First in Human Study of an on/Off Switchable CAR-T Cell Platform Targeting CD19 for B Cell Malignancies (CLBR001 + SWI019)

• Published in: Blood 2021-11, Vol.138 (Supplement 1), p.2822-2822
• Main Authors: Nikolaenko, Liana, Mulroney, Carolyn, Riedell, Peter A., Flinn, Ian W., Cruz, Jose Carlos, Vaidya, Rakhee, van Besien, Koen, Emde, Michael, Klyushnichenko, Vadim, Strauss, Jonathan, Laborda, Eduardo, Li, Jing, Trikha, Mohit, Schultz, Peter G., Young, Travis S
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2021-151727

BACKGROUND: CD19 targeted chimeric antigen receptor (CAR) T cells are a transformative treatment option for patients with relapsed, refractory B cell malignancies. Despite remarkable responses in heavily pretreated patients, challenges remain related to toxicities including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), along with relapse related to tumor antigen loss. To address these challenges, we have developed a universal “switchable” CAR-T cell platform. The therapy consists of two parts including an autologous cell product comprised of a humanized, third generation CAR-T cell (CLBR001) along with a humanized antibody “switch” (SWI019) which is dosed following CLBR001 infusion. As designed, SWI019 acts as a switch to dynamically turn “on” or “off” CLBR001 cells, allowing for controllable activity of the adoptively transferred cells. This potentially offers a safer and more versatile approach to CAR-T cell therapy. METHODS: We initiated a multicenter, open label Phase I clinical study to test the safety and tolerability of CLBR001 + SWI019 in patients with relapsed/refractory B cell malignancies (NCT04450069). Autologous CLBR001 cells are manufactured from patient-derived apheresis material at a centralized manufacturing facility. Following cyclophosphamide and fludarabine lymphodepletion, patients receive a single dose of CLBR001 cells, followed by daily infusion of SWI019 for 7 days. SWI019 is administered on a 28-day cycle for up to 6 cycles. Dose escalation of CLBR001 and SWI019 is determined in the initial cohorts by a [3+3] design followed by implementation of Bayesian adaptive design (BAYDE) decision rules. RESULTS: Three patients (2 follicular lymphoma and 1 mantle cell lymphoma) in cohort 1 (140e6 CAR+ cells + 10 ug/kg SWI019) have evaluable safety and response data as of the data cut-off. CLBR001 + SWI019 was well tolerated with no DLTs observed in cohort 1. CLBR001 cell infusion was well tolerated with no adverse events attributable to the cell product in any patients during the observation period prior to SWI019 dosage, indicating CLBR001 cells do not have activity in the absence of SWI019. Elevated serum cytokine levels and CLBR001 expansion in peripheral blood was observed only after SWI019 administration. SWI019 dosage was well tolerated with 1 case of concomitant Grade 1 CRS and Grade 2 ICANS that occurred in cycle 2. This event subsided within 24 hours of administration of dexametha