883TiP A phase I/II open-label study (IOV-GM1-201) of TALEN-mediated PD-1 inactivated autologous tumor-infiltrating lymphocytes (TIL; IOV-4001) in patients with advanced melanoma and NSCLC

Abstract

Adoptive cell therapy with TIL has demonstrated efficacy in patients (pts) with advanced solid tumors, including melanoma (Sarnaik JCO 2021) and NSCLC (Schoenfeld SITC 2021). IOV-4001 is a TALEN®-mediated PDCD-1 knockout autologous TIL cell therapy product. Preclinical studies suggest that PD-1 inactivation by PDCD-1 gene knockout may enhance TIL cell therapy efficacy, with similar quality attributes and phenotypes to those of non-edited TIL (Natarajan AACR 2022). This first-in-human phase 1/2, open-label, nonrandomized, multicenter study (NCT05361174; open to enrollment) will enroll ∼53 adult pts. During the phase 1 portion, enrollment and dose level decisions will be based on emerging safety and tolerability data in a 28-day dose-limiting toxicity (DLT) observation period. Cohort 1 will include pts with unresectable/metastatic melanoma that has progressed during/within 12 wks of last anti–PD-1/PD-L1 dose (pts must have also received a BRAF ± MEK inhibitor if BRAF V600 mutation-positive). Cohort 2 will include pts with advanced NSCLC who have received ≤3 prior therapies and whose disease progressed either: (1) during/within 12 wks after last anti–PD-1/PD-L1 dose (pts without oncogene-driven mutations) or (2) during/after ≥1 targeted therapy and either platinum doublet chemotherapy or during/within 12 wks after last anti–PD-1/PD-L1 dose (pts with oncogene-driven tumors). Pts must have ECOG PS ≤1, ≥1 resectable lesion(s) (≥1.5 cm), ≥1 remaining RECIST-measurable lesion(s) and recovered from prior surgery/anticancer treatment-related AEs (grade ≤1). IOV-4001 is generated from resected tumor in a centralized GMP process. The regimen includes nonmyeloablative lymphodepletion, IOV-4001 infusion, and a short course of high-dose IL-2. The primary endpoints of phases 1 and 2 are safety (DLTs and AEs) and objective response rate per RECIST v1.1, respectively. Secondary endpoints include complete response rate, duration of response, disease control rate, progression-free survival, overall survival, feasibility, and additional safety. NCT05361174. Medical writing support was provided by Second City Science (Vaniam Group, LLC) and funded by Iovance Biotheraputics, Inc. Iovance Biotherapeutics, Inc.