Abstract CT082: Phase I study of autologous CD8+ and CD4+ transgenic T cells expressing high-affinity KRAS G12V mutation-specific T cell receptors (FH-A11KRASG12V-TCR) in patients with metastatic pancreatic, colorectal and non-small cell lung cancers with KRAS G12V mutations
Authors: Chiorean Elena Gabriela , Coveler Andrew , Safyan Rachael , Cohen Stacey , Lee Sylvia , Yeung Cecilia , Redman Mary , Schmitt Thomas , Chapuis Aude , Greenberg Philip D. 
Published: April 2024

Abstract
Background: KRAS, the most common driver oncogene in human malignancies, has predictable mutations. 85% of RAS mutations occur at the Glycine (G) 12 position with G12V being amongst the most common. Cancers driven by mutant KRAS include pancreatic (PDAC), colorectal (CRC), and non-small cell lung (NSCLC) malignancies. The prognosis of patients with activating KRAS mutations remains poor. Preliminary anti-tumor activity has been observed in the clinic with T cell receptor (TCR) T cell therapies targeting KRAS mutations, but durable clinical benefit is lacking.
Rationale: FH-A11KRASG12V-TCR is an autologous CD8+ and CD4+ transgenic T cell product expressing (1) an HLA-A11-restricted, high affinity KRASG12V mutation-specific T cell receptor (TCR) and (2) the wildtype CD8α/β coreceptor enabling CD4+ T cell recognition of KRAS G12V presented on an MHC class I allele mediating helper T cell activity and cytotoxicity. The TCR sequence is derived from the peripheral blood of a healthy HLA-A11+ adult based on a strong pre-clinical dataset.
Methods: This is an ongoing, investigator-initiated, Phase 1, first-in-human, single-center, open-label dose escalation study of FH-A11KRASG12V-TCR. The aims are to evaluate the safety, tolerability, maximum tolerated dose (MTD), and preliminary anti-tumor activity of FH-A11KRASG12V-TCR in patients with advanced PDAC, CRC, and NSCLC who express the HLA-A11-restricted KRAS G12V mutation. Dose modification will be guided by the Bayesian Optimal Interval design (BOIN). Patients will initially be treated in cohorts of 3 at each dose level (DL). BOIN will be used to identify the recommended dose for subsequent patients. The planned target doses are 5 x 109 transgenic TCR T cells in DL 1 with dose escalation up to 15 x 109 transgenic TCR T cells in DL 3. This study enrolls patients who are 18 years or older, HLA-A*11:01-positive, with KRAS G12V mutated metastatic PDAC, CRC, or NSCLC. Patients must have progressed on or be intolerant of at least two lines of prior therapies including any targeted therapies indicated for their current malignancy. Patients undergo leukapheresis prior to treatment and receive lymphodepleting chemotherapy with either cyclophosphamide intravenously (IV) and fludarabine IV on days -6, -5, -4, and -3 or bendamustine IV on days -4 and -3. FHA11KRASG12V-TCR is administered IV on day 0. The dose-limiting toxicity observation period is 28 days. Patients may receive an additional FHA11KRASG12V-TCR IV infusion at the same or lower dose as soon as 28 days or up to 1 year after the first infusion. One patient enrolled to date and the study is actively recruiting (NCT06043713).
Citation Format: Elena Gabriela Chiorean, Andrew Coveler, Rachael Safyan, Stacey Cohen, Sylvia Lee, Cecilia Yeung, Mary Redman, Thomas Schmitt, Aude Chapuis, Philip D. Greenberg. Phase I study of autologous CD8+ and CD4+ transgenic T cells expressing high-affinity KRAS G12V mutation-specific T cell receptors (FH-A11KRASG12V-TCR) in patients with metastatic pancreatic, colorectal and non-small cell lung cancers with KRAS G12V mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT082.