Fred Hutch’s Sylvain Simon named ‘Rising Star’ at Grand Rounds U.S. in Seattle

Chimeric T cell receptor platform could help prevent cancer relapse seen with CAR T cell therapies

Sylvain Simon and colleagues at Fred Hutchinson Cancer Research Center engineered a synthetic chimeric T cell receptor (ChTCR) that confers superior antigen sensitivity over conventional CAR T cells and is natively adaptable for multispecific targeting, offering a potential solution to the antigen escape that drives relapse after CAR T cell therapy in B cell malignancies and multiple myeloma.

The platform will be recognized at BioCentury Grand Rounds U.S., an interdisciplinary R&D forum convening academic innovators, biopharma decision-makers, and investors at the interface of translational science and drug development, taking place June 3-5 in Seattle.

With a modular design applicable across antigen pairs and cancer types, and a manufacturing approach compatible with existing lentiviral delivery workflows, the ChTCR represents a broadly deployable advance in the engineering of T cell therapies.

Published in Nature Cancer in March 2025, Simon and the Riddell lab introduced ChTCRs by fusing a complete single-chain variable fragment (scFv) to the T cell receptor alpha constant (TRAC) chain, with cytosine base editing used to remove the native TCR to prevent chain mispairing and competition for signaling components.

Unlike conventional CARs, which bypass much of the natural TCR apparatus and signal through a limited set of activation motifs, ChTCRs assemble with all CD3 subunits, form organized immune synapses, and trigger rapid phosphorylation of ZAP70 and LAT that mirrors natural TCR kinetics. Standard CARs, including the two dominant clinical formats CD28/ζ and 4-1BB/ζ, showed blunted and delayed signaling by comparison.

The functional payoff is a marked sensitivity advantage at low antigen densities. ChTCR T cells outperformed both CAR formats in vitro and in mouse models of leukemia, though durable control of antigen-low disease in vivo required another engineering step: a bispecific design.

The unoccupied TCR beta constant (TRBC) chain provides a second antigen-binding site: fusing a second scFv of distinct specificity to TRBC yields a bispecific ChTCR (Bi-ChTCR) that targets two tumor antigens simultaneously without sacrificing sensitivity to either. This directly addresses a recurring limitation of bispecific CARs — clinical data have shown that existing CD19/CD22 bispecific CAR designs compromise sensitivity to each individual antigen, with patients relapsing on antigen-low tumors.

Bi-ChTCR T cells retained full sensitivity to each antigen individually, matching the performance of monospecific ChTCRs against their single targets, and outperformed mixed CAR T cell products in vivo against heterogeneous, antigen-sparse tumors.

The platform extends beyond B cell malignancies. Simon and colleagues designed a BCMA/SLAMF7 Bi-ChTCR for multiple myeloma, incorporating simultaneous base editing of SLAMF7 to prevent fratricide, and demonstrated superior signaling and antigen sensitivity over existing CAR designs.

Simon’s presentation at Grand Rounds U.S. Seattle on Thursday evening will showcase that the architecture can be extended to a trispecific format — a CD19/CD20/CD22 Tri-ChTCR — by functionalizing CD3ε chains as additional antigen-binding sites, pushing the platform’s multispecificity further than the paper describes.

The binding module is also not limited to scFvs; the architecture is designed to accommodate VHH nanobodies and miniproteins, broadening the range of targets that could be addressed.