Wednesday, August 20, 2025 8/20/2025

Immunogenomic predictors of outcomes in patients with locally advanced cervical cancer treated with immunotherapy and chemoradiation

Award Number: R01CA276087
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2023
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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Immunogenomic predictors of outcomes in patients with locally advanced cervical cancer treated with immunotherapy and chemoradiation - Project Summary/Abstract Locally advanced cervical cancer (LACC) associated with human papillomavirus (HPV) infection continues to be a significant source of morbidity and mortality in the US and globally. In particular, patients with evidence of metastases to lymph nodes have a dismal 3-year overall survival of 39%, despite treatment with the current standard of care of chemotherapy combined with radiation (CRT). There is thus a critical need to develop new therapeutic strategies for patients with high-risk LACC. Combinations of CRT with immune checkpoint blockade (ICB) drugs targeting PD-L1 (durvalumab) or PD-1 (pembrolizumab) are being studied in global prospective trials CALLA and KEYNOTE A18, respectively. Unfortunately, the results of the CALLA trial failed to demonstrate substantial improvement in 24-month survival with addition of durvalumab, highlighting several critical knowledge gaps in combination of CRT and ICB in LACC. First, optimal sequencing of CRT and ICB is unknown, and there are clear concerns that concurrent initiation of CRT and ICB carries a potential to kill activated proliferating T cells in tumors and tumor-draining lymph nodes, leading to tolerance. Second, predictors of long-term outcomes for the patients treated with ICB and CRT are unknown. In this application, our key study objectives are to examine the evolution of blood and tumor microenvironment (TME) immune parameters in response to differential ICB-CRT sequencing and to establish the predictors of long-term outcomes. To achieve these goals, we conducted and completed an NCI-sponsored clinical trial of PD-L1 inhibitor atezolizumab in combination with CRT in patients with high-risk LACC, randomizing patients to atezolizumab administration prior to and concurrent with CRT vs. concurrent with CRT in 36 patients. The study incorporated comprehensive collection of pre- and on-treatment tumor biopsies and blood and PET scans that will enable us to address the knowledge gaps above. In Aim 1 we will determine how the tumor immune microenvironment evolves as a function of differential immunotherapy and CRT sequencing. By using multi-parameter fluorescence microscopy, we will determine how activation of T cells and their interaction with other cells in the tumors change in response to therapy and how these changes predict long term outcomes. In Aim 2, we will take advantage of T cell receptor (TCR) repertoire sequencing as well as advanced bioinformatics techniques to evaluate how evolution of T cells in tumors and peripheral blood could serve as an indicator of anti-tumor immune response and long-term outcomes. In Aim 3 we will establish radiographic and blood biomarkers as predictors of outcomes in high-risk LACC patients by examining blood HPV DNA and post-treatment PET-CT as markers of disease burden pre- and post-therapy. Identification of early biomarkers predictive of outcomes will be critical for risk-stratification of patients with LACC in order to guide patient selection for clinical trials or maintenance therapy, while minimizing the potential clinical toxicities and financial burden in patients at low risk for recurrence.


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 = $529,039 )
2025	2025	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Cancer Biology Research	002	4	7/1/2025	NON-COMPETING CONTINUATION	$529,039
2025	2023	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Cancer Biology Research	001	2	2/19/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$23,201
2025	2023	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Biology Research	000	1	2/19/2025	NEW	-$23,201
														Subtotal = $529,039

Issue Date FY: 2024 ( Subtotal = $536,602 )
2024	2024	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Cancer Biology Research	000	3	7/5/2024	NON-COMPETING CONTINUATION	$536,602
														Subtotal = $536,602

Issue Date FY: 2023 ( Subtotal = $618,575 )
2023	2023	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Cancer Biology Research	002	2	9/11/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$595,374
2023	2023	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Biology Research	000	1	6/21/2023	NEW	$618,575
2023	2023	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVENUE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Biology Research	001	1	9/11/2023	NEW	-$595,374
														Subtotal = $618,575

Grand Total All Awards = $1,684,216

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Immunogenomic predictors of outcomes in patients with locally advanced cervical cancer treated with immunotherapy and chemoradiation

Award Number: R01CA276087

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2023

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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