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Development of a high-throughput pipeline for discovery of T cell based immunotherapeutics

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Redirecting T cells towards tumor-associated antigens (TAAs) is an emerging treatment modality in cancer immunotherapy. Two key redirection strategies widely used, involve engineering exogenous receptors on T cells termed chimeric antigen receptors (CARs) and the usage of soluble bispecific antibodies called Bispecific T cell engagers (BiTEs) to ligate T cells with cancer cells expressing specific TAAs. Both BiTE and CAR-T based treatment strategies have been clinically approved for CD19 positive B cell-based cancers. However, this success has not been clinically translatable to other targets. A key challenge to the limited success of T cell redirection therapies across differ cancer types is the non-availability of a versatile discovery platform that facilitates quick functional screening. In this work, we describe the development of a novel high throughput discovery pipeline for T cell-based redirection therapies. In particular, we utilize a droplet based microfluidic system to assess a predefined library of BiTE variants and report the discovery of novel functional BiTE sequences. We also obtain insights into hitherto undiscovered BiTE design principles which could inform future discovery. In addition, we also present a proof-of-concept study to adapt the droplet microfluidic based platform for discovery of CAR-Ts.

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This item is under embargo until August 15, 2025.