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

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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.