject or patient with the NSCLC. 
 
     
     
         10 . The method of any one of  claims 7  to  9  wherein the third population of TILs is at least 50-fold greater in number than the second population of TILs after 7-8 days from the start of the rapid expansion. 
     
     
         11 . The method of  claims 1  to  10 , wherein the patient or subject has a TPS of PD-L1 of <1%. 
     
     
         12 . The method of  claims 1  to  10 , wherein the patient or subject has a TPS of PD-L1 of 1%-49%. 
     
     
         13 . The method of  claims 1  to  10 , wherein the patient or subject has a NSCLC that is not indicated for treatment by an EGFR inhibitor, a BRAF inhibitor, an ALK inhibitor, a c-Ros inhibitor, a RET inhibitor, an ERBB2 inhibitor, BRCA inhibitor, a MAP2K1 inhibitor, PIK3CA inhibitor, CDKN2A inhibitor, a PTEN inhibitor, an UMD inhibitor, an NRAS inhibitor, a KRAS inhibitor, an NF1 inhibitor, MET inhibitor a TP53 inhibitor, a CREBBP inhibitor, a KMT2C inhibitor, a KMT2D mutation, an ARID1A mutation, a RB1 inhibitor, an ATM inhibitor, a SETD2 inhibitor, a FLT3 inhibitor, a PTPN11 inhibitor, a FGFR1 inhibitor, an EP300 inhibitor, a MYC inhibitor, an EZH2 inhibitor, a JAK2 inhibitor, a FBXW7 inhibitor, a CCND3 inhibitor, and a GNA11 inhibitor. 
     
     
         14 . The method of  claims 1  to  10 , wherein the patient or subject has a predetermined absence of one or more driver mutations. 
     
     
         15 . The method of  claims 1  to  10 , wherein the patient or subject has a TPS of PD-L1 of <1% and has a predetermined absence of one or more driver mutations. 
     
     
         16 . The method of  claim 15 , wherein the one or more driver is selected from the group consisting of an EGFR mutation, an EGFR insertion, EGFR exon20, a KRAS mutation, a BRAF-mutation, a BRAF V600 mutation, an ALK-mutation, a c-ROS-mutation (ROS1-mutation), a ROS1 fusion, a RET mutation, a RET fusion, an ERBB2 mutation, an ERBB2 amplification, a BRCA mutation, a MAP2K1 mutation, PIK3CA, CDKN2A, a PTEN mutation, an UMD mutation, an NRAS mutation, a KRAS mutation, an NF1 mutation, a MET mutation, a MET splice and/or altered MET signaling, a TP53 mutation, a CREBBP mutation, a KMT2C mutation, a KMT2D mutation, an ARID1A mutation, a RB1 mutation, an ATM mutation, a SETD2 mutation, a FLT3 mutation, a PTPN11 mutation, a FGFR1 mutation, an EP300 mutation, a MYC mutation, an EZH2 mutation, a JAK2 mutation, a FBXW7 mutation, a CCND3 mutation, and a GNA11 mutation. 
     
     
         17 . The method of  claims 1  to  10 , wherein the patient or subject has a TPS of <1% and has a NSCLC that is not indicated for treatment by an EGFR inhibitor, a BRAF inhibitor, an ALK inhibitor, a c-Ros inhibitor, a RET inhibitor, an ERBB2 inhibitor, BRCA inhibitor, a MAP2K1 inhibitor, PIK3CA inhibitor, CDKN2A inhibitor, a PTEN inhibitor, an UMD inhibitor, an NRAS inhibitor, a KRAS inhibitor, an NF1 inhibitor, MET inhibitor a TP53 inhibitor, a CREBBP inhibitor, a KMT2C inhibitor, a KMT2D mutation, an ARID1A mutation, a RB1 inhibitor, an ATM inhibitor, a SETD2 inhibitor, a FLT3 inhibitor, a PTPN11 inhibitor, a FGFR1 inhibitor, an EP300 inhibitor, a MYC inhibitor, an EZH2 inhibitor, a JAK2 inhibitor, a FBXW7 inhibitor, a CCND3 inhibitor, and a GNA11 inhibitor. 
     
     
         18 . The method of  claims 1  to  15 , wherein the NSCLC has low or no expression of PD-L1. 
     
     
         19 . The method of  claims 1  to  18 , wherein the NSCLC is refractory or resistant to treatment with a chemotherapeutic agent. 
     
     
         20 . The method of  claims 1  to  19 , wherein the NSCLC is refractory or resistant to treatment with a VEGF-A inhibitor. 
     
