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

Background

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 2^nd-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.

Trial design

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.

Clinical trial identification

NCT04727151.

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Triumvira.

Disclosure

E.E. Ileana Dumbrava: Financial Interests, Personal, Research Grant: Bayer HealthCare Pharmaceuticals Inc, Immunocore LTD, Amgen, NCI, Aileron Therapeutics, Compugen Ltd, Tracon Pharmaceuticals Inc, Unum Therapeutics, Immunomedics, BOLT Therapeutics, Aprea Therapeutics, Bellicum Pharmaceuticals, PMV Pharma, Triumvira, Seagen Inc, Mereo BioPharma 5 Inc, Sanofi, Astex Therapeutics ; Financial Interests, Personal, Advisory Board: BOLT Therapeutics, Mersana; Financial Interests, Personal, Advisory Role: Bolt Therapeutics. K. Moss: Financial Interests, Personal, Full or part-time Employment: Triumvira. N. Turnus: Financial Interests, Personal, Full or part-time Employment: Triumvira. A. Bader: Financial Interests, Personal, Full or part-time Employment: Triumvira. D. Adib: Financial Interests, Personal, Full or part-time Employment: Triumvira. All other authors have declared no conflicts of interest.