Abstract
BackgroundCancer immunotherapies are emerging as promising treatment strategies for ovarian cancer patients that experience disease relapse following first line therapy. As such, identifying strategies to bolster anti-tumor immunity and limit immune suppression, while recognizing diverse patterns of tumor response to immunotherapy is critical to selecting treatment combinations that lead to durable therapeutic benefit.MethodsUsing a pre-clinical mouse model, we evaluated a heterologous prime/boost vaccine in combination with checkpoint blockade to treat metastatic intraperitoneal ovarian cancer. Vaccine-elicited CD8+ T cell responses and changes in the tumor microenvironment following treatment were analyzed and compared to treatment outcome. Kinetics of intraperitoneal tumor growth were assessed using non-invasive magnetic resonance imaging (MRI).ResultsVaccine priming followed by antigen-armed oncolytic Maraba virus boosting elicited robust tumor-specific CD8+ T cell responses that improved tumor control and led to unique immunological changes in the tumor, including a signature that correlated with improved clinical outcome of ovarian cancer patients. However, this treatment was not curative and T cells in the tumor microenvironment (TME) were functionally suppressed. Combination PD-1 blockade partially overcame the adaptive resistance in the tumor observed in response to prime/boost vaccination, restoring CD8+ T cell function in the TME and enhancing the therapeutic response. Non-invasive MRI of tumors during the course of combination treatment revealed heterogeneous radiologic response patterns following treatment, including pseudo-progression, which was associated with improved tumor control prior to relapse.ConclusionsOur findings point to a key hierarchical role for PD-1 signaling and adaptive immune resistance in the ovarian TME in determining the functional fate of tumor-specific CD8+ T cells, even in the context of robust therapy mediated anti-tumor immunity, as well as the ability of multiple unique patterns of therapeutic response to result in durable tumor control.
Highlights
Cancer immunotherapies are emerging as promising treatment strategies for ovarian cancer patients that experience disease relapse following first line therapy
Improved clinical outcome in ovarian cancer has been associated with increased intraepithelial CD3+ and/or CD8+ tumor infiltrating lymphocytes (TILs) [4,5,6], vaccine strategies aimed at expanding tumor-specific T cells in ovarian cancer patients have demonstrated modest clinical responses [7,8,9]
We investigated the capacity of oncolytic Maraba virus (MRB) [24, 25] “armed” with a tumor antigen to enhance therapeutic vaccination by driving antigen specific T cells into the the immunosuppressive microenvironment (TME) in an intraperitoneal metastatic murine ovarian cancer model
Summary
Cancer immunotherapies are emerging as promising treatment strategies for ovarian cancer patients that experience disease relapse following first line therapy. As such, identifying strategies to bolster anti-tumor immunity and limit immune suppression, while recognizing diverse patterns of tumor response to immunotherapy is critical to selecting treatment combinations that lead to durable therapeutic benefit. While immune checkpoint inhibitors have generated remarkable results in several tumor types (e.g. melanoma, NSCLC, bladder cancer) leading to FDA approval, the response rates in EOC are lower (~ 5–10%) [10, 11]. Efforts to improve or restore anti-tumor immunity by reprogramming the TME to overcome multiple immunosuppressive pathways are highly desirable [15, 16]. A major gap in ovarian cancer remains a lack of understanding of the optimal context(s) for generating or restoring tumor immune attack by vaccination or blocking checkpoint receptors [17]
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