     
         21 . The method of  claims 1  to  20 , wherein the NSCLC has been treated with a chemotherapeutic agent but is not being currently treated with a chemotherapeutic agent. 
     
     
         22 . The method of  claims 1  to  21 , wherein the NSCLC has been treated with a chemotherapeutic agent but is not being currently treated with a chemotherapeutic agent and has a TPS of <1%. 
     
     
         23 . The method of  claims 1  to  22 , wherein the NSCLC has been treated with a VEGF-A inhibitor but is not being currently treated with a VEGF-A inhibitor. 
     
     
         24 . The method of  claims 1  to  23 , wherein the NSCLC has been treated with a VEGF-A inhibitor but is not being currently treated with a VEGF-A inhibitor and has a TPS of <1%. 
     
     
         25 . The method of  claims 1  to  24 , wherein the NSCLC has been treated with a chemotherapeutic agent and/or a VEGF-A inhibitor, but is not being currently treated with a chemotherapeutic agent and/or a VEGF-A inhibitor. 
     
     
         26 . The method of  claims 1  to  25 , wherein the NSCLC has been treated with a chemotherapeutic agent and/or a VEGF-A inhibitor but is not being currently treated with a chemotherapeutic agent and/or a VEGF-A inhibitor and has a TPS of <1%. 
     
     
         27 . The method of  claims 1  to  26 , wherein the NSCLC has not been previously treated with an anti-PD-1 and/or anti-PD-L1 antibody. 
     
     
         28 . The method of  claims 1  to  27 , wherein the NSCLC has not been previously treated with an anti-PD-1 and/or anti-PD-L1 antibody and has been previously treated a chemotherapeutic agent and/or a VEGF-A inhibitor. 
     
     
         29 . The method of  claims 1  to  28 , wherein the NSCLC has not been previously treated with an anti-PD-1 and/or anti-PD-L1 antibody and has been previously treated a chemotherapeutic agent and/or a VEGF-A inhibitor but is not being currently treated with a chemotherapeutic agent and/or a VEGF-A inhibitor. 
     
     
         30 . The method of  claims 1  to  29 , wherein the NSCLC has not been previously treated with an anti-PD-1 and/or anti-PD-L1 antibody and has been previously treated a VEGF-A inhibitor but is not being currently treated with a VEGF-A inhibitor. 
     
     
         31 . The method of  claims 1  to  30 , wherein the NSCLC has not been previously treated with an anti-PD-1 and/or anti-PD-L1 antibody and has been previously treated a chemotherapeutic agent and/or a VEGF-A inhibitor but is not being currently treated with a chemotherapeutic agent and/or a VEGF-A inhibitor. 
     
     
         32 . The method of  claims 1  to  31 , wherein the NSCLC has not been previously treated with an anti-PD-1 and/or anti-PD-L1 antibody and has low or no expression of PD-L1. 
     
     
         33 . The method of  claims 1  to  32 , wherein the NSCLC has not been previously treated with an anti-PD-1 and/or anti-PD-L1 antibody and has been previously treated a chemotherapeutic agent and/or a VEGF-A inhibitor but is not being currently treated with a chemotherapeutic agent and/or a VEGF-A inhibitor and has a TPS of <1%. 
     
     
         34 . The method of  claims 1  to  26 , wherein the NSCLC has been previously treated with an anti-PD-1 and/or anti-PD-L1 and/or anti-PD-L2 antibody. 
     
     
         35 . The method of  claim 1  to  26  or  34 , wherein the NSCLC has been previously treated with an anti-PD-1 and/or anti-PD-L1 antibody and has been previously treated a chemotherapeutic agent and/or a VEGF-A inhibitor. 
     
     
         36 . The method of  claims 1  to  26  or  33  to  34 , wherein the NSCLC is refractory or resistant to treatment with an anti-PD-1 and/or anti-PD-L1 antibody. 
     
     
         37 . The method of  claims 1  to  26  or  33  to  35 , wherein the NSCLC has been previously treated with an anti-PD-1 and/or anti-PD-L1 antibody and the tumor proportion score was determined prior to the anti-PD-1 and/or anti-PD-L1 antibody treatment. 
     
     
         38 . The method of  claims 1  to  26  or  33  to  36 , wherein the NSCLC has been previously treated with an anti-PD-L1 antibody and the tumor proportion score was determined prior to the anti-PD-L1 antibody treatment, or the NSCLC has been previously treated with an anti-PD-1 antibody and the tumor proportion score was determined prior to the anti-PD-1 antibody treatment. 
     
     
         39 . The method of  claims 1  to  38 , wherein the NSCLC has been treated with a chemotherapeutic agent and/or a VEGF-A inhibitor. 
     
