# T cell plasticity, fusion proteins and CAR T cell-based immunotherapy of head and neck cancer

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $386,970

## Abstract

ABSTRACT
The limited efficacy of the available therapy for squamous cell carcinoma of the head and neck (SCCHN) has
prompted us to design a novel effective combinatorial immunotherapy for this disease. In this strategy, T cells
engineered with a tumor antigen (TA)-specific chimeric antigen receptor (CAR) are used as the effector
mechanism, since this approach allows specificity of tumor recognition and self amplification due to T lymphocyte
self renewal capacity. We have selected chondroitin sulfate proteoglycan 4 (CSPG4) as the target, since i)
CSPG4 is highly expressed in about 60% of SCCHN tumors with limited heterogeneity within each tumor; ii)
CSPG4 is expressed on both differentiated SCCHN cells and SCCHN cells with high aldehyde dehydrogenase
activity. The latter cells referred to as ALDHbright cells, display the characteristics of cancer initiating cells (CICs),
since they are drug-resistant, express stemness genes and are tumorigenic in immunodeficient mice. Therefore,
CSPG4 CAR T cells target both differentiated SCCHN cells and SCCHN CICs. According to the cancer stem
cell theory, CICs have to be completely eliminated for a therapy to be successful, since these cells play an
important role in disease recurrence and in metastatic spread; and iii) CSPG4 is not detected in normal tissues
except for activated pericytes in the tumor microenvironment. Therefore, immunotargeting of CSPG4 with CAR
T cells is expected to inhibit neo-angiogenesis in the tumor microenvironment and to contribute to the elimination
of SCCHN cells, even those with low or lack of CSPG4 expression.
In recent studies, we have shown that CSPG4 CAR T cells are effective in eliminating CSPG4+ SCCHN cells in
vitro under normoxic conditions. In addition, they significantly inhibit the growth of human SCCHN tumors in
immunodeficient mice but they do not eradicate them. This proposal will test our working hypothesis that the
hypoxia driven hostile microenvironment of SCCHN tumors causes CAR T cell dysfunction and reduces SCCHN
cell susceptibility to CAR T cell mediated lysis. T cell plasticity allows us i) to restore CAR T cell function by
disrupting PD-1/PD-L1 axis to counteract CAR T cell “exhaustion” and ii) to enhance viability and anti-tumor
activity of CAR T cells by selectively increasing IL-15 level in the tumor microenvironment through the use of
fusion proteins generated by linking IL-15 to anti-B7-H3 monoclonal antibody (mAb) HEK5. In addition, the
susceptibility to CAR T cell mediated lysis of SCCHN cells will be restored by modulating anti-apoptotic molecule
expression level through the inhibition with the small molecule sonidegib of hypoxia induced activation of Sonic
Hedgehog Homolog pathway. The experiments will be performed in vitro utilizing SCCHN cell lines and in
immunodeficient mice orthotopically grafted with both SCCHN cell lines and PDXs (some of which have already
been established). The resulting information will determine whether the combinatorial str...

## Key facts

- **NIH application ID:** 9982679
- **Project number:** 5R01DE028172-03
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** SOLDANO FERRONE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $386,970
- **Award type:** 5
- **Project period:** 2018-09-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9982679

## Citation

> US National Institutes of Health, RePORTER application 9982679, T cell plasticity, fusion proteins and CAR T cell-based immunotherapy of head and neck cancer (5R01DE028172-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9982679. Licensed CC0.

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