A phase I/II trial investigating safety and efficacy of autologous TAC T cells targeting HER2 in relapsed or refractory solid tumors (TACTIC-2).

Abstract Background: Despite recent therapeutic advances for patients (pts) with breast, colorectal and gastroesophageal cancers with HER2 overexpression, there is still a significant unmet medical need for better treatment options for HER2-positive solid tumors, especially those with low or intermediate HER2 expression (1+ and 2+ by immunohistochemistry (IHC)). T Cell Antigen-Coupler (TAC) technology is a novel way to genetically modify T cells and to redirect these T cells to target cancer antigens and to activate T cells naturally by co-opting the natural T cell Receptor (TCR). TAC01-HER2 is an autologous T-cell product comprising T cells expressing the HER2 TAC, a chimeric receptor that is genetically engineered into T cells via lentiviral transduction to furnish T cells with two main functions: redirection to and specific recognition of HER2-positive cells, and T cell activation via the endogenous TCR. In vivo models, TAC T-cells can infiltrate tumors and persist for extended period of time, leading to robust and persistent anti-tumor efficacy, with a favorable safety profile. The safety and efficacy of TAC01-HER2 is investigated in the ongoing (TACTIC-2) first-in-human phase I-II study (NCT04727151). Methods: Eligible pts are ≥ 18 years with HER2-positive solid tumors (1+, 2+ or 3+ by IHC, regardless of amplification status) who progressed after at least two lines of systemic therapy. Upon enrollment, pts undergo leukapheresis to obtain T cells for TAC01-HER2 manufacturing. Bridging therapy can be administered prior to lymphodepleting chemotherapy (LDC). TAC01-HER2 is a single infusion after LDC with a starting dose of 1-3 x 105 cells/kg and escalating based on the keyboard statistical dose escalation method. Data safety monitoring committee meetings will be held after each dose level. Once the recommended phase 2 dose (RP2D) is identified, an additional 3-6 pts will be treated at that dose level. Current planned phase II expansion cohorts include HER2 3+ breast cancer (N=20), HER2 3+ other solid tumors (N=20), and HER2 2+ breast and other solid tumors (N=10). The primary objective for the trial is to determine the safety and tolerability of TAC01-HER2 with primary endpoints of incidence of dose limiting toxicities (DLTs) and type, frequency, and severity of adverse events (AEs). Secondary endpoints include the RP2D, overall response rate, duration of response, overall survival and pharmacokinetics. Exploratory endpoints include assessment of potential biomarkers of response or resistance and characterization of soluble immune factors and relationship to cytokine release syndrome (CRS), neurotoxicity and TAC T cell engraftment. Tumor response assessments are performed at 4 weeks, then at months 3, 6, 9, 12, 18 and 24. After study completion, subjects are followed for survival and long-term safety for up to 15 years. The trial opened in January 2021 and it is actively enrolling pts. Citation Format: Ecaterina E. Dumbrava, Daniel Olson, Benjamin L. Schlechter, Sam Saibil, Donna Rill, Andreas Bader, Deyaa Adib, Michael Bishop. A phase I/II trial investigating safety and efficacy of autologous TAC T cells targeting HER2 in relapsed or refractory solid tumors (TACTIC-2) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT247.