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

Award Number: R01CA282074
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2024
PERIOD OF PERFORMANCE END DATE: 03/31/2029

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


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $655,244 )
2025	2025	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cancer Biology Research	000	2	3/20/2025	NON-COMPETING CONTINUATION	$589,719
2025	2025	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cancer Biology Research	001	2	5/22/2025	NON-COMPETING CONTINUATION	$65,525
														Subtotal = $655,244

Issue Date FY: 2024 ( Subtotal = $655,244 )
2024	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cancer Biology Research	000	1	3/14/2024	NEW	$655,244
														Subtotal = $655,244

Grand Total All Awards = $1,310,488

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

Award Number: R01CA282074

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 04/01/2024

PERIOD OF PERFORMANCE END DATE: 03/31/2029

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