Abstract 5570: Development of piggyBac transposon-mediated HER2-CAR-T cells for the treatment of solid tumors

Abstract Background: Although chimeric antigen receptor (CAR)-T therapies have achieved remarkable success in the treatment of hematologic malignancies, the outcome for patients with solid tumors remains poor. There are several reasons behind this, including exhaustion of CAR-T cell, poor homing and penetration in the tumor, and the lack of persistence in the immunosuppressive tumor microenvironment. To solve these problems, we have developed HER2-CAR-T cells (BP2301) using the piggyBac (PB) transposon-based gene transfer system. Methods and Results: Second generation HER2-CAR construct plus PB transposase were introduced into autologous peripheral blood mononuclear cells (PBMC) by electroporation. These cells were activated with UV-inactivated genetically-engineered antigen presenting autologous PBMC (AP cells) expressing HER2, CD80, and 4-1BBL, and propagated for 14 days to obtain the final product (BP2301). BP2301 exhibited dominant fraction of less exhausted stem cell memory-like T cells (Tscm), which could be associated with antitumor efficacy. BP2301 showed robust in vitro killing activity against HER2+ tumor cells even after multiple rounds of cancer cell challenge, suggesting the long-term functionality without immune-exhaustion. In a xenograft murine model of rhabdomyosarcoma cell line (SJCRh30), a single intravenous administration of BP2301 (5 × 106 CAR-positive cells) eradicated the tumor, and mice treated with BP2301 rejected the second tumor establishment owing to the in vivo expansion of BP2301. Conclusion: BP2301 has demonstrated potent anti-tumor activity in vitro and in vivo. We have established a GMP manufacturing process for BP2301, completed non-clinical safety and efficacy studies, and plan to launch an investigator-initiated phase 1 clinical trial to evaluate the safety and efficacy of BP2301 in HER2-expressing sarcoma and gynecologic malignancies in the second quarter of 2022. Citation Format: Koichiro Shioya, Tomio Matsumura, Yuta Ohira, Naomi Komatsuzaki, Manaka Shinagawa, Miyuki Tanaka, Shigeki Yagyu, Yozo Nakazawa, Lilin Zhang. Development of piggyBac transposon-mediated HER2-CAR-T cells for the treatment of solid tumors [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 5570.