Oncolytic virotherapy for small-cell lung cancer induces immune infiltration and prolongs survival
Patrick Kellish, Daniil Shabashvili, Masmudur M. 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, Grant McFadden, Frederic J. Kaye, Maria Zajac-Kaye
Patrick Kellish, Daniil Shabashvili, Masmudur M. 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, Grant McFadden, Frederic J. Kaye, Maria Zajac-Kaye
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Research Article Oncology

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

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.

Authors

Patrick Kellish, Daniil Shabashvili, Masmudur M. 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, Grant McFadden, Frederic J. Kaye, Maria Zajac-Kaye

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Figure 4

MYXV localizes to the lungs of tumor bearing mice resulting in a prolonged immune response.

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MYXV localizes to the lungs of tumor bearing mice resulting in a prolong...
(A) Bioluminescence imaging of conditional Ad-Cre–treated p53–/–/Rb1–/–/p130–/– mice before treatment, 3 days after treatment, and 7 days after treatment with vMyx-FLuc. vMyx-FLuc was administered by intranasal instillation (5 × 107 FFU in 60 μl PBS). (B) Bioluminescent imaging of resected lungs from conditional Ad-Cre–treated p53–/–/Rb1–/–/p130–/– mice (SCLC positive) at 3 and 7 days after treatment with vMyx-FLuc, compared with resected lungs from control mice lacking p53/Rb1/p130 knockouts (SCLC negative) 3 days after vMyx-FLuc. (C) Timeline indicating experimental design for examining immune responses 30 days after vMyx-M135KO-GFP. Three months after Ad-Cre tumor induction, mice were treated twice with MYXV (5 × 107 FFU in 60 μl PBS) 48 hours apart via intranasal instillation, 30 days after MYXV treatment mice were euthanized and the lungs examined. (D) Histological analysis of mice 30 days after intranasal instillation of PBS or MYXV showing H&E-stained FFPE sections. Higher magnification inset shows effects on individual tumorlets. (E) Anti-CD45 IHC-stained FFPE serial sections. Scale bars, 500 μm.