IntroductionTriple negative breast cancer (TNBC) is the most aggressive and hard-to-treat subtype of breast cancer, affecting 10-20% of all women diagnosed with breast cancer. Surgery, chemotherapy and hormone/Her2 targeted therapies are the cornerstones of treatment for breast cancer, but women with TNBC do not benefit from these treatments. Although the prognosis is dismal, immunotherapies hold significant promise in TNBC, even in wide spread disease because TNBC is infiltrated with more immune cells. This preclinical study is proposing to optimize an oncolytic virus-infected cell vaccine (ICV) based on a prime-boost vaccination strategy to address this unmet clinical need. MethodsWe used various classes of immunomodulators to improve the immunogenicity of whole tumor cells in the prime vaccine, followed by their infection with oncolytic Vesicular Stomatitis Virus (VSVd51) to deliver the boost vaccine. For in vivo studies, we compared the efficacy of a homologous prime-boost vaccination regimen to a heterologous strategy by treating 4T1 tumor bearing BALB/c mice and further by conducting re-challenge studies to evaluate immune memory responses in surviving mice. Due to the aggressive nature of 4T1 tumor spread (akin to stage IV TNBC in human patients), we also compared early surgical resection of primary tumors versus later surgical resection combined with vaccination.ResultsIn vitro results demonstrated that immunogenic cell death (ICD) markers and pro-inflammatory cytokines were released at the highest levels following treatment of mouse 4T1 TNBC cells with oxaliplatin chemotherapy and influenza vaccine. These ICD inducers also contributed towards higher dendritic cell recruitment and activation. With the top ICD inducers at hand, we observed that treatment of TNBC-bearing mice with the influenza virus-modified prime vaccine followed by VSVd51 infected boost vaccine resulted in the best survival. Furthermore, higher frequencies of both effector and central memory T cells along with a complete absence of recurrent tumors were observed in re-challenged mice. Importantly, early surgical resection combined with prime-boost vaccination led to improved overall survival in mice.ConclusionTaken together, this novel cancer vaccination strategy following early surgical resection could be a promising therapeutic avenue for TNBC patients.

Pancreatic ductal adenocarcinoma (PDAC) is a high fatality cancer with one of the worst prognoses in solid tumors. Most patients present with late stage, metastatic disease and are not eligible for potentially curative surgery. Despite complete resection, the majority of surgical patients will recur within the first two years following surgery. Postoperative immunosuppression has been described in different digestive cancers. While the underlying mechanism is not fully understood, there is compelling evidence to link surgery with disease progression and cancer metastasis in the postoperative period. However, the idea of surgery-induced immunosuppression as a facilitator of recurrence and metastatic spread has not been explored in the context of pancreatic cancer. By surveying the existing literature on surgical stress in mostly digestive cancers, we propose a novel practice-changing paradigm: alleviate surgery-induced immunosuppression and improve oncological outcome in PDAC surgical patients by administering oncolytic virotherapy in the perioperative period.

MiRNAs (miRNA, miR) play important functions in the tumor microenvironment (TME) by silencing gene expression through RNA interference. They are involved in regulating both tumor progression and tumor suppression. The pathways involved in miRNA processing and the miRNAs themselves are dysregulated in cancer. Consequently, they have become attractive therapeutic targets as underscored by the plethora of miRNA-based therapies currently in pre-clinical and clinical studies. It has been shown that miRNAs can be used to improve oncolytic viruses (OVs) and enable superior viral oncolysis, tumor suppression and immune modulation. In these cases, miRNAs are empirically selected to improve viral oncolysis, which translates into decreased tumor growth in multiple murine models. While this infectious process is critical to OV therapy, optimal immunomodulation is crucial for the establishment of a targeted and durable effect, resulting in cancer eradication. Through numerous mechanisms, OVs elicit a strong antitumor immune response that can also be further improved by miRNAs. They are known to regulate components of the immune TME and promote effector functions, antigen presentation, phenotypical polarization, and varying levels of immunosuppression. Reciprocally, OVs have the power to overcome the limitations encountered in canonical miRNA-based therapies. They deliver therapeutic payloads directly into the TME and facilitate their amplification through selective tumoral tropism and abundant viral replication. This way, off-target effects can be minimized. This review will explore the ways in which miRNAs can synergistically enhance OV immunotherapy to provide the basis for future therapeutics based on this versatile combination platform.