Back to Search
Start Over
Localized oncolytic virotherapy overcomes systemic tumor resistance to immune checkpoint blockade immunotherapy.
- Source :
-
Science translational medicine [Sci Transl Med] 2014 Mar 05; Vol. 6 (226), pp. 226ra32. - Publication Year :
- 2014
-
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.
- Subjects :
- Animals
CD4-Positive T-Lymphocytes cytology
CD8-Positive T-Lymphocytes cytology
CTLA-4 Antigen metabolism
Immune System
Inflammation
Interferon Type I metabolism
Killer Cells, Natural cytology
Lymphocytes cytology
Melanoma, Experimental
Mice
Neoplasm Transplantation
Newcastle disease virus
Oncolytic Viruses
Immunotherapy methods
Oncolytic Virotherapy methods
Subjects
Details
- Language :
- English
- ISSN :
- 1946-6242
- Volume :
- 6
- Issue :
- 226
- Database :
- MEDLINE
- Journal :
- Science translational medicine
- Publication Type :
- Academic Journal
- Accession number :
- 24598590
- Full Text :
- https://doi.org/10.1126/scitranslmed.3008095