P-31 A phase I/II trial investigating safety and efficacy of autologous TAC01-HER2 in relapsed or refractory solid tumors

Despite recent therapeutic developments for patients with advanced or metastatic HER2 - positive (HER2 +) solid tumors, significant unmet medical needs still exist. The T cell antigen coupler (TAC) technology is a novel adoptive approach to modifying T cells ex vivo, which allows recognition and cytotoxicity against solid tumor cells by co-opting the natural T cell receptor. TAC T cells produce safer anti-tumor responses than chimeric antigen receptor T cells. TAC01-HER2 is an autologous T-cell product comprising T cells expressing the HER2 TAC. In murine preclinical studies, TAC01-HER2 led to tumor regression or clearance in models resistant to other HER2-directed therapies without any TAC-related toxicities. The ongoing clinical trial (NCT04727151) is evaluating the safety and preliminary anti-tumor activity of TAC01-HER2 treatment of HER2+ solid tumors. Subjects undergo leukapheresis followed by bridging therapy, if needed while TAC01-HER2 cells are manufactured and lymphodepletion chemotherapy (LDC) prior to the 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 10ˆ6 cells/kg (Cohorts 1-4, respectively) in adult subjects with HER2+ solid tumors (as identified by immunohistochemistry) who have progressed after ≥2 lines of systemic therapy. Dose limiting toxicities (DLTs) are assessed up to 28 days from TAC01-HER2 infusion. In phase II, dose expansion groups will further evaluate the safety, efficacy, and pharmacokinetics of the optimal TAC01-HER2 dose in HER2+ solid tumors. As of 21 Feb 2023, 18 patients with solid tumors have been treated in Cohorts 1-4. Three of those patients were HER2-low (HER2 1+ or 2+/FISH -ve). All patients had TAC transgene detected in blood, and in the tumor bed of 1 patient at cohort 4 (where post-treatment biopsy was available). One DLT event of grade 3 pneumonitis has been reported in one subject in Cohort 4. No neurotoxicity has been reported. Most subjects treated at Cohorts 3 and 4 experienced Grade ≤2 CRS which resolved with supportive 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. A 64% disease control rate was observed in Cohorts 2-4 at 4 weeks restaging after the TAC01-HER2 infusion. Two patients had an unconfirmed partial response (PR), while 12 had stable disease. At Cohort 4, an unconfirmed PR was observed in a subject with refractory metastatic GEJ adenocarcinoma (HER2 2+, FISH +ve) at 4 weeks restaging, with 100% reduction of target lesion. This patient had progressed on 4 prior lines of therapy including trastzumab and trastuzumab deruxtecan. The second unconfirmed PR was observed in Cohort 2, with a 35% reduction of target lesions. Treatment with the novel T cell therapy, TAC01-HER2 showed manageable safety and promising clinical activity in a heavily pre-treated cancer population, refractory to prior HER2 targeted treatments, including a complete reduction of target lesions in one patient. Dose escalation of TAC01-HER2 is ongoing.