First in Human Study of an on/Off Switchable CAR-T Cell Platform Targeting CD19 for B Cell Malignancies (CLBR001 + SWI019)
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 
Published: November 2021

Abstract
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 dexamethasone with no recurrence of CRS observed with continued administration of a reduced dose (50%) of SWI109, providing support for the tunability of the platform. In the first cohort, 2 of 3 patients experienced a complete response by Lugano criteria.
CONCLUSION: This is the first report of a switchable CAR-T cell platform in patients with B cell malignancies. CLBR001 + SWI019 is safe and well tolerated in patients with B cell malignancies with encouraging clinical activity in cohort 1 using the lowest doses of both CLBR001 and SWI019. Accrual is ongoing in dose expansion cohorts of both CLBR001 cells and SWI019 switch. Updated results will be presented at the meeting.

Disclosures
Nikolaenko: Pfizer: Research Funding; Rafael Pharmaceuticals: Research Funding. Riedell: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Consultancy; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Calibr: Research Funding; Kite/Gilead: Research Funding, Speakers Bureau; Xencor: Research Funding; Tessa Therapeutics: Research Funding; MorphoSys: Research Funding. Flinn: MorphoSys: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Seagen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; AbbVie: Consultancy, Other: All Consultancy and Research Funding payments made to Sarah Cannon Research Institute, Research Funding; Kite, a Gilead Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; ArQule: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Agios: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Calithera Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Great Point Partners: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Forma Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Gilead Sciences: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Incyte: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Forty Seven: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Infinity Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Karyopharm Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Curis: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Janssen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Nurix Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Juno Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Verastem: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Trillium Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Triphase Research & Development Corp.: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Roche: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Takeda: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Loxo: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; IGM Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Celgene: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Iksuda Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Constellation Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Acerta Pharma: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; TG Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Teva: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Unum Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Genentech: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; BeiGene: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; AstraZeneca: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Merck: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Rhizen Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Novartis: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Pfizer: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Portola Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Century Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Hutchison MediPharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Vincerx Pharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Sarah Cannon Research Institute: Current Employment; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Seagen: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Unum Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute, Research Funding; Johnson & Johnson: Current holder of individual stocks in a privately-held company; Seattle Genetics: Research Funding. Trikha: Abbvie: Current Employment, Current equity holder in publicly-traded company. Young: Qihan Bio: Membership on an entity's Board of Directors or advisory committees; Shoreline Bio: Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding.