Preliminary phase 1 results of a MICA/B-targeted CAR T cell designed to overcome solid tumor escape mechanisms and avoid the requirement for conditioning chemotherapy.

Abstract

2560 Background: FT836 is a multi-engineered CAR T cell targeting the conserved α3 domain of MICA/B stress ligands, enabling recognition of diverse solid tumors with additional edits including, (i) the hnCD16a FC receptor to enable multi-antigen targeting in combination with monoclonal antibodies (mAb), (ii) Sword and Shield engineering consisting of alloimmune-defense receptor (ADR) expression and CD58 deletion to coordinately avoid host recognition eliminating the need for conditioning chemotherapy (CCT), and (iii) CXCR2 and TGFβ signal redirection receptors to maximize tumor trafficking and adaptability within an immunosuppressive tumor niche, respectively. Manufactured from an iPSC-master cell bank, it is available off-the-shelf and delivered on-demand to patients (pts). Methods: The Phase 1 trial of FT836 in pts with advanced solid tumors (NCT07216105) evaluates multiple regimens including monotherapy (Regimen A), combination with EGFR-targeting mAb cetuximab or HER2-targeting mAb trastuzumab (Regimen C or E, respectively). CCT is not required and FT836 is given twice during the treatment cycle, with retreatment available for eligible patients. First dose of FT836 is administered with a 24-hour hospital stay while the 2 nd dose is given as outpatient. Results: First three pts (all MSS mCRC; median: age 45 y, prior therapies of 5, disease duration of 51 months) were treated in Regimen C dose level 1 (DL1 = 300 million cells/dose, Days 1 and 15 with cetuximab, no CCT) and completed dose limiting toxicity (DLT) evaluation (data cut-off 15 JAN 2026) with no DLTs, FT836-related serious adverse events, cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), or graft-versus-host disease (GvHD) reported. One of the three pts demonstrated a CEA response with >50% reduction (480 ng/mL at BL; 230 ng/mL at 4 weeks after first FT836 infusion) that correlated to mass shrinkage in all target lesions in a week 7 CT scan (obtained after data cut-off date). Of the other two pts, one experienced PD while the other was not yet assessed at the time of abstract submission. FT836 was detected in peripheral blood (PB) following the first dose, with persistence observed up to 1 week. Notably, FT836 cells were detected beyond the initial PB detection in a tumor biopsy obtained at Day 22 (±3 days) indicating greater persistence in tissue compared to PB, supporting the value of additional engineered elements. EGFR and MICA/B antigens were identified in 3/3 baseline tumor biopsies, highlighting the relevance of multi-antigen targeting in driving patient outcome. Conclusions: FT836 Regimen C DL1 was well-tolerated and early clinical data supports anti-tumor activity in highly refractory mCRC where there is significant unmet need. This trial is actively enrolling and updated clinical and translational data will be presented. Clinical trial information: NCT07216105 .