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 2

SCLC patient specimens and a genetically engineered mouse model for SCLC show scant immune cell infiltration.

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SCLC patient specimens and a genetically engineered mouse model for SCLC...
(A) Data from 26 SCLC patient specimens showing CD45 infiltration score (0–3+) defined by CD45+ immunostaining. (B) Dose-dependent study of Ad-Cre delivered by intratracheal injection showing the number of tumor lesions observed at the indicated time points for each Ad-Cre dose. Results are representative of 3 animals per group, and data indicate mean + SD. (C) NCAM-1 (CD56) immunohistochemistry 5 months after intratracheal delivery of Ad-Cre compared with PBS-treated control. Scale bars, 50 μm. (D) IHC of FFPE sections from a p53–/–/Rb1–/–/p130–/– mouse at survival endpoint; CD45 IHC shows negligible infiltrating immune cells and CD3 IHC shows negligible infiltrating T lymphocytes. The advanced SCLC lesion (T) occupies majority of the section with lymph node (LN) upper right confirming CD45 and CD3 reactivity. Scale bars, 400 μm. (E) CD45 and CD3 populations from an enzymatically digested whole lung obtained from adult normal lung (no Ad-Cre tumor induction) (top) or p53–/–/Rb1–/–/p130–/– mouse at survival endpoint (bottom) that confirms IHC results showing few immune cells (CD45+) and T lymphocytes (CD3+) in endpoint SCLC lung. (F) Quantification from whole-lung tissue using control (no Ad-Cre induction; n = 3) and SCLC endpoint (n = 3) showing reduction in immune CD45+ or CD3+ cells and presence of CD45–/CD56+ SCLC tumor cells. Bar showing mean + SD with all data points. ****P < 0.0001 by unpaired Student’s t test.