# Cancer Center Support Grant (CCSG)

> **NIH NIH P30** · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · 2022 · $227,500

## Abstract

PROJECT SUMMARY/ABSTRACT
This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA-
21-100. Novel therapies for pediatric osteosarcoma (OS) are urgently needed. Patients with recurrent and
metastatic disease have dismal prognoses, with less than 20% surviving beyond three years. As intensification
of conventional chemotherapy is unlikely to yield further benefit according to expert consensus, alternative
therapeutic classes such as immunotherapies must be developed. The long-term goal of this research is to
develop an effective immunotherapy for OS. Immunotherapy with chimeric antigen receptor (CAR) T cells
has shown great preclinical promise in solid tumor treatment. However, clinical efficacy has been limited, in part
due to ineffective homing of CAR T cells to tumor sites. Our preliminary studies show that OS tumors secrete
the chemokine CXCL16, but that less than 5% of activated T cells express the cognate receptor CXCR6,
indicating a ligand/receptor mismatch that adversely affects CAR T cell efficacy. We therefore hypothesize that
expressing CXCR6 in CAR T cells will enhance their ability to home to OS tumor sites and result in
enhanced cytotoxicity. Our preliminary data also shows that OS tumors express very little of the chemokine
XCL1, which functions to recruit dendritic cells for antigen uptake and presentation and to attract endogenous
immune cells to tumor sites. We therefore further hypothesize that the antitumor activity of CAR T cells
can be augmented by expression of XCL1, thereby attracting additional immune cells into the tumor at
the time of CAR-mediated killing and priming the endogenous immune system for antitumor response.
We will evaluate these hypotheses using CAR T cells against the tumor-associated antigen B7H3, which is highly
expressed on OS tumors. In Aim 1, we will determine the in vitro and in vivo efficacy, including functional
characteristics, homing, and cytotoxicity, of CXCR6-modified B7H3.CAR T cells in an immunocompetent model
of OS. In Aim 2, we will evaluate XCL1-expressing B7H3.CAR T cell performance in our immunocompetent
murine model, specifically investigating endogenous immune cell recruitment in response to vXCL1.mB7H3.CAR
T cell treatment. In Aim 3, we will combine these strategies to seek a truly synergistic CAR T cell therapy in
which mCXCR6.B7H3.CAR T cells are engineered to specifically deliver vXCL1 to tumor sites and express
vXCL1 during CAR-mediated killing. We will also further characterize the response of the endogenous immune
system to XCL1 expression at tumor sites and assess whether mice who have received XCL1-expressing CAR
T cells are able to reject subsequent OS tumor challenges through endogenous immune activity post-CAR T cell
treatment. At the end of this work, we expect to have developed an effective and novel CAR T cell therapy
approach for OS that synergistically combines enhanced chemokine-mediated homing and endogenous immune
s...

## Key facts

- **NIH application ID:** 10538385
- **Project number:** 3P30CA021765-43S1
- **Recipient organization:** ST. JUDE CHILDREN'S RESEARCH HOSPITAL
- **Principal Investigator:** CHARLES ROBERTS
- **Activity code:** P30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $227,500
- **Award type:** 3
- **Project period:** 1997-04-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10538385

## Citation

> US National Institutes of Health, RePORTER application 10538385, Cancer Center Support Grant (CCSG) (3P30CA021765-43S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10538385. Licensed CC0.

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