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 Therapeutics

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 6

Primary human SCLC specimen is permissive to MYXV, and a direct intratumoral delivery of MYXV to human SCLC PDX tumors shows viral replication and extensive tumor necrosis.

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Primary human SCLC specimen is permissive to MYXV, and a direct intratum...
(A) Primary SCLC patient specimen collected from bronchoscopy was immediately infected with vMyx-GFP-TdT at 10 MOI, demonstrating both early (GFP) and late (TdTomato) gene expression for replication at 48 hours. Scale bars, 200 μm. Early infection is evident at 24 hours and replication propagating through the patient specimen is evident by 48 hours. (B) Primary SCLC patient specimen infected with vMyx-M135KO-GFP at 10 MOI shows expression of early/late (GFP) gene expression at 48 hours. Scale bars, 200 μm. vMyx-M135KO-GFP lacks a TdTomato reporter gene and expression of the GFP reporter gene is under a poxvirus synthetic early/late promoter expressing GFP during both infection and replication stages. (C) Patient-derived xenograft (PDX) tumor after direct intratumoral injection (5 × 107 FFU in 50 μl PBS) of vMyx-FLuc expressing Firefly luciferase under poxvirus synthetic early/late promoter indicating viral infection and replication. (D) Histological analysis of H&E stained FFPE sections from PDX tumors at 4 and 7 days after vMyx-FLuc injection (5 × 107 FFU in 50 μl PBS) showing progressively increasing necrosis. vMyx-M135KO-GFP infection illustrates similar necrotic effects as vMyx-FLuc at 7 days. Scale bars, 500 μm. Percentage of tissue area showing necrosis is indicated in each micrograph.