     
         40 . The method of  claims 1  to  33 , wherein the NSCLC has not been previously treated with an anti-PD-1 and/or anti-PD-L1 antibody and has bulky disease at baseline. 
     
     
         41 . The method of  claims 1  to  26  or  33  to  39 , wherein the NSCLC has been previously treated with an anti-PD-1 and/or anti-PD-L1 antibody and has bulky disease at baseline. 
     
     
         42 . The method of  claims 1  to  41 , wherein the NSCLC has been treated with a chemotherapeutic agent and has bulky disease at baseline. 
     
     
         43 . The method of  claims 1  to  41 , wherein the NSCLC has been treated with a chemotherapeutic agent and/or VEGF-A inhibitor but is not being currently treated with a chemotherapeutic agent and/or VEGF-A inhibitor and has bulky disease at baseline. 
     
     
         44 . The method of  claims 40  to  43 , 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. 
     
     
         45 . The method of  claims 1  to  44 , wherein the NSCLC is refractory or resistant to at least two prior systemic treatment courses, not including neo-adjuvant or adjuvant therapies. 
     
     
         46 . The method of  claims 1  to  45 , wherein the NSCLC is refractory or resistant to an anti-PD-1 or an anti-PD-L1 antibody selected from the group consisting of nivolumab, pembrolizumab, JS001, TSR-042, pidilizumab, BGB-A317, SHR-1210, REGN2810, MDX-1106, PDR001, anti-PD-1 from clone: RMP1-14, anti-PD-1 antibodies disclosed in U.S. Pat. No. 8,008,449, durvalumab, atezolizumab, avelumab, and fragments, derivatives, variants, as well as biosimilars thereof. 
     
     
         47 . The method of  claims 1  to  46 , wherein the NSCLC is refractory or resistant to pembrolizumab or a biosimilar thereof. 
     
     
         48 . The method of  claims 1  to  47 , wherein the NSCLC is refractory or resistant to nivolumab or a biosimilar thereof. 
     
     
         49 . The method of  claims 1  to  48 , wherein the NSCLC is refractory or resistant to an anti-CTLA-4 antibody. 
     
     
         50 . The method of  claims 1  to  49 , wherein the NSCLC is refractory or resistant to an anti-CTLA-4 antibody and pembrolizumab or a biosimilar thereof. 
     
     
         51 . The method of  claims 1  to  50 , wherein the NSCLC is refractory or resistant to an anti-CTLA-4 antibody, and nivolumab or a biosimilar thereof. 
     
     
         52 . The method of  claims 49 ,  50 , and/or  51 , wherein the anti-CTLA-4 antibody is ipilimumab or a biosimilar thereof. 
     
     
         53 . The method of  claims 1  to  52 , wherein the NSCLC is refractory or resistant to durvalumab or a biosimilar thereof. 
     
     
         54 . The method of  claims 1  to  53 , wherein the NSCLC is refractory or resistant to atezolizumab or a biosimilar thereof. 
     
     
         55 . The method of  claims 1  to  54 , wherein the NSCLC is refractory or resistant to avelumab or a biosimilar thereof. 
     
     
         56 . The method of  claims 19  to  55 , wherein the chemotherapeutic agent is a platinum doublet chemotherapeutic agent(s). 
     
     
         57 . The method of  claim 56 , wherein the platinum doublet chemotherapeutic agent therapy comprises:
 i) a first chemotherapeutic agent selected from the group consisting of cisplatin and carboplatin,   ii) and a second chemotherapeutic agent selected from the group consisting of vinorelbine, gemcitabine and a taxane (including for example, paclitaxel, docetaxel or nab-paclitaxel).   
     
     
         58 . The method of  claims 56  to  57 , wherein the chemotherapeutic agent, including the first and/or second chemotherapeutic agent, is in combination with pemetrexed. 
     
     
         59 . The method of  claims 56  to  58 , wherein the NSCLC is refractory or resistant to a combination therapy comprising carboplatin, paclitaxel, pemetrexed, and cisplatin. 
     
     
         60 . The method of  claims 56  to  59 , wherein the NSCLC is refractory or resistant to a combination therapy comprising carboplatin, paclitaxel, pemetrexed, cisplatin, nivolumab, and ipilimumab. 
     
     
         61 . The method of  claims 1  to  60 , wherein the NSCLC is refractory or resistant to a VEGF-A inhibitor. 
     
     
         62 . The method of  claims 1  to  61 , wherein the NSCLC is refractory or resistant to a VEGF-A inhibitor selected from the group consisting of bevacizumab, ranibizumab, and icrucumab. 
     
