CAR engineered T cell therapy has developed rapidly in recent years. Use of chimeric antigen receptors (CARs) as the basis of targeted adoptive T cell therapies has enabled dramatic efficacy against multiple hematopoietic malignancies, but potency against solid tumors has lagged, potentially due to insufficient CAR-T cell expansion and persistence. To improve CAR-T cell efficacy, Creative Biolabs is proud to present a new generation dual-switch CAR with two-dimensional regulation system of CAR-T cell therapy for both hematological and solid tumor models.
To improve CAR-T cell efficacy, we have developed a potent activation switch based on rimiducid-inducible MyD88 and CD40 (iMC)-signaling elements. To offset potential toxicity risks by this enhanced CAR, an orthogonally regulated, rapamycin-induced, caspase- 9-based safety switch (iRC9) is developed to allow in vivo elimination of CAR-T cells. iMC costimulation induced by systemic rimiducid administration enhanced CAR-T cell proliferation, cytokine secretion, and antitumor efficacy in both in vitro assays and xenograft tumor models. Conversely, rapamycin-mediated iRC9 dimerization rapidly induced apoptosis in a dose-dependent fashion as an approach to mitigate therapy-related toxicity. This novel, regulatable dual-switch system may promote greater CAR-T cell expansion and prolonged persistence in a drug-dependent manner while providing a safety switch to mitigate toxicity concerns.
Fig.1 Schematic representation of signaling components in dual-switch (DS) CAR. (Duong, 2018)
Cell dose control remains a key factor in the maturation of cell therapy. Our DS platform demonstrates that Rim-activated DS CAR-T cells can effectively kill both liquid and solid tumors while concomitantly retaining the capacity for efficient Rap-mediated T cell elimination if acute toxicity is to occur.
Creative Biolabs’s DS platform has developed DS CAR-T cells specifically targeting multiple tumor antigens, such as the CD123 or CD23-specific DS CAR-T in AML, and HER2-specific DS CAR-T in solid tumor, breast cancer. For some highly malignant indications, while maximizing the efficacy of CAR-T cells, DS CAR-T would prevent severe cytokine release storms, effectively eliminating tumor cells. To further assess DS efficacy in vivo, we also developed several mouse disease models to comprehensively assess the negative impact of iMC-encoding CAR-T cells on iMC-dependent activities (e.g., cytokine production, tumor killing, and CAR-T cell proliferation).
Creative Biolabs is a leading global company which is dedicated to helping our worldwide customers shorten the discovery and development time in CAR-T cell therapy. We utilize unrivaled, proprietary drug design, study data, product candidate, advanced project life-cycle management, as well as real-time data to ensure the ideal outcomes. Through our full spectrum of early discovery, nonclinical and commercialization services, we are committed to developing the most promising CAR-T cell therapy product candidate for our clients.
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