# Development of a novel platform for the discovery of antigen-specific TCRs

> **NIH NIH K08** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2023 · $196,884

## Abstract

PROJECT SUMMARY
 As a Clinical Instructor in Hematology/Oncology, my career goal is to become an independent physician
scientist with a scientific focus on developing new approaches to cancer immunotherapy. This K award period
will provide the critical training and support to achieve this goal.
 This research proposal extends from published work I developed under the mentorship of Dr. Gay Crooks
over the past two years. Our interest in the molecular regulation of T cell differentiation from hematopoietic
stem and progenitor cells (HSPCs) led us to the discovery that an “artificial thymic organoid” (ATO) culture
system permits in vitro thymic-like differentiation of human HSPCs to fully mature human T cells in a robust
and highly reproducible manner. This finding was significant in that prior strategies to direct in vitro T cell
differentiation from human HSPCs were largely unable to support the generation of functional T cells. We
found that ATOs supported the differentiation of cord blood (CB) HSPCs to CD8+ T cells with a highly diverse
T cell receptor (TCR) repertoire comparable to that of naïve T cells from the thymus or blood; and further
demonstrated that HSPCs engineered with a TCR specific for a tumor-associated antigen efficiently generated
mature, tumor-specific T cells in ATOs (Seet et al., Nature Methods, 2017).
 The focus of this proposal is to exploit a unique property of the ATO system for the de novo discovery of
high affinity antigen specific TCRs for cancer immunotherapy. TCR-directed adoptive cell immunotherapy
currently relies on the labor-intensive identification from patient samples of TCRs specific to “public” tumor-
associated antigens. However, as many public tumor antigens are non-mutated self-antigens, T cells
expressing high affinity TCRs against these targets are typically deleted in the thymus during negative
selection, ultimately resulting in the isolation of low affinity TCRs from patient samples. We hypothesize that T
cells generated in vitro in ATOs are not subject to negative selection, and thus may present a unique source of
high affinity tumor antigen specific TCRs for immunotherapy. In this proposal, I will develop a novel ATO-based
platform for the discovery of antigen specific TCRs against public tumor antigens; characterize the nature of
ATO-derived TCRs relative to those isolated from peripheral blood; and finally apply these methods to the
proof-of-concept capture and preclinical validation of TCRs reactive to prostate cancer specific antigens, a
disease in which the identification of tumor-specific TCRs from patients has thus far proved challenging.
 This is an ambitious project, but one in which the chances of success are maximized through collaboration
with the labs of my mentor Dr. Gay Crooks, co-mentor Dr. Owen Witte at UCLA, and Dr. David Baltimore at
Caltech. Development of a new technology for rapidly identifying high-affinity TCRs against public tumor
antigens would be a significant contribution ...

## Key facts

- **NIH application ID:** 10656291
- **Project number:** 5K08CA235525-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Christopher Seet
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $196,884
- **Award type:** 5
- **Project period:** 2019-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10656291

## Citation

> US National Institutes of Health, RePORTER application 10656291, Development of a novel platform for the discovery of antigen-specific TCRs (5K08CA235525-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10656291. Licensed CC0.

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