Future role for adoptive T-cell therapy in checkpoint inhibitor-resistant metastatic melanoma

Abstract

Personalized cell therapy targeting tumor antigens with expanded tumor-infiltrating lymphocytes (TILs) has shown great promise in metastatic melanoma (MM) since the 90s. However, MM was first-in line to benefit from the wave of checkpoint inhibitors (CPI), which shifted the focus of immunotherapy almost fully to immune CPI. Still, the majority of patients fail to benefit from CPI treatment, raising the intriguing question on how TIL therapy may fit into the changing landscape of melanoma treatment. We took advantage of data from a unique cohort of patients with MM treated with T-cell therapy in consecutive clinical trials at our institution across the last 10 years. Based on detailed data on patient characteristics, pre-TIL and post-TIL treatments and long-term follow-up, we were able to address the important issue of how TIL therapy can be positioned in the current CPI era. We found that previous progression on anticytotoxic T-lymphocyte-associated protein 4 do not seem to harm neither rate nor duration of response to TIL therapy. Importantly, even in the hard-to-treat population of patients who progressed on antiprogrammed cell death protein 1 (anti-PD-1), an objective response rate of 32% was achieved, including durable responses. Yet, median progression-free survival was reduced in this anti-PD-1 refractory population. Trial registration number: ClinicalTrials.gov ID: NCT00937625, NCT02379195 and NCT02354690.

Keywords: immunotherapy; immunotherapy, adoptive; melanoma; tumor-infiltrating lymphocytes.

Conflict of interest statement

Competing interests: THB has received travel support from Roche and MSD, and travel support and speaker’s fee from Bristol-Myers Squibb (BMS). EE has received honorarium from Roche and BMS, and travel support from MSD and BMS. MD has received honorarium from Genzyme, Merck Sharp & Dohme (MSD) and BMS, and travel support from Novartis, MSD, BMS, Roche and Pfizer. IMS has an advisory board relationship with or lectured for Roche, Novartis, MSD, Celgene, Incyte, TILT bio, Pfizer, BMS and AstraZeneca, and has received limited grants for translational research from BMS, Roche and Novartis. RA and ÖM report no conflicts of interest.

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

Median overall survival (mOS) and median progression-free survival (mPFS) after infusion of tumor-infiltrating lymphocytes (TIL). Kaplan-Meier curves showing OS (A) and PFS (B) for the entire cohort (n=55).

Figure 2

Median overall survival (mOS) and median progression-free survival (mPFS) for Response Evaluation Criteria in Solid Tumors (RECIST) responders. Kaplan-Meier curves showing OS (A) and PFS (B) for RECIST responders (n=20). TIL, tumor-infiltrating lymphocytes.

Figure 3

Overall survival (OS) and progression-free survival (PFS) according to antiprogrammed cell death protein 1 (anti-PD-1) status prior to tumor-infiltrating lymphocytes (TIL) therapy. Kaplan-Meier curves showing OS (A) and PFS (B) in anti-PD-1-näive patients (n=32) or patients previously progressed on anti-PD-1 blockade (n=23). Dotted lines represent SE.