1335 Infectious Bursal Disease Virus (IBDV) as a novel virotherapy for remodeling the tumor microenvironment (TME) and stimulating innate and adaptive immune responses in different murine cancer models

<h3>Background</h3> Within cancer immunotherapy, oncolytic viruses (OVs) are recognized as a promising and robust treatment approach. This study presents the potential of Infectious Bursal Disease Virus (IBDV), an avian-specific pathogen with no known human zoonosis, as a novel therapeutic agent. We assessed IBDV’s efficacy against several cancer types, including glioblastoma (CT-2A, GL261, and patient-derived stem cells), melanoma (B16-F10), colorectal carcinoma (CT-26), and B-cell lymphoma (A20). <h3>Methods</h3> We have evaluated the infectivity, cytotoxicity, replication kinetics, and analyzed the expression of pro-inflammatory and anti-viral (IFN-I/IFN-III) cytokine responses in all tumoral models following viral infection, in comparison to those elicited by a very well-known OV, Newcastle disease virus (NDV). We further evaluated IBDV’s anti-tumor effects in preclinical glioblastoma, colon, melanoma, and B-cell lymphoma models using immunocompetent mice. Immunological responses to IBDV virotherapy were analyzed locally, in the tumor microenvironment (TME) and systemically (in tumor-draining and distal lymph nodes) via spectral flow cytometry. <h3>Results</h3> Results demonstrate that IBDV significantly exhibits oncolytic activity both in vitro and in vivo, effectively infecting, replicating in, and killing all cancer models, while inducing type-I/III IFN responses and enhancing pro-inflammatory (IL-1β and IL-6) responses. Notably, in melanoma (B16-F10) and glioblastoma (CT-2A) in vivo models, IBDV treatment delayed tumor growth and improved overall survival compared to PBS-treated mice, while complete tumor elimination was achieved in 30% of colorectal carcinoma (CT-26) and 60% B-cell lymphoma (A20) engrafted mice. Moreover, a systemic immune response was achieved (abscopal effect) in B-cell lymphoma engrafted mice, delaying distal tumor growth and eliminating treated tumors. Overall, IBDV virotherapy elicited robust innate and adaptive immune responses within the TME, disrupting tumor immunotolerance. This was evidenced by the elevated ratios of M1/M2 and CD8+/Treg immune cell populations upon IBDV treatment compared to PBS-treated mice. In melanoma and colorectal carcinoma models, there was an upregulation of immunosuppressive markers on both CD4+ and CD8+ T cells in TME and tumor-draining lymph nodes. <h3>Conclusions</h3> These findings highlight IBDV’s potential as a robust anti-tumor immunostimulatory agent (figure 1), opening its use in Neoadjuvant strategies as well as in combination with check-point blockade immunotherapy targeting PD1/PDL1 blockade. <h3>Ethics Approval</h3> All animal studies were performed in accordance with Institutional Animal Care and Use committee (IACUC) guidelines and have been approved by the IACUC of Icahn School of Medicine at Mount Sinai (IACUC-2014-0234).