Safety of adoptive therapy with tumor-infiltrating lymphocytes and high-dose recombinant interleukin 2 in advanced cutaneous melanoma: a systematic review and meta-analysis

Abstract

Background: Adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TILs) has consistently shown efficacy in advanced melanoma. Its combination with nonmyeloablative but lymphodepleting (NMA-LD) chemotherapy and high-dose interleukin 2 (HD-IL-2) inevitably lead to severe treatment-related adverse events. The systematic recording of the observed toxicities, which is the aim of the present meta-analysis, will further enhance the implementation and management of this treatment schema.

Materials and methods: A comprehensive search was conducted in PubMed up to 29 February 2024. In this meta-analysis we focused on studies of treatment-refractory advanced cutaneous melanoma with TILs administered in combination with NMA-LD chemotherapy and HD-IL-2 (≥600 000 IU/kg). Our primary endpoint was severe adverse events (AEs) of grade 3 or higher. The safety data were consistently coded using Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Findings were synthesized using tables, while pooled estimates for groups of AEs of particular interest were derived from random effects models.

Results: A total of 12 HD-IL-2 studies of 670 patients with available toxicity information were included in this meta-analysis. Blood toxicities were identified as the most common AEs. In the frame of the formal meta-analysis, the pooled estimate of the probability of febrile neutropenia was 60% [95% confidence interval (CI) 36% to 83%]. The total pooled estimate for the probability of severe 'immunologic reaction' events, was 4% (95% CI 1% to 6%), while the respective probability for experiencing a severe AE in Medical Dictionary for Regulatory Activities (MedDRA) System Organ Class (SOC) category 'Infections and infestations' was 8% (95% CI 4% to 11%). In addition, in total, nine fatal (grade 5) AEs were reported, mostly stated as not attributed to the treatment or attributed to NMA/HD-IL-2.

Conclusions: TIL-ACT, a new approved and promising therapy for melanoma patients, presents a distinctive toxicity profile that is currently manageable with supportive care methods, with reported toxicities mainly arising from NMA-LD chemotherapy and HD-IL-2, and a low risk of severe immunologic reaction events. Continued systematic recording and publication of AEs, even the rare ones, and their relation to treatment components, are essential to move the field forward.

Keywords: adoptive cell therapy (ACT); advanced melanoma; meta-analysis; safety; tumor-infiltrating lymphocytes (TIL).