Oncolytic Maraba virus armed with tumor antigen boosts vaccine priming and reveals diverse therapeutic response patterns when combined with checkpoint blockade in ovarian cancer

Abstract

Background 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. Methods Using 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). Results Vaccine 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. Conclusions Our 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. Electronic supplementary material The online version of this article (10.1186/s40425-019-0641-x) contains supplementary material, which is available to authorized users.

Measles Vaccines Designed for Enhanced CD8+ T Cell Activation

“…The present study suggests that measles vaccines can also be designed to promote CTL responses against specific tumor antigens by encoding the antigens or their immunodominant epitopes in the viral vector. Other oncolytic virus platforms, such as VSV and Maraba virus, have been used for this purpose [24][25][26][27][28]30,64]. Though not effective as a priming vector, Maraba viruses encoding tumor antigens have been shown to efficiently boost CTL-mediated anti-tumor immunity by infection of splenic follicular B cells [29,65].…”

“…As another approach to direct the immune response against the tumor, oncolytic viruses encoding tumor antigens have been developed [24][25][26][27][28][29][30][31]. Different antigen expression strategies have been realized in recombinant viral vectors for tumor vaccination.…”

“…Kottke et al and Pulido et al studied oncolytic vesicular stomatitis virus (VSV) with cDNA libraries from melanoma or prostate cancer [24,25]. Several studies have investigated oncolytic Maraba viruses encoding full-length differentiation or cancer testis antigens [26][27][28][29]. For the treatment of HPV-associated cancers, Atherton et al generated vectors encoding full-length HPV 16 and 18 E6 and E7 separated by linker sequences to mediate proteasomal degradation [30].…”

Optimizing Oncolytic Viral Design to Enhance Antitumor Efficacy: Progress and Challenges

“…One way to increase the abundance of tumor antigens would be to use an OV armed with a tumor antigen. A recent study by McGray et al demonstrated the feasibility of such an approach to boost vaccine priming and increase overall therapeutic response in an ovarian cancer model [113]. The authors used a Maraba virus encoding full-length ovalbumin (OVA) as a tumor antigen to treat a murine ovarian tumor model engineered to express OVA.…”

RNA editing enzyme APOBEC3A promotes pro-inflammatory (M1) macrophage polarization

“…Human monocyte-derived macrophage Maraba exposure: The attenuated strain MG1 Maraba virus has been previously described (Brun et al, 2010;Pol et al, 2014). Maraba virus was prepared and titered at McMaster University, shipped on dry ice to RPCCC, stored at − 80 °C and used as described (McGray et al, 2019).…”