# Cellular engineering to improve the efficacy and specificity of targeted immunotherapy

> **NIH CA K00** · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · 2026 · $94,921

## Abstract

Project Summary/Abstract
 Adoptive cell therapy (ACT) is a promising therapeutic approach for the treatment of cancer. However,
the initial success of ACT has been limited to chimeric antigen receptor (CAR)-T cell therapies for hematological
malignancies. Applying this cell therapy to solid tumors is challenged by the lack of targetable tumor antigens,
the severe systemic toxicity and the suppressive tumor microenvironment. T cell receptor (TCR) gene therapy
can overcome some of these challenges because it enables targeting of intracellular proteins presented as
peptide antigens on the human leukocyte antigen (HLA) complex. However, the majority of naturally occurring
TCRs are of low-affinity to their peptide-HLA targets. Engineering these TCRs via phage display or yeast display
for higher affinity is complicated by the introduction of unwanted cross-reactivity and the poor association
between affinity and function. This project seeks to tackle each of the major challenges of ACT in order to
effectively reprogram the immune system to combat solid tumors.
 The F99 phase is focused on a TCR engineering platform for the creation, modification, and profiling of
TCRs that can target tumor-associated self-proteins with minimal toxicity profiles. In this approach, I first raise T
cells from the natural repertoire that recognize a related ‘foreign’ peptide that differs by one amino acid from the
self-peptide. Then, I modulate the fine specificity of the TCR by directed evolution of the peptide binding region
to switch its specificity towards the tumor self-antigen of interest. I demonstrate the value of this approach by the
creation of libraries of viral-specific TCRs and the subsequent in vitro selection of TCRs that switched specificity
to a closely related epitope. The engineered TCRs showed robust T-cell activation after ligand recognition and
are of equal or higher efficiency than the parental receptor. Importantly, the engineered TCRs displayed no
additional promiscui

## Key facts

- **NIH application ID:** 11311308
- **Project number:** 5K00CA264312-05
- **Recipient organization:** MASSACHUSETTS INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** Nouran Saied Abdelfattah
- **Activity code:** K00 (R01, R21, SBIR, etc.)
- **Funding institute:** CA
- **Fiscal year:** 2026
- **Award amount:** $94,921
- **Award type:** 5
- **Project period:** 2021-09-01T00:00:00 → 2028-03-31T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11311308

## Citation

> US National Institutes of Health, RePORTER application 11311308, Cellular engineering to improve the efficacy and specificity of targeted immunotherapy (5K00CA264312-05). Retrieved via AI Analytics 2026-07-09 from https://api.ai-analytics.org/grant/nih/11311308. Licensed CC0.

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