778TiP A phase I/II trial investigating safety and efficacy of autologous TAC T-cells targeting HER2 in relapsed or refractory solid tumors

Abstract

Despite historic and recent therapeutic developments for patients with advanced, metastatic, unresectable HER2-positive (HER2+) solid tumors, significant unmet medical needs still exist, especially in tumors other than breast and gastric cancers. The T cell antigen coupler (TAC) technology is a novel approach to modifying T cells, allowing them to recognize and treat HER2+ solid tumors. Mechanistically, the TAC receptor redirects T cells to tumor cells, and upon tumor cell recognition, co-opts the natural T cell receptor (TCR) to yield safer anti-tumor responses versus chimeric antigen receptor (CAR) T cells. In preclinical studies, TAC T cells led to complete tumor clearance in various mouse models of human cancer, without any TAC-related toxicities, and potentially superior results to T cells engineered with a 2nd-generation CAR. In the ongoing clinical trial (NCT04727151), TAC T cell treatment in HER2+ solid tumors is hypothesized to result in safe and effective anti-tumor responses, with fewer cytokine release syndrome (CRS) and neurotoxicity events. Procedurally, subjects undergo leukapheresis, bridging therapy (if needed) while their TAC T cells are engineered, lymphodepletion chemotherapy, and finally TAC T cell infusion. Phase I dose escalation is investigating TAC T cells doses of 0.08, 0.3 (starting dose), 0.8, 3, 8 x 106 cells/kg in HER2+ solid tumors (1+, 2+ or 3+ by immunohistochemistry) in adult subjects who have progressed after ≥2 lines of systemic therapy. Dose limiting toxicities (DLTs) are assessed up to 28 days from engineered cell infusion. In Phase 2, dose expansion groups will further evaluate the safety, efficacy, and pharmacokinetics of the optimal TAC T cell dose in breast, lung, pancreatic, colorectal, gastric, endometrial, ovarian, and other tumor types. As of 13 Apr 2022, 3 patients have been treated in Cohort 1 (0.3 x 106 cells/kg): rectosigmoid, gastro-esophageal, and gastric adenocarcinoma. No DLTs, CRS, or neurotoxicity events have been reported, with the Data Safety Monitoring Committee recommending commencement of patient enrollment in Cohort 2. NCT04727151. The authors.