Treatment of NSCLC patients with tumor-infiltrating lymphocyte therapy

Abstract

Provided herein are methods of producing TILs via (i) REP pre-stimulation with a combination of interferon gamma (IFNγ) and anti-PD-1 antibody, with or without a CD40 agonist, and with or without an anti-CTLA-4 antibody; (ii) various concentrations of IL-15 and IL-21, with or without an AKT inhibitor (AKTi), with or without low concentrations of IL-2, during REP expansion and / or REP pre-expansion; (iii) low concentrations of IL-2 and AKTi during REP expansion and / or REP pre-expansion; (iv) a combination of (i) and (ii); or (v) a combination of (i) and (iii).

Claims

1. A method for producing a cryopreserved TIL population from NSCLC patients, wherein the patients are naive to cancer treatment, and the method is (a) Obtaining and / or receiving a first TIL population from tumors resected from the subject or the patient by processing tumor samples obtained from the subject into multiple tumor fragments or tumor digests before the patient receives cancer treatment, (b) Cryopreserving tumor fragments or tumor digests containing the first TIL population from step (a) to produce cryopreserved tumor fragments or tumor digests, Subsequently, the patient received ICI treatment and / or standard treatment. The method wherein, optionally, if the patient exhibits a progressive disease during or after treatment with the ICI and / or standard treatment, the first TIL population is further expanded to a therapeutic TIL population.

2. A method for producing a cryopreserved TIL population from an NSCLC patient, wherein the patient is receiving interrupted maintenance therapy, and the method is (a) Before resuming the maintenance therapy, obtain and / or receive a first TIL population from tumors resected from the subject or patient by processing tumor samples obtained from the subject into multiple tumor fragments or tumor digests, (b) Cryopreserving tumor fragments or tumor digests containing the first TIL population from step (a) to produce cryopreserved tumor fragments or tumor digests, Subsequently, the patient resumed the maintenance therapy. The method wherein, optionally, if the patient exhibits progressive disease at or after the resumption of the maintenance therapy, the first TIL population is further expanded to a therapeutic TIL population.

3. Cancer patients, (a) Naive about any cancer treatment, or (b) Naive to ICI treatment, anti-VEGF treatment, or chemotherapy treatment The method according to any one of the prior claims.

4. The patient is receiving maintenance therapy that was interrupted at step (a), and the maintenance therapy is resumed after step (a), Optionally, if the patient is in a washout period at the start of step (a), Furthermore, optionally, the thawing step and subsequent steps may be performed after the patient receives the cancer treatment or resumes the maintenance therapy and the patient exhibits progressive disease. The method according to claim 2.

5. (a) The patient exhibits a progressive disease at least about one week, two weeks, three weeks, one month, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, twelve months, thirteen months, fourteen months, fifteen months, sixteen months, seventeen months, eighteen months, nineteen months, twenty months, twenty-one months, twenty-two months, twenty-three months, twenty-four months, twenty-five months, twenty-six months, twenty-seven months, twenty-eight months, twenty-nine months, thirty-one months, thirty-one months, thirty-two months, thirty-three months, thirty-four months, thirty-five (b) The patient receives or will receive first-line ICI treatment and / or standard treatment, (c) The patient receives or will receive second-line ICI treatment and / or standard treatment. (d) The patient is diagnosed with NSCLC, (e) The patient is diagnosed with metastatic stage IV NSCLC, (f) The subject or patient i) A predetermined tumor percentage score (TPS) of PD-L1 < 1%, ii) PD-L1 TPS score of 1% to 49%, or iii) Having at least one of the following: the absence of one or more driver mutations, wherein the one or more drivers are EGFR mutations, EGFR insertions, EGFR exon 20, KRAS mutations, BRAF mutations, BRAF V600 mutations, ALK mutations, c-ROS mutations (ROS1 mutations), ROS1 fusions, RET mutations, RET fusions, ERBB2 mutations, ERBB2 amplifications, BRCA mutations, MAP2K1 mutations, PIK3CA, CDKN2A, PTEN mutations, UMD mutations, NRAS mutations, KRAS mutations, NF1 mutations, MET mutations, MET splices and / or altered MET sigma Selected from the group consisting of Nal transmission, TP53 mutation, CREBBP mutation, KMT2C mutation, KMT2D mutation, ARID1A mutation, RB1 mutation, ATM mutation, SETD2 mutation, FLT3 mutation, PTPN11 mutation, FGFR1 mutation, EP300 mutation, MYC mutation, EZH2 mutation, JAK2 mutation, FBXW7 mutation, CCND3 mutation, and GNA11 mutation. The method according to claim 1 or 2.

