# Immune Activating CAR-Modified Antigen Presenting Cells

> **NIH NIH DP5** · WASHINGTON UNIVERSITY · 2021 · $393,750

## Abstract

Project Summary/Abstract
 The most successful cancer immune therapies thus far rely on anticancer T cells to eliminate tumor. If a patient is
fortunate enough to possess these antitumor T cells, immune checkpoint inhibitor (CI) therapy can induce a lasting
complete response (CR) (Robert et al. 2015). If those T cells are not present, but the patient is fortunate enough to possess
a tumor that universally expresses an antigen not also expressed by critical tissues (exemplified by CD19 on ALL),
Chimeric Antigen Receptor (CAR) T cells may eliminate the tumor and induce a lasting CR (Sadelain 2015). However,
what if a patient does not have antitumor T cells, and has an antigenically diverse, solid tumor that cannot be eliminated
by CAR T cells engineered to target one or two antigens? These are the majority of metastatic cancer patients, who
continue to succumb to their disease. Pancreatic cancer is one such example of a highly incurable, poorly immunogenic
cancer with inhomogenous tumor antigen expression, unresponsive thus far to immune therapies.
 Antitumor T cells arise through a series of steps. They first require encounter with an Antigen Presenting Cell
(APC). The APC must have engulfed a tumor cell, expressed (rather than degraded) the tumor antigens, encountered a
reactive T cell, AND expressed costimulatory molecules to activate the T cell (without which, the T cell would have
undergone activation-induced cell death). That T cell must then proliferate, maintain activation, and avoid exhaustion.
 Here, I describe a new therapeutic approach that endows APCs with the genetic responsibility to generate an
adaptive antitumor T cell response by achieving all of the above steps. The first component of this approach utilizes a
CAR consisting of intracellular phagocytic receptor domains (either TLR4 or FcGRIIA), attached to a tumor-targeting
scFv extracellular domain, introduced into APCs. These CAR APCs engulf tumor cells that express the targeted surface
antigen (in this case, Lewis A, expressed on 90% of pancreatic cancer cells), and present endogenous tumor antigens.
 Aim 1 will characterize TLR4 and FcGRIIA CAR APCs’ ability to selectively engulf tumor and present endogenous
tumor antigens in vitro (1A), and eliminate orthotopic pancreatic cancer in vivo (1B).
 The second component of this approach utilizes CAR APCs that upon tumor antigen encounter synthesize and express
immune modulating molecules that facilitate an adaptive antitumor T cell response.
 Aim 2 will determine the in vivo function of “Immune Activating CAR APCs,” which engulf antigen positive (Ag+)
tumor cells and subsequently produce a T cell stimulator (41BBL), an APC stimulator (CD40L), or soluble PD1-CTLA4
CIs induced by tumor antigen binding. Ag+ tumor will be injected in the mouse flank, while Ag- tumor will be injected in
the pancreas, to separately assess direct CAR APC killing and indirect killing through an adaptive immune response.
Finally, I test the additional role o...

## Key facts

- **NIH application ID:** 10249320
- **Project number:** 5DP5OD026427-04
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Carl DeSelm
- **Activity code:** DP5 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $393,750
- **Award type:** 5
- **Project period:** 2018-09-19 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10249320

## Citation

> US National Institutes of Health, RePORTER application 10249320, Immune Activating CAR-Modified Antigen Presenting Cells (5DP5OD026427-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10249320. Licensed CC0.

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