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

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2024 · $536,602

## Abstract

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 ...

## Key facts

- **NIH application ID:** 10873255
- **Project number:** 5R01CA276087-03
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Dmitriy Zamarin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $536,602
- **Award type:** 5
- **Project period:** 2023-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10873255

## Citation

> US National Institutes of Health, RePORTER application 10873255, Immunogenomic predictors of outcomes in patients with locally advanced cervical cancer treated with immunotherapy and chemoradiation (5R01CA276087-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10873255. Licensed CC0.

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