# Building better T cell receptors for targeted immunotherapy

> **NIH NIH R01** · UNIVERSITY OF NOTRE DAME · 2020 · $755,580

## Abstract

Project Summary / Abstract
T cell receptors (TCRs) have emerged as a new class of immunological therapeutics. Clinical trials with TCR
gene-modified T cells have shown that objective clinical responses can be obtained for patients with advanced
malignancies. Similar approaches are in development for treatment of infectious disease. However, there is
considerable debate over the nature of the TCR to be used in engineered T cells, and whether naturally occurring
TCRs can be improved. Emphasis has been on identifying natural “high affinity” TCRs, and these have been
emphasized in clinical trials. As T cell potency can sometimes be strengthened with the affinity of the TCR for
antigen, there have also been efforts to use TCRs engineered for enhanced antigen affinity in immunotherapy.
However, adverse events, including deaths, have occurred in some trials with gene-modified T cells. In some
cases, this is clearly attributable to TCR cross-reactivity. Moreover, as high affinity can curtail function and low
affinity TCRs are clearly functional, the presumption that improved TCR affinity is better for immunotherapy is
questionable. In this multi-PI proposal, we propose an ambitious and innovative program to ask and answer how
to build better TCRs for immunotherapy. Our overall hypothesis is that structure-guided design coupled with
comprehensive in vitro and in vivo functional studies can be used to engineer TCRs for improved antigen
recognition while limiting off-target cross-reactivity. To achieve this, we will combine the T cell biology and
immunotherapy expertise of the Nishimura lab at Loyola with the TCR structure and biophysics expertise of the
Baker lab at Notre Dame. We will also incorporate emerging concepts of “2D affinity” measurements and assess
how they relate to specificity and other biophysical parameters, with 2D measurements to be performed by the
Evavold lab at Emory. Using the MART1 tumor antigen as a model and beginning with the clinically relevant
DMF5 TCR, we propose the following three aims: 1) Determine how structure-guided manipulations of TCR
binding impact antigen recognition and in vivo function; 2) Generate improved TCR variants through iterative
cycles of structure-guided design and biophysical/functional characterization, emphasizing the capacity to
engineer specificity independently of affinity; 3) Assess the generalities of the lessons learned by applying the
results from DMF5 to one or more unrelated MART1-specific TCRs. The completion of the aims will lead to a
better understanding of how TCRs recognize antigen and how to most effectively engineer TCRs for optimal
function in immunotherapy.

## Key facts

- **NIH application ID:** 9822962
- **Project number:** 5R01AI129543-04
- **Recipient organization:** UNIVERSITY OF NOTRE DAME
- **Principal Investigator:** Brian M Baker
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $755,580
- **Award type:** 5
- **Project period:** 2016-12-01 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9822962

## Citation

> US National Institutes of Health, RePORTER application 9822962, Building better T cell receptors for targeted immunotherapy (5R01AI129543-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9822962. Licensed CC0.

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