# Engineering CAR T cells to potentiate innate and adaptive immunity

> **NIH NIH F31** · WEILL MEDICAL COLL OF CORNELL UNIV · 2021 · $23,110

## Abstract

Project Summary/Abstract
Chimeric antigen receptor (CAR) T cell therapy redirects T cells to activate and subsequently kill antigen-
expressing cancer cells. This is achieved by coupling a cancer antigen-specific extracellular single-chain
variable IgG fragment (scFv) to intracytoplasmic, endogenous T cell activation signaling domains. CAR T cell
therapy has shown promise for treating hematopoietic malignancies; however, relapse of antigen-negative
tumors remains a significant source of failure for these patients. Further, little success has been seen in
treating solid tumors with immunosuppressive microenvironments. Combination therapy with CAR T cells and
checkpoint blockade is a possible approach to overcome these obstacles. Checkpoint blockade therapy
antagonizes the signaling pathways that suppress the immune system. Current checkpoint blockade strategies
have focused on altering T cell-tumor interactions, but recent studies also show promise in abrogating innate
immune checkpoints, specifically the CD47-SIRPα signaling axis. This pathway, known as the “do not eat me”
signal, prevents both antibody mediated macrophage phagocytosis and active cross priming of T cells by
dendritic cells, and is thus involved in suppressing both innate and adaptive immune processes. Cancer cells
have co-opted this pathway to evade immune attack. However, early stage clinical trials of anti-CD47 agents
show systemic toxicities of anemia and thrombocytopenia.
Our long-term goal is to engineer a more potent CAR T cell that can overcome antigen loss relapse and the
immunosuppressive tumor microenvironment. To accomplish this, we propose to investigate the combination
of CAR T cell therapy with intrinsic SIRPα protein secretion to activate antibody therapy and antigen
presentation, as this combination should potently engage both innate and adaptive immunity to lead to a more
complete antitumor response. We have already engineered human CD19 CAR T cells to secrete a small
molecule, high affinity, SIRPα mimic, CV1. These CV1-secreting CAR T cells, named OrexiCAR T cells, retain
their cytotoxic function and the cell-secreted CV1 can potentiate mAb therapy. In addition, we have shown that
cancer antigen stimulation of the OrexiCAR T cells in vitro leads to a large increase in secreted CV1. Here, we
propose to study OrexiCAR T cells in a fully immunocompetent, syngeneic setting to determine which
mechanisms contribute to their potency. We believe the proposed research will allow a better understanding of
OrexiCAR T cell efficacy and its applicability to the clinic. The Aims are: 1) To construct mouse CD19
OrexiCAR vectors, transduce into primary mouse cells, and validate functions of CAR and CV1 in vitro
and 2) To evaluate the anti-tumor effect of mOrexiCAR T cells in an immunocompetent, syngeneic
mouse model and to discover and describe the immunologic mechanism

## Key facts

- **NIH application ID:** 10115521
- **Project number:** 5F31CA239511-03
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Megan Dacek
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $23,110
- **Award type:** 5
- **Project period:** 2019-03-01 → 2021-05-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10115521

## Citation

> US National Institutes of Health, RePORTER application 10115521, Engineering CAR T cells to potentiate innate and adaptive immunity (5F31CA239511-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10115521. Licensed CC0.

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