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

Patrick Kellish, Daniil Shabashvili, Masmudur Rahman, Akbar Nawab, Maria V. Guijarro, Min Zhang, Chunxia Cao, Nissin Moussatche, Theresa Boyle, Scott Antonia, Mary Reinhard, Connor Hartzell, Michael Jantz, Hiren J. Mehta, Douglas McFadden, Frederic J. Kaye, Maria Zajac-Kaye

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Abstract

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.

Original languageEnglish (US)
JournalThe Journal of clinical investigation
Volume130
DOIs
StatePublished - Apr 29 2019

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Keywords

  • Lung cancer
  • Mouse models
  • Oncology
  • Therapeutics

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Kellish, P., Shabashvili, D., Rahman, M., Nawab, A., Guijarro, M. V., Zhang, M., Cao, C., Moussatche, N., Boyle, T., Antonia, S., Reinhard, M., Hartzell, C., Jantz, M., Mehta, H. J., McFadden, D., Kaye, F. J., & Zajac-Kaye, M. (2019). Oncolytic virotherapy for small-cell lung cancer induces immune infiltration and prolongs survival. The Journal of clinical investigation, 130. https://doi.org/10.1172/JCI121323