Abstract ND04: CLBR001+SWI019: A novel switchable CAR-T cell platform enabling functionally reversible on/off control of CAR-T cell activity for B cell malignancies

Abstract

Chimeric antigen receptor (CAR) T cell therapy targeting CD19 has been transformative in the treatment of patients with relapsed, refractory B cell malignancies. However, despite remarkable response rates, CAR-T cell therapy is limited by the potential for uncontrolled cytokine production from the genetically engineered cells, resulting in cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS). Further, continuous activity of CD19-targeted CAR-T cells can result in persistent B cell aplasia due to on-target, off-tumor activity of CAR-T cells. To address these challenges, we have developed a novel “switchable” CAR-T cell therapy which affords greater versatility and the potential for improved efficacy and safety compared with existing CAR-T cell approaches. The therapy has been designed in two parts - first, a “universal” genetically engineered autologous humanized, third generation CAR-T cell (CLBR001); and second, a humanized antibody-based “switch” molecule (SWI019) with conventional drug-like properties that controls the genetically engineered cells. As designed, SWI019 controls the turning “on” and “off” of the CLBR001 CAR-T cells. We have shown, the dose of SWI019 tightly correlates with the amount of cytokine produced from CLBR001 while retaining potent in vivo activity in mouse models of leukemia. Importantly, cessation of SWI019 dosing in preclinical models led to termination of CLBR001 cytotoxic and cytokine production within 5 days. This is expected to be important in mitigating adverse events such as CRS and ICANS in patients. We further found that the cyclical nature of on/off stimulation of the switchable CAR-T cells affords greater memory and persistence of the cells in surrogate mouse models, while also allowing B cell repopulation, thus avoiding potential long-term adverse events due to B cell aplasia. A Phase 1 trial was initiated in mid-2020 for patients with relapsed, refractory B cell malignancies. We believe this approach has the potential to be applied to solid tumors in the future leveraging these “universal” CLBR001 CAR-T cells. Citation Format: Travis Young. CLBR001+SWI019: A novel switchable CAR-T cell platform enabling functionally reversible on/off control of CAR-T cell activity for B cell malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr ND04.