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.

Figure 1.

Survival analysis of patients after adoptive transfer of autologous tumor infiltrating lymphocytes (ACT) following a standard lymphodepletion. (A) Melanoma-specific survival and (B) progression-free survival of all patients with response to ACT illustrated (in gray) to demonstrate the durability of complete responses (CR). Median melanoma-specific survival of entire cohort was 22.2 months (95% CI 16.2–32.4). Median progression-free survival was 5.5 months (95% CI 4.1–7.1). PR: partial response; NR: no response.

Figure 2.

Survival of patients after adoptive transfer of autologous tumor infiltrating lymphocytes (ACT) following a standard lymphodepletion. (A) Decreased MSS and PFS was observed in patients refractory to anti-PD-1 therapy. (B) Presence or absence of BRAF V600E/K mutation did not significantly affect MSS or PFS after ACT. (C) In the presence of BRAF V600E/K mutation, decreased MSS and PFS was observed in patients refractory to BRAF±MEK inhibition.

Figure 3.

Characterization of infusion products. (A) Total CD3+ cells administered to patients with respect to (L to R) response to ACT-TIL, prior anti-PD-1 therapy, and BRAF mutation and inhibitor status. (B) Total CD8+ cells. (C) Total CD4+ cells.