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We use advanced receptor engineering, synthetic signaling circuits and mechanistic immunology to build T cells capable of recognizing heterogeneous blood and solid tumors and of sustaining anti-tumor functions within the challenging tumor microenvironment they encounter. We learn from real-world clinical data to understand mechanisms of resistance and efficacy, bring these insights back to the bench to design optimized cell therapies, test them in preclinical models, and translate our discoveries into new treatments to bring cures to cancer patients.
The Chimeric TCR platform
The Chimeric TCR platform
The problem
A major barrier to achieving durable remission with current CAR T-cell therapies is that tumors are heterogeneous and can escape by downregulating or losing the target antigen. Monospecific CAR T-cell therapies are fundamentally limited to address tumor heterogeneity as they can only recognize a single antigen; tumor cells that lack or lose this target are not recognized, enabling immune escape and relapse. Furthermore, conventional CAR designs rely on simplified signaling modules that produce non-physiologic T-cell activation and lack the sensitivity required to detect tumor cells with low antigen density. Together, these limitations lead to poor control of heterogeneous cancers limiting clinical benefits.
Our solution
To overcome tumor heterogeneity, we developed the Chimeric TCR (ChTCR) platform: a modular receptor architecture that preserves the full signaling machinery of the TCR while enabling highly programmable and multispecific antigen recognition. ChTCRs fuse constant TCR chains to tumor-specific binders (e.g., minibinders, scFvs, nanobodies) to create a receptor that engages tumor antigens in HLA-independent fashion while leveraging the natural TCR–CD3 complex for activation. By recapitulating the TCR complex, ChTCRs can form physiologic immune synapses supporting the entire TCR regulation mechanisms by opposition to conventional CARs. Because ChTCRs signal through the multi-ITAM CD3 machinery, they detect lower antigen densities than CARs—critical for targeting tumors with heterogeneous expression levels. By integrating two tumor-specific binding domains (Bi-ChTCRs), we overcome antigen escape and improve recognition of heterogeneous tumors. In preclinical models, Bi-ChTCRs surpass current bispecific CARs in controlling heterogeneous tumors. The ChTCR platform offers a fundamentally new way to design therapeutic receptors—combining the sensitivity of the TCR with the programmability of synthetic biology and represent a promising path toward more durable, relapse-resistant cellular therapies.
Novel receptor design
Novel receptor design
Building on our original ChTCR platform, we engineer next-generation bispecific ChTCRs (Bi-ChTCRs) with broad applicability across tumor types. We study the biological rules that shape receptor performance—how binder affinity, epitope location and geometry, receptor chassis and engagement with the native TCR–CD3 complex determine antigen sensitivity. Our goal is to define design principles that generalize across antigens to expand the ChTCR architecture to bring sensitive and multispecific targeting to solid tumors therapy.
Rewiring T cell signaling
Rewiring T cell signaling
Attaching high-affinity binders to highly sensitive TCR-based receptors may have unknown functional consequences. While this fusion enables superior antigen detection, it also rewires early signaling events in ways that can shape T cell activation, cell fate decisions, and long-term function. We systematically alter ChTCR design to perturbate activation strength and signaling circuits to promote durable anti-tumor responses in vivo while maintaining exquisite antigen sensitivity.
This work is coupled with the development of new technologies to measure receptor-proximal signaling with high resolution, including phospho-proteomics and advanced imaging of immune synapse formation. These tools allow us to map how engineered receptors reshape T cell signaling programs and translate these insights into next-generation designs.
Bringing ChTCR therapy to patients
Bringing ChTCR therapy to patients
We work with our colleagues at Fred Hutch (clinicians, regulatory experts, and cell manufacturing specialists) to build a translational pipeline to bring Bi-ChTCR therapy to a first-in-human clinical trial.
Our goal is to deliver improved treatments to patients, and learn directly from real-world clinical data. Insights from early clinical experience feed back into the lab, creating a virtuous cycle in which patient outcomes inform the next wave of innovations and guide new receptor designs.
Through this integrated bench-to-bedside approach, we aim to bring forward safe, effective, and durable engineered T cell therapies, while continuously improving the technology through clinical and experimental discovery.
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