Localized Oncolytic Virotherapy Overcomes Systemic Tumor Resistance to Immune Checkpoint Blockade Immunotherapy
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- 5 March 2014
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science Translational Medicine
- Vol. 6 (226), 226ra32
- https://doi.org/10.1126/scitranslmed.3008095
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.Keywords
This publication has 41 references indexed in Scilit:
- Depleting tumor-specific Tregs at a single site eradicates disseminated tumorsJCI Insight, 2013
- Safety, Activity, and Immune Correlates of Anti–PD-1 Antibody in CancerThe New England Journal of Medicine, 2012
- Host type I IFN signals are required for antitumor CD8+ T cell responses through CD8α+ dendritic cellsThe Journal of Experimental Medicine, 2011
- Type I interferon is selectively required by dendritic cells for immune rejection of tumorsThe Journal of Experimental Medicine, 2011
- IL-35-mediated induction of a potent regulatory T cell populationNature Immunology, 2010
- Improved Survival with Ipilimumab in Patients with Metastatic MelanomaThe New England Journal of Medicine, 2010
- Type I Interferon-Sensitive Recombinant Newcastle Disease Virus for Oncolytic VirotherapyJournal of Virology, 2010
- PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumorsProceedings of the National Academy of Sciences of the United States of America, 2010
- Enhancement of Oncolytic Properties of Recombinant Newcastle Disease Virus Through Antagonism of Cellular Innate Immune ResponsesMolecular Therapy, 2009
- Cancer immunotherapy: co-stimulatory agonists and co-inhibitory antagonistsClinical and Experimental Immunology, 2009