Background: The standard of care for patients with LACC is concurrent chemoradiation therapy (CRT) with weekly cisplatin. Five-year disease overall survival after contemporary CRT for LACC is only 66%. Human Papillomavirus (HPV) DNA is detected in virtually all cervical cancers, and HPV specific CD4+ helper and CD8+ cytotoxic T cells are found in cervical tumors, indicating the inherent immunogenicity of these tumors. The failure of the immune system to eradicate HPV DNA integration is thought to be associated with the cancer cells’ acquisition of mechanisms to avoid cytotoxic T cells, including, but not limited to, the expression of checkpoint inhibitory molecules such as PD-L1 and the recruitment of FoxP3+ immunosuppressive regulatory T cells. Low ratios of CD8+ T cells: regulatory T cells are associated with poor survival for cervical cancer patients, suggesting that strategies to enhance immune response would be effective. Additionally, in cervical cancer, PD-1 is expressed by the majority of infiltrating CD8+ T cells, suggesting that blocking of PD-1 could have therapeutic potential, inducing tumor-specific immunity in cervical cancer patients. We hypothesized that CRT may increase tumor responsiveness to anti-PD-1 therapy by enhancing antigen availability and disrupting immune-regulatory networks. However, it is unclear how treatment with cisplatin and/or ionizing radiation could influence the quality and quantity of the immune response. Methods: A randomized Phase II open-label multi-center study was designed in which 88 eligible subjects with LACC will be treated with standard CRT plus the PD-1 monoclonal antibody pembrolizumab. The primary objectives in the study are to estimate the safety and immune response to pembrolizumab given either sequentially or concurrently with CRT. Secondary objectives will evaluate the metabolic response and rates of distant metastases following treatment with pembrolizumab given sequentially or concurrently with CRT. The study design also affords the opportunity to characterize the effect of treatment on immune response pathways by estimating the effects of treatment on specific immune markers. Clinical trial information: NCT02635360