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Oncolytic virotherapy for small-cell lung cancer induces immune infiltration and prolongs survival
Patrick Kellish, … , Frederic J. Kaye, Maria Zajac-Kaye
Patrick Kellish, … , Frederic J. Kaye, Maria Zajac-Kaye
Published April 29, 2019
Citation Information: J Clin Invest. 2019;129(6):2279-2292. https://doi.org/10.1172/JCI121323.
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Research Article Oncology

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

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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.

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 7

MYXV infection inhibits tumor development and Intratumoral delivery of MYXV to murine syngeneic SCLC allografts show necrosis, immune cell infiltration, and tumor growth inhibition.

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MYXV infection inhibits tumor development and Intratumoral delivery of M...
(A) Subcutaneous allograft (SQA) SCLC tumor in an immunocompetent mouse showing replication and rapid clearance by 7 days after vMyx-FLuc treatment. (B) Quantification of the fold increase in vMyx-FLuc bioluminescence signal from SQA tumors in immunocompetent mice (n = 4) compared with PDX tumors in immunodeficient NSG mice (n = 3) following direct intratumoral injection of MYXV (vMyx-FLuc, 5 × 107 FFU in 50 μl PBS). Data represent mean + SD. (C) Histological analysis of representative H&E-stained FFPE sections from SQA tumors 7 days after intratumoral injection of vMyx-FLuc (5 × 107 FFU in 50 μl PBS) and 7 days after PBS injection (50 μl PBS). Extensive necrosis is observed in representative MYXV-treated tumor. Higher magnification illustrates the necrotic debris field with select immune cells further enlarged to observe nuclear morphology. Anti-CD45 IHC confirms high levels of immune cell infiltration following MYXV treatment. Scale bars, 200 μm. (D and E) Effect of either intratumoral injection of MYXV (vMyx-FLuc, 5 × 107 FFU in 50 μl PBS) or PBS (50 μl). (D) Effect on tumor volume over time (n = 4 mice in each group). Data represent mean + SEM. (E) Final tumor volume at experimental endpoint (n = 4 mice in each group). Box-and-whisker plot showing the minimum to maximum with all data points and the horizontal line representing the median. **P < 0.01, by unpaired Student’s t test. (F) Murine SCLC cell line (737274-A) infected with vMyx-M135KO-GFP for 24 hours at 10 MOI (ex vivo infection) was injected into immunocompetent mice (n = 3) and monitored for tumor development then compared with control PBS-treated tumor development (n = 4). Data represent mean + SEM.

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