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

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 5

MYXV increases overall survival in conditional p53–/–/Rb1–/–/p130–/– SCLC GEMM.

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MYXV increases overall survival in conditional p53–/–/Rb1–/–/p130–/– SCL...
Survival is enhanced when MYXV is combined with low-dose cisplatin. (A) Timeline for survival experiment indicating time of Ad-Cre tumor induction at 6–8 weeks of age, treatment start at 100 days after tumor induction, and the indicated time points for the therapeutic intervention. Mice receiving vMyx-M135KO-GFP were given 2 doses (5 × 107 FFU in 60 μl PBS) 48 hours apart, and cisplatin was administered by i.p. injection (2.5 mg/kg in 100 μl PBS) at the indicated time points. (B) Kaplan-Meier survival analysis of the experiment outlined in Figure 3A. Conditional p53–/–/Rb1–/–/p130–/– SCLC mice were randomized into 4 treatment groups. PBS control mice received intranasal instillation and i.p. injections of PBS. Mice treated with MYXV alone received i.p. injections of PBS at the same cisplatin treatment intervals, and the cisplatin-only group received intranasal instillation of PBS at the MYXV treatment interval. Survival data represent 31 mice in the PBS group, 30 mice in the cisplatin (Cis) group, 27 mice in the MYXV group, and 29 mice in the MYXV+Cis group. *P < 0.05, **P < 0.01, ****P < 0.0001, NS indicates P > 0.05, by log-rank (Mantel-Cox) test. Median survival for each treatment group was as follows: PBS: 149 days (95% CI, 113–213 days); Cis: 161.5 days (95% CI, 150–175 days); MYXV: 217 days (95% CI, 169–243 days); MYXV+Cis: 239 (95% CI, 220–254 days).