Deciphering the Immunomodulatory Capacity of Oncolytic Vaccinia Virus to Enhance the Immune Response to Breast Cancer

Abstract

Vaccinia virus (VACV) is a double-stranded DNA virus that devotes a large portion of its 200 kbp genome to suppressing and manipulating the immune response of its host. Here, we investigated how targeted removal of immunomodulatory genes from the VACV genome impacted immune cells in the tumor microenvironment with the intention of improving the therapeutic efficacy of VACV in breast cancer. We performed a head-to-head comparison of six mutant oncolytic VACVs, each harboring deletions in genes that modulate different cellular pathways, such as nucleotide metabolism, apoptosis, inflammation, and chemokine and interferon signaling. We found that even minor changes to the VACV genome can impact the immune cell compartment in the tumor microenvironment. Viral genome modifications had the capacity to alter lymphocytic and myeloid cell compositions in tumors and spleens, PD-1 expression, and the percentages of virus-targeted and tumor-targeted CD8 þ T cells. We observed that while some gene deletions improved responses in the nonimmunogenic 4T1 tumor model, very little therapeutic improvement was seen in the immunogenic HER2/neu TuBo model with the various genome modifications. We observed that the most promising candidate genes for deletion were those that interfere with interferon signaling. Collectively, this research helped focus attention on the pathways that modulate the immune response in the context of VACV oncolytic virotherapy. They also suggest that the greatest benefits to be obtained with these treatments may not always be seen in "hot tumors."

The mismatched nucleotides encoded in vaccinia virus flip-and-flop hairpin telomeres serve an essential role in virion maturation

“…These mice exhibit defective B and T lymphocytes, but normal NK cells, macrophage, and granulocytes. The mice were housed in BSL-2 containment and in conditions as detailed in Umer et al [30]. At day 0 the mice were anesthetized and 5 μl of PBS or viral inoculum was applied with a 10 μL pipette tip to a 1 cm scarification zone near the base of the tail.…”

Trial watch: intratumoral immunotherapy

“… 230 Since the disease eradication in the late 1970s, even though national vaccination programs ended, continuous research on vaccinia virus has produced numerous strains with improved safety profiles, some of them with oncolytic activity. 231 Recently initiated trials are evaluating five oncolytic strains of vaccinia virus either as single agents or in combination with ICIs ( Table 2 ). The Phase I NCT03954067 aims to evaluate the safety and tolerability of ASP9801 (which expresses IL7 and IL12) as a single agent and determine the RP2D in (sub)cutaneous and visceral tumors.…”

Viroimmunotherapy for breast cancer: promises, problems and future directions

“…In this study the virus was found to induce a mild anti-tumor response, however, the response was increased when the virus was combined with PD-1 and CTLA-4 antibodies. Another study examining the oncolytic activity of VACV mutants in BrCa was recently published by Umer et al [58]. In this study, the authors used six mutants of the Western Reserve (WR) strain of VACV each deleted in one or more immunomodulatory genes.…”