Abstract 3605: Phase II study of pembrolizumab in conjunction with lymphodepletion, TIL ACT, and high- or low-dose IL-2 in patients with metastatic melanoma
Authors: Hasanov Merve , Kiany Simin , Forget Marie-Andrée , Bassett Roland L. , Davies Michael A. , Diab Adi , Gershenwald Jeffrey E. , Glitza Isabella C. , Lee Jeffrey E. , Lucci Anthony , McQuade Jennifer L. , Patel Sapna P. , Ross Merrick I. , Tawbi Hussein A. , Wargo Jennifer , Wong Michael K. , Bernatchez Chantale , Hwu Patrick , Haymaker Cara , Amaria Rodabe N. 
Published: March 2024

Abstract
Background: In metastatic melanoma (MM) patients (pts), adoptive cell transfer (ACT) using tumor-infiltrating lymphocytes (TIL) can yield lasting responses. However, TIL ACT with high-dose IL-2 has notable toxicities. Anti-PD1 (pembrolizumab) is FDA approved for MM treatment. Our study aimed to merge TIL infusion with anti-PD1 in two arms, comparing high (HD, arm 1) and low (LD, arm 2) IL-2 doses.
Methods: After tumor harvest and TIL expansion, pts were lymphodepleted with cyclophosphamide and fludarabine, followed by infusion with their ex-vivo expanded TIL combined with IL-2 (arm 1: 720,000 IU/kg IV q 8 hrs up to 15 doses; arm 2: 2 million IU SC for 14 days). Pts were given 200 mg of IV anti-PD1 starting 21 days post-TIL infusion, followed by doses every 3 weeks for up to 2 years. Blood was taken before lymphodepletion and before the first two anti-PD1 doses for flow cytometry and cytokine analysis The primary endpoint of the study was determination of overall response rate by RECISTS 1.1 criteria. Enrollment aimed for 18 pts per arm, monitoring the primary ORR endpoint using a Bayesian rule. Enrollment would halt in any arm if the ORR dropped below 40%.
Results: The median age was 50 years (n=14: 6 F and 8 M). Of these 14 pts, 8, 2, 2, and 2 had cutaneous, uveal, mucosal, or unknown primary melanoma. Pts had a median of 3 lines of prior therapies (range 1-6), including anti-PD-1 (n=13). In arm 1, one pt had a partial response (PR) for 10 months, 2 had stable disease (SD), 3 had progressive disease (PD), and 1 was not evaluable (NE). In arm 2, one pt had an ongoing PR for over 76 months, 1 had SD, and 5 had PD. Due to ORR &lt;40% in each arm, enrollment was stopped after treatment of 14 pts. There was no significant different in progression-free survival or overall survival between the two arms (p=0.99 and p=0.71, respectively). In general, toxicity levels were comparable in both arms; however, pts in arm 2 had slightly lower grade 3 febrile neutropenia (57% vs. 71%) and shorter hospitalization (median 16 days vs. 18 days) than pts in Arm 1. While no correlation was observed between the phenotype of the TIL product and clinical response, both PR pts received high numbers of TIL (38.6 × 10^9 and 93.7 × 10^9; mean: 32.6 × 10^9 cells), with a high CD8+/CD4+ T cell ratio (284.7 and 2.7; median: 2.7). IL-2 dose did not affect circulating Treg frequency, phenotype, or proliferation by flow cytometry 3 weeks post TIL infusion. IL-2 dose was not associated with CD4+ non-Treg and CD8+ T cell phenotype or proliferation. Addition of anti-PD1 reduced expression of checkpoints but did not boost T cell proliferation.
Conclusion: Our treatment strategy did not yield any distinct difference between low and high dose IL-2, suggesting the potential of low-dose IL-2 as an alternative. Anti-PD1 did not have any appreciable effect on immune states potentially due to the cohorts being comprised of a heavily pre-treated heterogenous pt population.
Citation Format: Merve Hasanov, Simin Kiany, Marie-Andrée Forget, Roland L. Bassett, Michael A. Davies, Adi Diab, Jeffrey E. Gershenwald, Isabella C. Glitza, Jeffrey E. Lee, Anthony Lucci, Jennifer L. McQuade, Sapna P. Patel, Merrick I. Ross, Hussein A. Tawbi, Jennifer Wargo, Michael K. Wong, Chantale Bernatchez, Patrick Hwu, Cara Haymaker, Rodabe N. Amaria. Phase II study of pembrolizumab in conjunction with lymphodepletion, TIL ACT, and high- or low-dose IL-2 in patients with metastatic melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3605.