Localized Oncolytic Virotherapy Overcomes Systemic Tumor Resistance to Immune Checkpoint Blockade Immunotherapy

Abstract

Preexisting lymphocytic infiltration of tumors is associated with superior prognostic outcomes in a variety of cancers. Recent studies also suggest that lymphocytic responses may identify patients more likely to benefit from therapies targeting immune checkpoints, suggesting that therapeutic efficacy of immune checkpoint blockade can be enhanced through strategies that induce tumor inflammation. To achieve this effect, here we explored the immunotherapeutic potential of oncolytic Newcastle Disease Virus (NDV). We find that localized intratumoral therapy of B16 melanoma with NDV induces inflammatory responses leading to lymphocytic infiltrates and anti-tumor effect in distant (non-virally injected) tumors without distant virus spread. The inflammatory effect coincided with distant tumor infiltration with tumor-specific CD4+ and CD8+ T cells, which was dependent on the identity of the virus-injected tumor. Combination therapy with localized NDV and systemic CTLA-4 blockade led to rejection of pre-established distant tumors and protection from tumor re-challenge in poorly-immunogenic tumor models, irrespective of tumor cell line sensitivity to NDV-mediated lysis. Therapeutic effect was associated with marked distant tumor infiltration with activated CD8+ and CD4+ effector but not regulatory T cells, and was dependent on CD8+ cells, NK cells and type I interferon. Our findings demonstrate that localized therapy with oncolytic NDV induces inflammatory immune infiltrates in distant tumors, making them susceptible to systemic therapy with immunomodulatory antibodies, which provides a strong rationale for investigation of such combination therapies in clinic.

Inhibiting DNA Methylation Causes an Interferon Response in Cancer via dsRNA Including Endogenous Retroviruses

“…The high correlation of viral defense signaling with mutational burden suggests that genetic changes, increases in ERVs, and viral defense genes could predict response to immune checkpoint and other immunomodulatory approaches. Finally, our drug approach to upregulate viral defense signaling might be compared to the use of oncolytic viruses to induce inflammatory immune infiltrates at tumor sites to sensitize to immunomodulation (Zamarin et al, 2014). methods at 1, 3, or 7 days following removal of drug.…”

Therapeutic antitumor immunity by checkpoint blockade is enhanced by ibrutinib, an inhibitor of both BTK and ITK

“…However, dramatic as they are, these remissions occur in a minority of the patients. A number of strategies are being developed to enhance the therapeutic effects of PD1/PD-L1 blockade, such as combining it with other anticancer therapies (13)(14)(15).…”

Cancer Immunotherapy Out of the Gate: The 22nd Annual Cancer Research Institute International Immunotherapy Symposium

“…Most interestingly, they found that NDV treatment not only had a local effect on the tumor to which it was injected, but also stimulated a systemic abscopal response; tumors at distant sites also shrunk. Specifically, the oncolytic NDVs induced immunogenic cell death of the injected tumor, eliciting tumor-specific effector T cells that could then seek out and destroy other tumors bearing those same antigens (24). Zamarin and colleagues found that distant tumors are efficiently infiltrated with activated effector T cells but not with Tregs.…”