# Project 4: Using Synthetic Immunology to Improve Activity and Specificity, and Overcome Resistance, in Cellular Therapy

> **NIH NIH P01** · SLOAN-KETTERING INST CAN RESEARCH · 2022 · $417,945

## Abstract

Abstract
T cell-based therapies have emerged recently as important therapies for cancer. Resistance to
the activity of these cells, relapse, toxicities and deaths are still important hurdles to their
success and strongly call for mechanisms to potentiate efficacy, while at the same time, to
better control the safety of cell therapies. The goal of this project is to create a new generation
of synthetic, tumor-specific T cells (based on CAR and TCRm technology) that will selectively
home to cancer cells in vivo and then synthesize and release anti-neoplastic drugs at the cancer
cell surface or into the tumor microenvironment. The selective and local elaboration of potent
anti-neoplastic drugs at the tumor site, or on the cancer cells, should simultaneously: 1) reduce
toxicity relative to conventional cancer drug therapy; 2) overcome immune mediated resistance
to conventional CAR T cell therapy from regulatory cells and cytokines in the tumor
microenvironment (because the cytotoxic drugs made will not be affected;) 3) overcome antigen
loss variant mechanisms of resistance (because the drugs will kill cancer cells without antigen
on the cell surface;) 4) reduce toxicity relative to conventional CAR T cells because the prodrug
infusions can be pharmacologically regulated, scheduled, or stopped. In addition, the enzyme
expression can be made conditional. The components of the proposed strategy are: 1)
prodrug/drug pair in which the prodrug is not toxic to normal cells or tissues and the resulting
drug potently kills cancer cells. Several types of prodrug systems will be developed for various
functions and properties (Aim 1). 2) A CAR T cell directed to a tumor specific antigen via a
lineage specific scFv (such as CD19 or MUC16) or a more specific TCRm-based scFv (such as
to WT1 or PRAME,) 3) An enzyme genetically engineered into the CAR T cell capable of
converting the prodrug into the active drug locally. We term these cells “Synthetic Enzyme
Armed KillER” cells or SEAKER cells. These cells will be designed and tested in vitro (Aim 2)
and in animal models (Aim 3.) This work will be carried out through a multi-PI, multidisciplinary
collaboration between the labs of David A. Scheinberg (PI), Derek S. Tan (Co-PI), and Renier
Brentjens (Co-Investigator), comprising extensive expertise in synthetic and medicinal
chemistry, biochemistry, pharmacology, cell biology, and cancer immunology, that builds on
prior work from the leaders over 15 years.

## Key facts

- **NIH application ID:** 10442489
- **Project number:** 5P01CA023766-42
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** DAVID A SCHEINBERG
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $417,945
- **Award type:** 5
- **Project period:** 1997-09-30 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10442489

## Citation

> US National Institutes of Health, RePORTER application 10442489, Project 4: Using Synthetic Immunology to Improve Activity and Specificity, and Overcome Resistance, in Cellular Therapy (5P01CA023766-42). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10442489. Licensed CC0.

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