A phase I/II trial investigating safety and efficacy of autologous TAC01-HER2 in relapsed or refractory solid tumors.

2519 Background: Despite recent therapeutic developments for patients with advanced, metastatic, unresectable HER2+ solid cancers, significant unmet medical needs still exist, especially in tumors other than breast and gastric. The T cell antigen coupler (TAC) technology is a novel approach to modifying T cells, allowing them to recognize and treat HER2+ solid tumors. 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 mouse models of human cancer, without any TAC-related toxicities. Methods: In the ongoing clinical trial (NCT04727151), TAC01-HER2 treatment of HER2+ solid tumors is hypothesized to result in safe and effective anti-tumor responses. Subjects undergo leukapheresis, bridging therapy (if needed) while their TAC01-HER2 are engineered, lymphodepletion chemotherapy (LDC), and finally TAC01-HER2 infusion. In phase I dose escalation, the primary objective is to evaluate the safety of TAC01-HER2 at increasing doses of 0.3, 0.8, 3, and 8 x 106 cells/kg in HER2+ solid tumors (1+, 2+ or 3+ as identified 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 cell infusion. In Phase II, dose expansion groups will further evaluate the safety, efficacy, and pharmacokinetics of the optimal TAC01-HER2 dose in HER2+ breast and other solid tumor types. Results: As of 10 Feb 2023, 18 patients have been treated in Cohorts 1-4 with breast, colorectal, gall bladder, gastroesophageal junction, gastric, esophageal, lung, and ovarian cancers. One DLT event of grade 3 pneumonitis has been reported in one subject in Cohort 4 (8 x 106 cells/kg). No neurotoxicity has been reported. Most subjects treated at Cohorts 3 and 4 experienced Grade ≤2 CRS which resolved with standard therapy. Twelve subjects have reported a total of 21 serious adverse events, 17 unrelated to TAC01-HER2 except for one Grade 3 pneumonitis, one Grade 1 and two Grade 2 CRS. Most adverse events were related to LDC or the underlying malignancy. At Cohort 2 (0.8 x 106 cells/kg), a partial response was observed in a subject with refractory metastatic gastric adenocarcinoma (3+ HER2) at 1st scan, with a 35% reduction in measurable disease and clinical benefit was maintained for 4 months. A 55% disease control rate was observed at Cohorts 2-4 at 1st scan. Conclusions: Dose escalation of TAC01-HER2 is ongoing, with seven subjects treated and three more scheduled in Cohort 4. These results in a heavily pre-treated cancer population show manageable safety and promising clinical activity with a novel T cell therapy that may have broad clinical applicability in HER+ cancers. Clinical trial information: NCT04727151 .

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