Oncolytic virotherapy for small-cell lung cancer induces immune infiltration and prolongs survival

• Published in: The Journal of clinical investigation 2019-06, Vol.129 (6), p.2279-2292
• Main Authors: Kellish, Patrick, Shabashvili, Daniil, Rahman, Masmudur M, Nawab, Akbar, Guijarro, Maria V, Zhang, Min, Cao, Chunxia, Moussatche, Nissin, Boyle, Theresa, Antonia, Scott, Reinhard, Mary, Hartzell, Connor, Jantz, Michael, Mehta, Hiren J, McFadden, Grant, Kaye, Frederic J, Zajac-Kaye, Maria
• Format: Article
• Language: English
• Subjects: Analysis; Animal models; Animals; Biomedical research; Brain cancer; Cancer therapies; Carcinoma; Cell Line, Tumor; Chemotherapy; Cisplatin; Cisplatin - pharmacology; Cytokines; Cytotoxicity; Efficiency; Gene expression; Growth inhibition; Health aspects; Humans; Immune checkpoint inhibitors; Immune response; Immunostimulation; Immunotherapy; Infections; Lung cancer; Lung Neoplasms - genetics; Lung Neoplasms - immunology; Lung Neoplasms - pathology; Lung Neoplasms - therapy; Lymphocytes; Mammals; Medical equipment industry; Medical prognosis; Medical schools; Melanoma; Metastases; Mice; Mice, Knockout; Mutation; Myxoma; Myxoma virus; Necrosis; Neuroendocrine tumors; Oncolysis; Oncolytic Virotherapy; Oncolytic Viruses; Patients; Response rates; Small cell lung carcinoma; Small Cell Lung Carcinoma - genetics; Small Cell Lung Carcinoma - immunology; Small Cell Lung Carcinoma - pathology; Small Cell Lung Carcinoma - therapy; Solid tumors; Studies; Talimogene laherparepvec; Transplantation; Tumor cells; Tumors; Virus replication; Viruses; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI121323

Oncolytic virotherapy has been proposed as an ablative and immunostimulatory treatment strategy for solid tumors that are resistant to immunotherapy alone; however, there is a need to optimize host immune activation using preclinical immunocompetent models in previously untested common adult tumors. We studied a modified oncolytic myxoma virus (MYXV) that shows high efficiency for tumor-specific cytotoxicity in small-cell lung cancer (SCLC), a neuroendocrine carcinoma with high mortality and modest response rates to immune checkpoint inhibitors. Using an immunocompetent SCLC mouse model, we demonstrated the safety of intrapulmonary MYXV delivery with efficient tumor-specific viral replication and cytotoxicity associated with induction of immune cell infiltration. We observed increased SCLC survival following intrapulmonary MYXV that was enhanced by combined low-dose cisplatin. We also tested intratumoral MYXV delivery and observed immune cell infiltration associated with tumor necrosis and growth inhibition in syngeneic murine allograft tumors. Freshly collected primary human SCLC tumor cells were permissive to MYXV and intratumoral delivery into patient-derived xenografts resulted in extensive tumor necrosis. We confirmed MYXV cytotoxicity in classic and variant SCLC subtypes as well as cisplatin-resistant cells. Data from 26 SCLC human patients showed negligible immune cell infiltration, supporting testing MYXV as an ablative and immune-enhancing therapy.