Abstract A003: Preliminary safety results from a phase I study of autologous transgenic T cells expressing high affinity mesothelin-specific T cell receptor (TCR) (FH-TCR TMSLN) in patients (pts) with metastatic pancreatic ductal adenocarcinoma (mPDA)
Authors: Chiorean Elena G. , Chapuis Aude , Coveler Andrew , Yeung Cecilia , Gooley Ted , Zhen David B. , King Gentry , Cohen Stacey , Hannan Lindsay , Safyan Rachael , Germani Anthony , Ra Susan , Casserd Jennifer , Schmitt Tom , Greenberg Philip 
Published: January 2024

Abstract
Background: We previously demonstrated murine CD8+ T cells engineered to express a high affinity MSLN-specific TCR exhibit efficacy in the KPC mouse model, particularly with serial infusions, and thus developed a human TCR for expression in autologous T cells for targeting MSLN, which is overexpressed by 80% of PDAs. In this first-in-human phase I trial, we are determining safety, preliminary efficacy, as well as persistence, activation, localization, and functional capacity of autologous FH-TCR-TMSLN (T) cells in refractory, MSLN+ mPDA. Methods: Eligible pts have ECOG PS 0-1, ≥1 prior therapy for mPDA, life expectancy ≥12 weeks, MSLN 2+ expression in ≥30% tumor cells by IHC, HLA-A*2:01, no HLA-B*13:02. Pts undergo leukapheresis, and 3-4 weeks later receive the first T cell infusion. Three T-cell infusions, if sufficient T cells can be manufactured, are being administered every 21 days (d) at 3 dose level cohorts: 1 × 109, 3.3 × 109 and 1 × 1010 T cells, with a 3+3 design. Dose limiting toxicities (DLTs) are assessed during the 21d after each T cell dose. Only pts who receive ≥75% of the assigned T cell dose are DLT evaluable, but all pts are evaluable for safety. Lymphodepleting chemotherapy (LDC) with fludarabine/cyclophosphamide is administered prior to the last T cell infusion (cohorts 1-2) or prior to the first T cell infusion (cohort 3). Primary endpoints are safety and DLTs. Secondary endpoints are response rate, progression-free and overall survival. Exploratory endpoints include TCR-TMSLN cells in tumor biopsies and blood as biomarkers. Results: Between Dec 2021 to July 2023, 7 pts were enrolled, and 6 pts treated (n=3 at dose at level 1, n=3 at dose level 2), 4 women, median age 60 years (range 51-70), median 3 prior systemic therapies. All pts underwent research-related tumor biopsies at baseline, and 2-3 weeks post first T cell infusion, and 2 pts had biopsies after the last T-cell infusion. Treatment exposure was median 3 (range 1-3) T cell infusions. No DLTs occurred among 6 pts treated at dose levels 1 × 109 and 3.3 × 109 T cells. Treatment related adverse events (TRAE) thought at least possibly related to T cells infusions were fever [n=2 grade (gr) 1, n=1 gr 2], and gr 2 chills, cytokine release syndrome (CRS), dizziness, fatigue, hypertension, hypotension, nausea, acute generalized exanthematous pustulosis (AGEP) rash, and sinus tachycardia (n=1 each). TRAE due to LDC were transient leukopenia (n=2 gr 4, n=1 gr 3, n=2 gr 2), neutropenia (n=4 gr 4, n=1 gr 2), lymphopenia (n=3 gr 4), dysgeusia (n=2 gr 2), anemia (n=1 gr 3) and fatigue (n=1 gr 2). One patient had a serious adverse event with gr 2 CRS and gr 2 AGEP, which resolved. Due to anticipated difficulty attaining sufficient T cells doses for three high dose infusions, we amended the protocol to allow treatment with at least one T cell infusion, with the first dose preceded by LDC at the 1 × 1010 T cells dose level. Conclusions: FH-TCR-TMSLN cells are well tolerated with no on-target toxicity, and the study is open to accrual (NCT04809766).
Citation Format: Elena G. Chiorean, Aude Chapuis, Andrew Coveler, Cecilia Yeung, Ted Gooley, David B. Zhen, Gentry King, Stacey Cohen, Lindsay Hannan, Rachael Safyan, Anthony Germani, Susan Ra, Jennifer Casserd, Tom Schmitt, Philip Greenberg. Preliminary safety results from a phase I study of autologous transgenic T cells expressing high affinity mesothelin-specific T cell receptor (TCR) (FH-TCR TMSLN) in patients (pts) with metastatic pancreatic ductal adenocarcinoma (mPDA) [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A003.