Impact of Prior Treatment on the Efficacy of Adoptive Transfer of Tumor-Infiltrating Lymphocytes in Patients with Metastatic Melanoma

Abstract

Purpose: Adoptive cell transfer (ACT) of autologous tumor-infiltrating lymphocytes (TIL) can mediate durable responses in patients with metastatic melanoma. This retrospective analysis provides long-term follow-up and describes the effect of prior therapy on outcomes after ACT-TIL. Patients and Methods: Patients with metastatic melanoma underwent surgical resection of a tumor for generation of TILs and were treated with a lymphodepleting preparative regimen followed by adoptive transfer of TILs and intravenous IL2. Clinical characteristics of enrolled patients and treatment characteristics of TIL infusion products over two decades of ACT were analyzed to identify predictors of objective response. Results: Adoptive transfer of TILs mediated an objective response rate of 56% (108/192) and median melanoma-specific survival of 28.5 months in patients naïve to anti–programmed cell death-1 (PD-1) therapy compared with 24% (8/34) and 11.6 months in patients refractory to anti–PD-1 (aPD-1). Among patients with BRAF V600E/K–mutated disease, prior treatment with targeted molecular therapy was also associated with a decreased response rate (21% vs. 60%) and decreased survival (9.3 vs. 50.7 months) when compared with those patients naïve to targeted therapy. With a median potential follow-up of 89 months, 46 of 48 complete responders in the aPD-1–naïve cohort have ongoing responses after a single treatment and 10-year melanoma-specific survival of 96%. Conclusions: Patients previously treated with PD-1 or MAPK inhibition are significantly less likely to develop durable objective responses to ACT-TIL. While ACT-TIL is currently being investigated for treatment-refractory patients, it should also be considered as an initial treatment option for eligible patients with metastatic melanoma. See related commentary by Sznol, p. 5156

Phase I study of adjuvant immunotherapy with autologous tumor-infiltrating lymphocytes in locally advanced cervical cancer

“…Most clinical trials for TIL-based ACT have been successfully launched in metastatic cancers such as HPV + CC, lung cancer, and melanoma, and tumor regression has been observed in some cancers: the objective response rate (ORR) ranges from 28% to 50% and changes in cancers of different origins ( 5 – 7 , 13 , 25 , 26 ). However, recently, some researchers have pointed out that the use of TIL-based ACT prior to other immunotherapeutic strategies in eligible patients may provide benefit in terms of the clinical response ( 15 , 27 ); a randomized trial of auto-TIL–based ACT as adjuvant immunotherapy was reported in stage III melanoma without distant metastasis in 2002, and the researchers updated the follow-up period in 2007 and 2014. This study revealed that, after adjusting for tumor metastatic lymphoid node numbers, the patients who received auto-TIL–based ACT treatment had a longer relapse-free survival (RFS) and OS compared with the patients who received the IL-2 injection only ( 16 , 28 , 29 ).…”

“…Recently, accumulating evidence has identified that TIL-based ACT treatment is beneficial for some metastatic cancers, including in some patients with checkpoint inhibition immunotherapy resistance ( 5 , 12 – 14 ). However, some researchers have pointed out that TIL-based ACT might be used prior to other immunotherapies in eligible patients ( 15 , 16 ). We have established the primary treatment pattern of TIL-based ACT combined with CCRT in patients with EBV + nasopharyngeal carcinoma at advanced stages of disease and observed an objective clinical response and EBV-specific reactivity of T cells in some patients ( 17 ).…”

Effective generation of tumor-infiltrating lymphocyte products from metastatic non-small-cell lung cancer (NSCLC) lesions irrespective of location and previous treatments

“…Nonetheless, none of the specific pre-treatment regimen or the tested locations of metastatic lesions should exclude a patient from receiving TIL therapy. However, because TIL therapy is less effective when used as second-or third-line treatment, 65 it is key to identify the most suitable therapy early on, and to consider TIL therapy as first-line treatment.…”

Effective generation of tumor-infiltrating lymphocyte products from metastatic non-small-cell lung cancer (NSCLC) lesions irrespective of location and previous treatments

“…Our results indicate that neither a specific pre-treatment regimen, or the tested locations of metastatic lesions should be a reason to exclude a patient from receiving TIL therapy. However, because the efficacy of TIL therapy is reduced when used as second or third treatment regimen 64 , it may be key for effective treatment to identify which therapy is most suitable for a patient, and to consider TIL therapy as first line treatment.…”