# Expanding CAR T cell applications through high-throughput forward- and reverse immune engineering

> **NIH NIH DP2** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2024 · $1,525,500

## Abstract

Adaptive immunity is one of the most complex and clinically relevant aspects of human biology, where immune
cells have evolved over millions of years to discriminate non-self from self, and the dangerous from the
innocuous. Though cancer cells pose an intrinsic danger to an organism, their derivation from self enables them
to evade immune recognition. Nevertheless, an increased understanding of interactions between immune cells
and cancer cells has culminated in extraordinary cures in refractory cancers by harnessing the immune response.
However, the success of these therapies remains relegated to subsets of cancers (mostly leukemias and high
mutational tumors), owing largely to a lack of highly specific immunotherapy targets in the majority of cancers.
In my previous work, I developed new methods to identify novel tumor antigens and engineer a new class of
chimeric antigen receptors (CAR) T cells called peptide-centric (PC)-CAR T cell, which are capable of targeting
low mutational solid tumors. These PC-CAR T cells completely eradicate highly aggressive tumors in all
relevant preclinical models and are entering clinical trials in 2024. The process that I developed for generating
PC-CARs provides a roadmap that can be applied to all tumor types, significantly expanding the population of
patients that are eligible for CAR therapies (Yarmarkovich et al., Nature 2021). Having pioneered the first-
generation of PC-CARs, I am uniquely familiar with the challenges of the process and have carefully devised
strategies to improve this process such as to develop safer and more effective immunotherapies. The work
described in my DP2 is focused on developing new technologies that address two major bottle-necks in the
current CAR development process, identifying tumor-specific antigens and engineering antigen-specific
receptors. To identify tumor-specific targets, I describe a comprehensive immunoproteomic search tool that I
expect will uncover targets in any given tumor. I also propose new strategies for identifying logic-gated CAR
targets and methods to streamline their screening in a high-throughput manner. To generate safer and more
effective PC-CAR receptors, I describe new library systems that allows for screening of CAR T cells at an
unprecedented scale, enabling the efficient generation of 104 antigen-specific CAR clones and a system to screen
them in the most relevant contexts. I also describe an entirely new approach for developing CAR T cells through
“reverse engineering” the immune response from patients who have been cured of cancer using immune
checkpoint inhibitors. Finally, I describe new computational methods for de novo engineering of PC-CAR
receptors and in silico cross-reactivity screening that have the potential to dramatically scale PC-CAR
development. This multi-pronged strategy describes several new approaches, each of which can transform
the development of immunotherapies and benefit a large population of cancer patients if successful...

## Key facts

- **NIH application ID:** 10910581
- **Project number:** 1DP2CA301080-01
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Mark Yarmarkovich
- **Activity code:** DP2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,525,500
- **Award type:** 1
- **Project period:** 2024-09-01 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10910581

## Citation

> US National Institutes of Health, RePORTER application 10910581, Expanding CAR T cell applications through high-throughput forward- and reverse immune engineering (1DP2CA301080-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10910581. Licensed CC0.

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