6. The method according to claim 1 or 2, wherein the patient or subject has NSCLC having <1% TPS and is not indicated for treatment with EGFR inhibitors, BRAF inhibitors, ALK inhibitors, c-Ros inhibitors, RET inhibitors, ERBB2 inhibitors, BRCA inhibitors, MAP2K1 inhibitors, PIK3CA inhibitors, CDKN2A inhibitors, PTEN inhibitors, UMD inhibitors, NRAS inhibitors, KRAS inhibitors, NF1 inhibitors, MET inhibitors, TP53 inhibitors, CREBBP inhibitors, KMT2C inhibitors, KMT2D mutations, ARID1A mutations, RB1 inhibitors, ATM inhibitors, SETD2 inhibitors, FLT3 inhibitors, PTPN11 inhibitors, FGFR1 inhibitors, EP300 inhibitors, MYC inhibitors, EZH2 inhibitors, JAK2 inhibitors, FBXW7 inhibitors, CCND3 inhibitors, and GNA11 inhibitors.

7. (a) The NSCLC has low or no expression of PD-L1, (b) The patient has the predetermined absence of one or more driver mutations, (c) The NSCLC is unresponsive or resistant to treatment with chemotherapeutic agents. (d) The NSCLC is unresponsive or resistant to treatment with a VEGF-A inhibitor. (e) The above NSCLCs are being treated with chemotherapy agents, but are not currently being treated with chemotherapy agents and have a TPS of <1%, (f) The above NSCLCs are being treated with VEGF-A inhibitors, but are not currently being treated with VEGF-A inhibitors and have a TPS of <1%, (g) The NSCLCs described above have been treated with chemotherapeutic agents and / or VEGF-A inhibitors, but are not currently being treated with chemotherapeutic agents and / or VEGF-A inhibitors, and optionally have a TPS of <1%. (h) The NSCLC has not been previously treated with an anti-PD-1 and / or anti-PD-L1 antibody, optionally has been previously treated with a chemotherapeutic agent and / or a VEGF-A inhibitor, and optionally is not currently being treated with a chemotherapeutic agent and / or a VEGF-A inhibitor. (i) The NSCLC has not been previously treated with an anti-PD-1 and / or anti-PD-L1 antibody, and has been previously treated with a VEGF-A inhibitor, but is not currently being treated with a VEGF-A inhibitor. (j) The NSCLC has not been previously treated with anti-PD-1 and / or anti-PD-L1 antibodies, and has been previously treated with chemotherapeutic agents and / or VEGF-A inhibitors, but is not currently being treated with chemotherapeutic agents and / or VEGF-A inhibitors. (k) The NSCLC has not been previously treated with an anti-PD-1 and / or anti-PD-L1 antibody and has low or no PD-L1 expression, (l) The NSCLC has not been previously treated with anti-PD-1 and / or anti-PD-L1 antibodies, has been previously treated with chemotherapeutic agents and / or VEGF-A inhibitors, but is not currently being treated with chemotherapeutic agents and / or VEGF-A inhibitors, and has a TPS of <1% (m) The NSCLC has been previously treated with an anti-PD-1 and / or anti-PD-L1 and / or anti-PD-L2 antibody, (n) The NSCLC has been previously treated with an anti-PD-1 and / or anti-PD-L1 antibody and has been previously treated with a chemotherapeutic agent and / or a VEGF-A inhibitor, (o) The NSCLC is unresponsive or resistant to treatment with anti-PD-1 and / or anti-PD-L1 antibodies. (p) The NSCLC has been previously treated with an anti-PD-1 and / or anti-PD-L1 antibody, and the tumor percentage score was determined prior to the anti-PD-1 and / or anti-PD-L1 antibody treatment. (q) The NSCLC has been previously treated with an anti-PD-L1 antibody and the tumor percentage score was determined before the anti-PD-L1 antibody treatment, or the NSCLC has been previously treated with an anti-PD-1 antibody and the tumor percentage score was determined before the anti-PD-1 antibody treatment, (r) The NSCLC is being treated with a chemotherapeutic agent and / or a VEGF-A inhibitor, (s) The NSCLC is indicated if it has not been previously treated with an anti-PD-1 and / or anti-PD-L1 antibody, has a large mass lesion at baseline, and optionally, the maximum tumor diameter is greater than 7 cm when measured in either the transverse or coronal plane, or the swollen lymph nodes have a short-axis