IND-Enabling Studies of a Switchable Chimeric Antigen Receptor-T Cell (CLBR001+SWI019) to Support First in Human Clinical Study

• Published in: Blood 2021-11, Vol.138 (Supplement 1), p.1695-1695
• Main Authors: Laborda, Eduardo, Woods, Ashley, Doedens, Andrew, Kang, Yunyi, Nunez, Vanessa, Joseph, Sean, Emde, Michael, Stone, Jennifer, Li, Jing, Trikha, Mohit, Schultz, Peter G., Young, Travis S
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2021-149277

Despite the tremendous clinical benefits, adverse events associated with CAR-T cell therapy remain a challenge. Most frequent adverse events are cytokine release and immune effector cell-associated neurotoxicity syndromes due to the inability to modulate the level of activity of current CAR-T cell products after administration to patients. Additional challenges include on target, off tumor toxicities and antigen loss mediated relapse of disease. To address these challenges, we have developed a “switchable” CAR-T (sCAR-T) where the activity of the sCAR-T cells is controlled by an antibody-based switch. The switch targets the tumor antigen, and the sCAR recognizes a unique peptide engrafted on the switch. The switch creates a bridge between the sCAR-T cell and the tumor cell, activating the sCAR-T cells and inducing tumor cell killing. Combined, the switch and sCAR-T cells afford complete elimination of tumors in xenograft and syngeneic models, but individually, each is designed to be inactive. A short half-life of the switch allows for a rapid modulation of sCART-cell activity through the switch dosing. Moreover, by swapping different switches, sCAR-T cells can be modularly redirected against other tumor targets. Further, we have shown the cyclical on/off stimulation of the sCAR-T cells affords improved memory and persistence of the sCAR-T cells. Here, we report IND-enabling studies for an optimized CD19-targeted switch (SWI019) and sCAR-T cell (CLBR001) to support a first in human (FIH) clinical study of the combination. The preclinical development of a platform which includes a sCAR-T cell that lacks any endogenous antigen target, in combination with an antibody-based switch molecule that lacks intrinsic activity in the absence of the sCAR-T cell, necessitated development of novel approaches. Fidelity of such a system is essential to control, thus, to confirm CLBR001 cells did not activate in the presence of normal tissues, in vitro activity studies were performed by co-culturing CLBR001 cells, in the presence or absence of SWI019, and a panel of 14 primary cells. This panel represented a survey of vital tissues throughout the body. CLBR001 did not demonstrate activity in any of the 14 cell types tested, supporting a high fidelity of CLBR001 recognition for SWI019. Because SWI019 lacks activity in the absence of CLBR001 cells, traditional toxicology studies to identify the no adverse effect level (NOAEL) in support of the first in human starting dose were