Abstract
Successful CAR T cell therapy for the treatment of solid tumors requires exemplary CAR T cell expansion, persistence and fitness, and the ability to target tumor antigens safely. Here we address this constellation of critical attributes for successful cellular therapy by using integrated technologies that simplify development and derisk clinical translation. We have developed a CAR-CD19 T cell that secretes a CD19-anti-Her2 bridging protein. This cell therapy strategy exploits the ability of CD19-targeting CAR T cells to interact with CD19 on normal B cells to drive expansion, persistence and fitness. The secreted bridging protein potently binds to Her2-positive tumor cells, mediating CAR-CD19 T cell cytotoxicity in vitro and in vivo. Because of its short half-life, the secreted bridging protein will selectively accumulate at the site of highest antigen expression, ie. at the tumor. Bridging proteins that bind to multiple different tumor antigens have been created. Therefore, antigen-bridging CAR-CD19 T cells incorporate critical attributes for successful solid tumor cell therapy. This platform can be exploited to attack tumor antigens on any cancer.
Highlights
The treatment of relapsed or refractory Acute Lymphocytic Leukemia (ALL) and Non-Hodgkin Lymphoma (NHL) with chimeric antigen receptor (CAR) T-cells that target CD19 (CAR-CD19 T cells) has led to FDA and EMA approvals of the adoptive cell therapies tisagenlecleucel and axicabtagene ciloleucel [1, 2]
Several proteins were created as specificity controls, containing just the CD19 extracellular domain (ECD) or containing a CD22 ECD linked to the anti-Her2 scFv
We investigated the impact of serial restimulation on Her2-bridging CAR-CD19 T cells using either Raji cells (CD19-positive lymphoma) or SKOV3 cells (Her2-positive ovarian carcinoma) or both, to model in vitro the potential encounters that the cells at a 2:1 ratio (CAR T) cell population would undergo in the patient setting in vivo
Summary
The treatment of relapsed or refractory Acute Lymphocytic Leukemia (ALL) and Non-Hodgkin Lymphoma (NHL) with chimeric antigen receptor (CAR) T-cells that target CD19 (CAR-CD19 T cells) has led to FDA and EMA approvals of the adoptive cell therapies tisagenlecleucel and axicabtagene ciloleucel [1, 2]. CAR-CD19 T cells have paved the way for the development of cellular therapeutics as ‘living drugs’, and have driven our understanding of CAR T cell regulatory, CMC and commercialization issues [3]. CAR-CD19 T cells are routinely used to evaluate all aspects of CAR T cell function, including optimization of signaling domains and hinge regions [4], development of dual CARs [5, 6], expression of cytokines, antibodies, and other mediators [7, 8], evaluation of toxicities [9, 10], and of switch technologies [11, 12]. CAR-CD19 T cells provide a simple and universal solution to the issue of CAR T cell persistence. Robust in vivo expansion followed by prolonged CAR-T cell persistence is critical for their efficacy in the treatment of hematologic malignancies [13, 14].
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