Accelerated Brachytherapy Forward Chemoradiation Therapy (ABC-RT) for Cervical Cancer

PROJECT SUMMARY Survival from cervical cancer is stagnating in the United States. Despite many intervening clinical trials, the standard of care (SOC) definitive chemoradiation therapy (CRT) has remained unchanged since the addition of concurrent platinum-based chemotherapy to radiation in the 1990’s. Reasons for this are several-fold, and

include a patient population that is disproportionately affected by barriers to care, inherent radioresistance of gross disease as evidenced by local recurrence after a mean primary tumor dose of >200Gy delivered with brachytherapy plus EBRT, and insufficient systemic control, with distant failure contributing to two thirds of

cervical cancer deaths. A suboptimal immune response at the time of definitive CRT is associated with local, regional, and distant recurrence, as well as death from cervical cancer. We have previously shown that enrichment of immunosuppressive cells and high expression of squamous cell carcinoma antigen (SCCA),

known as SERPINB3, are associated with higher risk of recurrence after SOC CRT in cervical cancer, and that CRT induces further infiltration of tumor permissive myeloid derived cells. Preliminary data suggest that tumor associated macrophages, myeloid-derived suppressor cells, and regulatory T cells are increased in mid-

treatment tumor specimens from patients undergoing standard CRT. Using preclinical models, we find that brachytherapy stimulated expression of immune-stimulatory signals to a greater degree than an equivalent dose of EBRT. Finally, SERPINB3 directly promotes expression of chemokines that recruit immune-suppressive cells,

particularly myeloid-derived sub-populations, blunting the T-cell anti-tumor response in cervical cancer. We hypothesize that brachytherapy alone delivered to the primary tumor prior to regional lymph node EBRT will safely minimize patient trips, further stimulate the immune system, and potentiate the efficacy of immunotherapy.

Two aims are proposed to directly test this hypothesis: Aim 1 will determine if accelerated brachytherapy-forward chemoradiation therapy (ABC-RT) is a safe and effective approach to shorten overall treatment time, and maximize anti-tumor immune response through a phase I/II clinical trial for patients with locally advanced cervical

cancer. Aim 2 will determine if ABC-RT potentiates the anti-tumor activity of immune checkpoint therapies and/or the myeloid-cell inhibitor CCR2i using a preclinical murine tumor model with a novel intracavitary brachytherapy system developed for this proposal. Secondary endpoints to validate candidate biomarkers SERPINB3, and post

therapy FDG-PET as predictors of recurrence after this experimental approach are proposed to precisely stratify patients for subsequent trials incorporating drug-ABC-RT combinations. Success of these aims will provide the preliminary data to support randomized trials of ABC-RT based regimens compared to the SOC and ultimately

a paradigm shift in the definitive treatment of cervical cancer. The proposed translational studies will provide a template for integration of therapies that synergize with CRT and the immune response. The overall goal of this proposal is to improve survival for patients with locally advanced cervical cancer.