# CD4+ T cells and neoantigens in melanoma immunotherapy.

> **NIH NIH R01** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2024 · $608,260

## Abstract

PROJECT ABSTRACT
Recent clinical trials, using checkpoint blockade, antigen-specific T cell receptor (TCR) or CD19-chimeric antigen
receptor (CAR), have shown promising clinical results for patients with metastatic cancer. However, despite the
impressive and durable clinical response in cancer patients treated with anti-PD-1 antibody, more than 50% of
cancer patients fail to respond to this checkpoint blockade treatment. Immunotherapy based on vaccines and
TCR in many solid tumors is still lacking due to lack of tumor-specific targets. Therefore, new targets and
strategies are urgently needed for the development of immunotherapeutic approaches for solid tumors including
melanoma. Whole exome sequencing approach in combination with computer-assisted prediction algorithms
has provided an exceptional opportunity to identify new patient-specific antigen targets for cancer
immunotherapy. By taking advantage of next-generation sequencing and tumor-reactive T cells, we recently
identified many neoantigens recognized by tumor-reactive CD4+ T cells as well as CD8+ T cells. Importantly, we
found that some of CD4+ T clones with a single TCR could recognize multiple neoantigens, but not the
corresponding wild-type antigens. Recent clinical studies show that mutation-specific CD4+ T cells can mediate
tumor growth inhibition in melanoma and epithelial cancers, suggesting that CD4+ T cells play a critical role in
inhibiting tumor growth and orchestrating overall antitumor immunity. However, clinical responses of cancer
patients are correlated with the trafficking, persistence and cytotoxic ability of T cells. We show that CD4+ T cells
can be reprogrammed to increase their cytotoxicity activity against cancer cells. Based on these premises, we
hypothesize that neoantigen-specific T cells, in particular CD4+ T cells, play an important role in recognizing
neoantigens that drive tumor-specific antitumor immunity, leading to tumor regression. These neoantigens can
be identified from melanoma and exploited as therapeutic targets for immunotherapy. We further hypothesize
that neoantigen-specific CD4+ T cells can be engineered for improving their T cell persistence and cytolytic
activity in combination with anti-PD-1 blockade. Based on these premises, we propose to identify novel
neoantigens with emphasis on MHC class II neoantigens using genome-wide sequencing analysis and a genetic
targeting expression system (Aim 1). We further plan to investigate whether potent therapeutic antitumor
immunity can be generated by immunodominant neoantigen and a novel SAPNANO vaccine technology (Aim
2). Finally, we pursue our studies to determine whether SAPNANO vaccine-induced or T cell transfer immunity
can be further enhanced by immune checkpoint blockade or reprogramming T cells to improve their cytotoxicity,
(Aim 3). In all, the successful completion of our proposed studies will potentially shift the paradigm by the
development of novel immunotherapies for many types of cancer in...

## Key facts

- **NIH application ID:** 10747365
- **Project number:** 5R01CA246547-04
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Rongfu Wang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $608,260
- **Award type:** 5
- **Project period:** 2020-12-01 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10747365

## Citation

> US National Institutes of Health, RePORTER application 10747365, CD4+ T cells and neoantigens in melanoma immunotherapy. (5R01CA246547-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10747365. Licensed CC0.

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