title: 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, 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.
authors.affiliation: Swim Across America Laboratory, Immunology Program, Sloan-Kettering Institute for Cancer Research, New York, NY 10065, USA.|Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.|Ludwig Center for Cancer Immunotherapy at Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Dmitriy
authors.initials: D
authors.lastname: Zamarin
authors.affiliation: Swim Across America Laboratory, Immunology Program, Sloan-Kettering Institute for Cancer Research, New York, NY 10065, USA.|Ludwig Center for Cancer Immunotherapy at Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Rikke B
authors.initials: RB
authors.lastname: Holmgaard
authors.affiliation: Department of Immunology, The University of Texas, MD Anderson Cancer Center, Houston, TX, 77030, USA.
authors.forename: Sumit K
authors.initials: SK
authors.lastname: Subudhi
authors.affiliation: Laboratory of Immune Cell Epigenetics and Signaling, The Rockefeller University, New York, NY 10065, USA.|Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, New York, NY 10021.
authors.forename: Joon Seok
authors.initials: JS
authors.lastname: Park
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029.|Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Mena
authors.initials: M
authors.lastname: Mansour
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Peter
authors.initials: P
authors.lastname: Palese
authors.affiliation: Swim Across America Laboratory, Immunology Program, Sloan-Kettering Institute for Cancer Research, New York, NY 10065, USA.|Ludwig Center for Cancer Immunotherapy at Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Taha
authors.initials: T
authors.lastname: Merghoub
authors.affiliation: Swim Across America Laboratory, Immunology Program, Sloan-Kettering Institute for Cancer Research, New York, NY 10065, USA.|Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.|Ludwig Center for Cancer Immunotherapy at Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.|Weill Cornell Medical College and Graduate School of Medical Sciences of Cornell University, New York, NY 10065, USA.
authors.forename: Jedd D
authors.initials: JD
authors.lastname: Wolchok
authors.affiliation: Department of Immunology, The University of Texas, MD Anderson Cancer Center, Houston, TX, 77030, USA.
authors.forename: James P
authors.initials: JP
authors.lastname: Allison
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology; D060908:CTLA-4 Antigen / Q000378:metabolism; D007107:Immune System; D007167:Immunotherapy / Q000379:methods*; D007249:Inflammation; D007370:Interferon Type I / Q000378:metabolism; D007694:Killer Cells, Natural / Q000166:cytology; D008214:Lymphocytes / Q000166:cytology; D008546:Melanoma, Experimental; D051379:Mice; D009368:Neoplasm Transplantation; D009522:Newcastle disease virus; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses
chemical_list: D060908:CTLA-4 Antigen; D007370:Interferon Type I