Notch Researchers Develop Improved Model for Predicting CAR-T Clinical Pharmacology and Response to Advance Next-Generation Product Design; Results Published in Nature Biotechnology

VANCOUVER, British Columbia, February 27, 2023— Notch Therapeutics, Inc., a biotechnology company developing renewable, induced pluripotent stem cell (iPSC)-derived cell therapies for cancer, announced today the publication of a study in Nature Biotechnology describing a novel computational workflow for predicting CAR-T pharmacology and clinical efficacy. The paper, entitled, “Deconvolution of clinical variance in CAR-T cell pharmacology and response,” documents a new model that is expected to help accelerate the design of next-generation CAR-T products, including those derived from iPSCs.

Engineered CAR-T cells—“living drugs” that circulate in patients’ immune systems—present distinctive challenges compared with development of small-molecule drugs or biologics. Because they expand, differentiate, traffic between tissues, and engage in two-way communication with the patient’s immune system, the resultant pharmacology of CAR-T cells is highly complex and variable, obscuring the relationship between administered dose and exposure.

Using clinical pharmacokinetic and tumor dynamic data from approved CAR-T therapies in different hematologic malignancies, the researchers discovered the primary determinants of CAR-T expansion, persistence, and anti-tumor response. Using a machine-learning workflow, they demonstrated that these determinants can be deduced from CAR-T gene expression patterns and that they accurately predict patient outcomes. The model enables both the inference of underlying biological principles governing response and the ability to generate quantitative predictions, ultimately to more accurately guide therapeutic design.

“Broadening the clinical applicability of CAR-T cell treatments required an improved understanding of the mechanisms that lead to an effective anti-tumor response,” said Dan Kirouac, PhD, Director of Systems Biology at Notch and corresponding author of the study. “We hypothesized that the principles governing T cell dynamics during infection also govern the pharmacology of CAR-Ts, and so we tested this using a mathematical model of T cell regulatory control. Our mechanism-based model yielded biological insights governing patient anti-tumor response as well as the ability to make quantitative clinical predictions, which we were able to confirm.”

“This new model recapitulates the biological effects of CAR-T cell products to more accurately predict clinical outcomes,” said Peter Zandstra, PhD, Chief Scientific Officer of Notch and co-author on the study. “We expect this mechanism-based model for predicting clinical response in patients to enable a new phase of predictive CAR-T product development, including for T cells derived from renewable sources like iPSCs.”

About Notch Therapeutics
Notch is an early-stage biotechnology company working to maximize the benefit of cell therapies through a proprietary T cell-production platform that combines sophisticated product design with commercial-compatible processes to enhance patient outcomes. Notch’s iPSC-based technology platform allows for precision control of notch signaling, which removes several critical limiting factors in the development of cell therapies, delivering the ability to design and manufacture a uniform and unlimited supply of therapeutic T cells. www.notchtx.com.

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