Clinical feasibility and treatment outcomes with nonselected autologous tumor-infiltrating lymphocyte therapy in patients with advanced cutaneous melanoma

Abstract

Nonselected autologous tumor-infiltrating lymphocytes (TILs) may provide advantages over other treatments for solid tumors, including checkpoint inhibitor-refractory melanoma. This retrospective analysis reports a single-center experience of nonselected autologous TILs derived from digested tumors for compassionate use treatment of advanced cutaneous melanoma, including after programmed cell death protein 1 (PD-1) inhibition. Patients with histologically confirmed metastatic cutaneous melanoma and no standard-of-care treatment options underwent tumor resection for TIL product manufacturing. Patients received lymphodepleting chemotherapy with cyclophosphamide for 2 days and fludarabine for 5 days, followed by a single TIL infusion and post-TIL high-dose interleukin (IL)-2. Safety assessments included clinically significant adverse events (AEs). Efficacy assessments included overall response rate (ORR), complete response (CR) rate, disease control rate (DCR), and overall survival. Between October 2011 and August 2019, 21 patients underwent treatment (median follow-up time, 52.2 months from TIL infusion). Among all treated patients, median age was 45 years, median number of disease sites was 4, 100% had M1c or M1d disease, and 90% received prior checkpoint inhibitor. Twelve patients received TILs after prior PD-1 inhibition. The safety profile among all treated patients and the prior PD-1 inhibitor subgroup was generally consistent with lymphodepletion and high-dose IL-2. No treatment-related deaths occurred. Among all patients, the ORR was 67%, CR rate was 19%, and the DCR was 86%, which was consistent with that observed in the prior PD-1 inhibitor subgroup (58%, 8%, and 75%, respectively). Median overall survival in all treated patients and the prior PD-1 inhibitor subgroup was 21.3 months. In total, 5 patients (24%) had durable ongoing responses (>30 months post-TIL infusion) at data cutoff, and all patients who achieved CR remained alive and disease free. To further illustrate how TIL therapy may integrate into established treatment paradigms, several case studies of patients treated in this series were included. Overall, these data demonstrate that manufacturing of nonselected autologous TILs from tumor digests is feasible and resulted in high rates of durable response in poor-risk patient populations, which may address significant unmet medical need.

Keywords: PD-1 inhibitor; T cell; Tumor-infiltrating lymphocytes; checkpoint inhibition; compassionate use; immunology; immunotherapy; interleukin-2; melanoma.

Figure 1

Response rates by subgroup in all treated patients (N=21). Data include 2 patients counted as responders who had dabrafenib and MEK inhibitor-refractory disease whose disease was unequivocally progressing on combination therapy prior to TIL therapy and who received post-infusion dabrafenib to prevent tumor flare. BRAF, B-raf proto-oncogene; IL-2, interleukin-2; LDH, lactate dehydrogenase; LLN, lower limit of normal; MEK, mitogen-activated protein kinase kinase; ORR, overall response rate; PD-1, programmed cell death protein 1; SLD, sum of target lesion diameters; TIL, tumor-infiltrating lymphocyte; ULN, upper limit of normal.

Figure 2

Time to response and survival status by patient. ^aPatient 1 received a checkpoint inhibitor at the time of disease progression; patients 15 and 12 received high-dose IL-2 and checkpoint inhibitor, respectively, prior to documented disease progression. ^bPatients 5 and 9 had unequivocally BRAF+MEK-refractory melanoma immediately prior to TIL treatment but were continued on dabrafenib, with brief interruptions for tumor harvest and TIL infusion, to prevent tumor flare upon discontinuation. Patient 5 was treated with dabrafenib for 3 months following TIL infusion, at which point the dabrafenib was stopped. Patient 9 achieved a PR that lasted approximately 14 months from TIL infusion during which time dabrafenib was continued. BRAF, B-raf proto-oncogene; CR, complete response; IL-2, interleukin-2; ipi, ipilimumab; MEK, mitogen-activated protein kinase kinase; nivo, nivolumab; PD, progressive disease; pembro, pembrolizumab; PR, partial response; TIL, tumor-infiltrating lymphocyte.

Figure 3

Overall survival among all treated patients (N=21) and the prior PD-1 inhibitor subgroup (n=12). NE, not estimable; OS, overall survival; PD-1, programmed cell death protein 1.

Figure 4

Final TIL product characteristics. (A) Analysis of cell composition in final product (n=11). Cell subsets were defined as follows: monocytes, CD14+; B cells, CD19+; residual melanoma cells, melanoma markers (CD146, MCAM, MCSP, CD228). (B) Distribution of CD4+ and CD8+ T cells in final product (n=11). (C) Phenotype of T cells in final product (n=10). Cell subsets were defined as follows: naive, CD62L+CD45RO-; central memory, CD62L+CD45RO+; effector memory, CD62L-CD45RO+; and effector, CD62L-CD45RO-. (D) Expression of activation and exhaustion markers on final product (n=18) CD4+ T cells and (E) CD8+ T cells. (F) Exhausted T-cell phenotype, defined as PD-1+TIM-3+LAG-3+ cells. CTLA-4, cytotoxic T-lymphocyte-associated protein 4; LAG-3, lymphocyte activation gene 3; MCAM, melanoma cell adhesion molecule; MSCP, melanoma-associated chondroitin sulfate proteoglycan; PD-1, programmed cell death protein 1; TIM-3, T-cell immunoglobulin and mucin-domain containing protein 3; TIL, tumor-infiltrating lymphocyte.

Figure 5

Hypothesis-generating patient cases. The starting event for each patient’s timeline is the initiation of first-line therapy. ^aPatient presented with hypophysitis while on ipilimumab, requiring hormone replacement with glucocorticoids; no pembrolizumab-associated toxicity was observed. ^bPatient presented with colitis/pneumonitis while on nivolumab, which was managed by reducing nivolumab frequency (given every 6 weeks). ^cCombination dabrafenib/trametinib required 50% dose reduction after 3 weeks due to fever and cholecystitis. ^dPatient went on to receive PD-1 inhibitor with MEK inhibitor. The patient died 21 months after initial TIL infusion, with a combination of progressive disease and possible pneumonitis caused by PD-1 and MEK inhibitors. Dac, dacarbazine; Dab, dabrafenib; Ipi, ipilimumab; MEK, mitogen-activated protein kinase kinase; Nivo, nivolumab; PD-1, programmed cell death protein 1; Pembro, pembrolizumab; SRS, stereotactic radiosurgery; TIL, tumor-infiltrating lymphocyte; Tram, trametinib; Vem, vemurafenib.

Figure 6

Successful treatment of brain metastases in a 16-year-old (Patient 2).