     
         63 . The method of  claims 1  to  62 , wherein the NSCLC is refractory or resistant to bevacizumab. 
     
     
         64 . The method of any one of  claims 1  to  63 , wherein the NSCLC has been analyzed for the absence or presence of one or more driver mutations. 
     
     
         65 . The method of any one of  claim 64 , wherein one or more driver mutations are not present. 
     
     
         66 . The method of any one of  claims 64  to  65 , wherein the NSCLC treatment is independent of the presence or absence of one or more driver mutations. 
     
     
         67 . The method of any one of  claims 64  to  66 , wherein the one or more driver mutations is selected from the group consisting of an EGFR mutation, an EGFR insertion, a KRAS mutation, a BRAF-mutation, an ALK-mutation, a c-ROS-mutation a c-ROS-mutation, EML4-ALK, and MET mutation. 
     
     
         68 . The method of  claim 67 , wherein the EGFR mutation results in tumor transformation from NSCLC to small cell lung cancer (SCLC). 
     
     
         69 . The method of any one of  claims 1  to  67 , wherein the NSCLC treatment is independent of the presence or absence of high-tumor mutational burden (high-TMB) and/or microsatellite instability-high (MSI-high) status. 
     
     
         70 . The method of any one of  claims 1  to  67 , wherein the NSCLC exhibits high-TMB and/or MSI-high status. 
     
     
         71 . The method of any one of  claims 1  to  68 , wherein the IL-2 is present at an initial concentration of between 1000 IU/mL and 6000 IU/mL in the first cell culture medium, when present. 
     
     
         72 . The method of any one of  claims 1  to  68 , wherein the IL-2 is present at an initial concentration of between 1000 IU/mL and 6000 IU/mL and the OKT-3 antibody is present at an initial concentration of about 30 ng/mL in the second cell culture medium, when present. 
     
     
         73 . The method of any one of  claims 1  to  72 , wherein the initial expansion, when present, is performed using a gas permeable container. 
     
     
         74 . The method of any one of  claims 1  to  73 , wherein the rapid expansion, when present, is performed using a gas permeable container. 
     
     
         75 . The method of any one of  claims 1  to  74 , wherein the first cell culture medium, when present, further comprises a cytokine selected from the group consisting of IL-4, IL-7, IL-15, IL-21, and combinations thereof. 
     
     
         76 . The method of any one of  claims 1  to  75 , wherein the second cell culture medium, when present, further comprises a cytokine selected from the group consisting of IL-4, IL-7, IL-15, IL-21, and combinations thereof. 
     
     
         77 . The method of any one of  claims 1  to  76 , 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. 
     
     
         78 . The method of  claim 77 , 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. 
     
     
         79 . The method of  claim 77 , wherein the non-myeloablative lymphodepletion regimen comprises the steps of administration of cyclophosphamide at a dose of 60 mg/m 2 /day and fludarabine at a dose of 25 mg/m 2 /day for two days followed by administration of fludarabine at a dose of 25 mg/m 2 /day for three days. 
     
     
         80 . The method of  claims 79  to  79 , wherein the cyclophosphamide is administered with mesna. 
     
     
         81 . The method of any one of  claims 1  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 any one of  claims 1  to  80 , further comprising the step of treating the patient with an IL-2 regimen starting on the same day as administration of the third population of TILs to the patient. 
     
     
         83 . The method of any one of  claims 1  to  82 , wherein the IL-2 regimen is a high-dose IL-2 regimen comprising 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. 
     
     
         84 . The method according to any one of  claims 1  to  83 , wherein a therapeutically effective population of TILs is administered and comprises from about 2.3×10 10  to about 13.7×10 10  TILs. 
     
     
         85 . The method of any one of  claims 7  to  83 , wherein the initial expansion is performed over a period of 21 days or less. 
     
     
         86 . The method of any one of  claims 7  to  83 , wherein the initial expansion is performed over a period of 7 days or less. 
     
     
         87 . The method of any one of  claims 7  to  83 , wherein the rapid expansion is performed over a period of 7 days or less. 
     
     
         88 . The method of any one of  claims 2  to  6  or  11  to  83 , wherein the first expansion in step (c) and the second expansion in step (d) are each individually performed within a period of 11 days. 
     
     
         89 . The method of any one of  claims 2  to  6  or  11  to  83 , wherein steps (a) through (f) are performed in about 10 days to about 24 days. 
     
     
         90 . The method of any one of  claims 2  to  6  or  11  to  83 , wherein steps (a) through (f) are performed in about 10 days to about 22 days.