# Mechanistic connection between HPV-specific TCRs and therapeutic responses to ICI in HPV+ HNSCC

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $655,244

## Abstract

Project Summary/Abstract
 Head and neck squamous cell carcinoma (HNSCC) are often associated with human papillomavirus
(HPV) infection. The incidence of HPV+ HNSCC has been rapidly rising during the past 2-3 decades. Thus, it is
critical to gain better understanding of the pathogenic mechanisms of HPV+ HNSCCs in the context of immune
recognition and elucidate the mechanistic determinants underlying therapy responsiveness vs. resistance in
HPV+ HNSCC. The effects of immune checkpoint inhibitors (ICI) are highly heterogeneous in HNSCC patients;
however, it remains incompletely understood whether anti-HPV responses contribute to ICI efficacy. Recent
studies showed that HPV+ HNSCC responded better than HPV− HNSCC in a neoadjuvant anti-PD1 trial,
suggesting that effective HPV-related responses may benefit ICI treatment. The goal of this proposal is to
determine whether and how effective anti-HPV immune responses may contribute to ICI efficacy by testing if the
breadth and depth of T cell receptor (TCR) responses against HPV antigens affect the outcomes and therapy
responses of HPV+ HNSCC using human samples from clinical trials and murine HNSCC models.
 Prior studies focused on defined E7-derived peptides for HPV-related cellular therapy. However, HNSCC
tumor-infiltrating lymphocytes (TILs) contain much more HPV E2-reactive CD8 T cells than E7-reactive ones.
Hence, we will test TCRs against different HPV antigens (e.g., E6/E7 vs. E2) and elucidate the mechanistic
connection between HPV-specific TCRs and therapeutic responses. Our proposed studies may overcome the
barrier of the HNSCC field and develop a new toolbox of targeting HPV+ HNSCCs with maximal breadth and
depth of TCRs. We will employ a novel “window of opportunity” trial open at our institution (HCC 18-139) that
tests the effects of anti-PD1 (nivolumab) vs. anti-PD1 + anti-CTLA4 or anti-LAG-3 in a neoadjuvant setting before
surgery resection of locally advanced resectable HPV+ HNSCC. Additionally, we will employ a HNSCC mouse
model (mEER) expressing HPV16 E6/E7 antigen in which a small fraction of tumor-bearing recipients responded
to anti-PD-L1 treatment, allowing unambiguous identification of responders vs. non-responders. Using these
neoadjuvant trial samples, we will test whether anti-HPV immune responses underlie ICI responses and examine
whether HPV-reactive TCR clonal dynamics and T cell transcriptomics in TILs correlate with ICI responses. Our
mouse model allows functional validation of expanded HPV-reactive TCR clonotypes correlating with ICI
responses and permits antigen manipulation to enhance clinical responsiveness as well as lay the groundwork
for future clinical and targetable trials.

## Key facts

- **NIH application ID:** 10878155
- **Project number:** 1R01CA282074-01A1
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Robert L. Ferris
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $655,244
- **Award type:** 1
- **Project period:** 2024-04-01 → 2029-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10878155

## Citation

> US National Institutes of Health, RePORTER application 10878155, Mechanistic connection between HPV-specific TCRs and therapeutic responses to ICI in HPV+ HNSCC (1R01CA282074-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10878155. Licensed CC0.

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