diameter of 20 mm or more. (t) The NSCLC is indicated if it has been previously treated with an anti-PD-1 and / or anti-PD-L1 antibody, has a giant mass lesion at baseline, and optionally, the maximum tumor diameter is greater than 7 cm when measured in either the transverse or coronal plane, or if the swollen lymph nodes have a short-axis diameter of 20 mm or more. (u) The NSCLC is treated with a chemotherapy agent, has a large mass lesion at baseline, and optionally, the largest tumor diameter is greater than 7 cm when measured in either the transverse or coronal plane, or the swollen lymph nodes have a short-axis diameter of 20 mm or more, indicating a large mass lesion. (v) The NSCLC is currently being treated with chemotherapy agents and / or VEGF-A inhibitors, but is not currently being treated with chemotherapy agents and / or VEGF-A inhibitors, and has a large mass lesion at baseline, optionally, if the maximum tumor diameter is greater than 7 cm when measured in either the transverse or coronal plane, or if the swollen lymph nodes have a short-axis diameter of 20 mm or more, then the large mass lesion is indicated. (w) The NSCLC is unresponsive to or resistant to at least two prior systemic treatment courses that do not include neoadjuvant or adjuvant therapy. (x) The NSCLC is unresponsive or resistant to an anti-PD-1 or anti-PD-L1 antibody selected from the group consisting of nivolumab, pembrolizumab, JS001, TSR-042, pizilizumab, BGB-A317, SHR-1210, REGN2810, MDX-1106, PDR001, clone-derived anti-PD-1: RMP1-14, anti-PD-1 antibodies disclosed in U.S. Patent No. 8,008,449, durvalumab, atezolizumab, avelumab, and their fragments, derivatives, variants, and biosimilars. (y) The above NSCLC, Pembrolizumab or its biosimilars, Nivolumab or its biosimilar Anti-CTLA-4 antibody Anti-CTLA-4 antibodies, and pembrolizumab or its biosimilars Anti-CTLA-4 antibodies, and nivolumab or its biosimilars durvalumab or its biosimilar Atezolizumab or its biosimilar, Refractory or resistant to avelumab or its biosimilars, Optionally, the anti-CTLA-4 antibody is ipilimumab or a biosimilar thereof. The method according to claim 1 or 2.

8. The chemotherapeutic agent is a platinum doublet chemotherapeutic agent (or multiple agents), and optionally, the therapy with the platinum doublet chemotherapeutic agent is 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 taxanes (e.g., paclitaxel, docetaxel, or nab-paclitaxel), Furthermore, optionally, the chemotherapeutic agent comprising the first chemotherapeutic agent and / or the second chemotherapeutic agent is in combination with pemetrexed. The method according to claim 7.

9. (a) The NSCLC is refractory or resistant to combination therapy including carboplatin, paclitaxel, pemetrexed, and cisplatin. (b) The NSCLC is refractory or resistant to combination therapy including carboplatin, paclitaxel, pemetrexed, cisplatin, nivolumab, and ipilimumab. (c) The NSCLC is unresponsive or resistant to the VEGF-A inhibitor. (d) The NSCLC is refractory to or resistant to a VEGF-A inhibitor selected from the group consisting of bevacizumab, ranibizumab, and iclucumab. (e) The NSCLC is refractory or resistant to bevacizumab, (f) The NSCLC has been analyzed for the absence or presence of one or more driver mutations, and optionally, one or more driver mutations are absent. (g) The NSCLC treatment is independent of the presence or absence of one or more driver mutations, and optionally, the one or more driver mutations are selected from the group consisting of EGFR mutations, EGFR insertions, KRAS mutations, BRAF mutations, ALK mutations, c-ROS mutations, c-ROS mutations, EML4-ALK, and MET mutations, and optionally, the EGFR mutation results in tumor transformation from NSCLC to small cell lung cancer (SCLC). (h) The NSCLC treatment is independent of the presence or absence of a high tumor mutation burden (high-TMB) and / or high microsatellite instability (MSI-high) state, or (i) The NSCLC exhibits a high-TMB and / or high-MSI state, The method according to claim 1 or 2.

