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

TLDR

Preexisting lymphocytic infiltration of tumors is linked to better prognoses and may identify patients who benefit most from immune checkpoint blockade, suggesting that inducing tumor inflammation can enhance therapeutic efficacy. The study investigates the immunotherapeutic potential of oncolytic Newcastle disease virus (NDV) to trigger inflammatory responses that improve checkpoint blockade efficacy. Localized intratumoral administration of NDV was used to induce inflammatory responses in B16 melanoma. Localized intratumoral NDV induced inflammatory responses and tumor‑specific CD4+ and CD8+ T‑cell infiltration in distant tumors, and when combined with systemic CTLA‑4 blockade it caused rejection of preestablished distant tumors and protection from rechallenge, an effect dependent on CD8+ T cells, NK cells, and type I interferon, thereby demonstrating that NDV can sensitize non‑injected tumors to checkpoint inhibitors.

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, 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 antitumor effect in distant (nonvirally 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 preestablished distant tumors and protection from tumor rechallenge 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, natural killer 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 the clinic.