10. The aforementioned patient, (i) receive first-line ICI treatment and / or standard treatment, (ii) Receiving second-line ICI treatment and / or standard treatment, The method according to claim 1 or 2.

11. Step (b) is, (a) comprising flash freezing of the tumor fragment or the tumor digest, optionally, the flash freezing is i) Incubating the tumor fragment or tumor digest in cryopreservation medium, and optionally incubating for about 30 minutes to about 60 minutes at about 2°C to about 8°C in cryopreservation medium containing 10% v / v DMSO, ii) Freezing the tumor, wherein the freezing is a flash freeze using the gas phase of liquid nitrogen, and / or (b) Freezing of the tumor fragment or tumor digest at a controlled rate, optionally, the controlled rate of freezing is i) Adding the cryopreservation medium to a resealable container, ii) Pre-cooling the closable container with a controlled-speed freezing device, iii) Placing the tumor in the resealable container containing the cryopreservation medium and closing the container, iv) Incubate the sealed container containing the tumor and the cryopreservation medium at a temperature of approximately 2 to 8°C for approximately 30 to 60 minutes. v) including slowly freezing the container in a freezing device at a controlled rate, The method according to any of the prior claims. The method according to claim 1 or 2.

12. The method according to claim 1 or 2, wherein the patient is in a washout period at the start of step (a).

13. The method further includes administering an ICI to the cancer patient, optionally the ICI being PD-1, CTLA-4, LAG-3, HAVCR2 (TIM-3), Cish, TGFβ, PKA, CBL-B, PPP2CA, PPP2CB, PTPN6, PTPN22, PDCD1, BTLA, CD160, TIGIT, TET2, BAFF (BR3), CD96, CRTAM, LAIR1, SIGLEC7, SIGLEC9, CD244, TNFRSF10B, TNFRSF10A, CASP8, CASP10, CA The method according to claim 1 or 2, wherein the inhibitor is a gene selected from the group consisting of SP3, CASP6, CASP7, FADD, FAS, SMAD2, SMAD3, SMAD4, SMAD10, SKI, SKIL, TGIF1, IL10RA, IL10RB, HMOX2, IL6R, IL6ST, EIF2AK4, CSK, PAG1, SIT1, FOXP3, PRDM1, BATF, GUCY1A2, GUCY1A3, GUCY1B2, GUCY1B3, TOX, SOCS1, ANKRD11, and BCOR.

14. The procedure further includes the step of treating the patient with a non-myeloablative lymphocyte depletion regimen before administering the TIL population to the patient, optionally, the non-myeloablative lymphocyte depletion regimen is (i) Administer cyclophosphamide at a dose of 60 mg / kg / day for 2 days, followed by fludarabine at a dose of 25 mg / m². ２ A step of administering at a daily dose for 5 days, or (ii) Cyclophosphamide at a dose of 60 mg / kg / day, and fludarabine at a dose of 25 mg / m². ２ Administer at a daily dose for two days, followed by fludarabine at 25 mg / m². ２ The step includes administering a daily dose for three days, Optionally, the cyclophosphamide may be administered together with mesna. The method according to claim 1 or 2.

15. A step of treating the patient with an IL-2 regimen that is initiated the day following the administration of the TIL population to the patient, or The further step includes treating the patient with an IL-2 regimen initiated on the same day as the administration of the TIL population to the patient, Optionally, the IL-2 regimen is a high-dose IL-2 regimen containing 600,000 or 720,000 IU / kg of aldesleukin, or its biosimilar or variant, administered as a 15-minute bolus intravenous infusion every 8 hours up to an acceptable level. The method according to claim 1 or 2.