Abstract 1465: Priming immunity against SCLC with oncolytic virotherapy
Authors: Kellish Patrick , Hartzell Connor , Shabashvili Daniil , Rahman Masmudur M. , Guijarro Maria V. , Nawab Akbar , McFadden Grant , Kaye Frederic J. , Zajac-Kaye Maria 
Published: August 2019

Abstract
Small cell lung cancer (SCLC) is an aggressive subtype of lung cancer with few treatment advances over the past 3 decades and poor survival. High levels of tumor infiltrating immune cells are associated with improved SCLC patient survival Independent of tumor stage, patient performance status or treatment. Oncolytic virotherapy presents a new approach where tumor specific infection and replication stimulate host immune responses and increase infiltrating immune cells. Myxoma virus (MYXV) has been widely tested in Australia to control rabbit populations with no toxicity to humans. We have now shown that MYXV selectively infects SCLC cells with no cytotoxicity to normal tissues. In vitro studies were performed using human, murine, and cisplatin-resistant SCLC cell lines. Efficient MYXV infection, replication, and cytotoxicity was observed in all SCLC cell lines with rapid induction of immunogenic cell death (ICD), demonstrating MYXV is effective for SCLC regardless of cisplatin resistance. In contrast, we did not detect productive infection or cytotoxicity in non-tumor cells. Using an optimized conditional genetically engineered mouse (GEM) model (Ad-Cre mediated p53/Rb1/p130 null) we show untreated advanced SCLC tumors are devoid of infiltrating immune cells. Following intrapulmonary MYXV treatment, MYXV localized exclusively within lungs of tumor bearing mice and was cleared by 7 days. Despite clearance within 7 days, a robust immune response was sustained 30 days after MYXV treatment. When intrapulmonary MYXV is administered in combination with anti-PD-1 or anti-CTLA-4, both combinations show greater reduction in tumor burden throughout the lung compared to MYXV alone at the 60 day post treatment timepoint. In addition, the immune cell population localized within SCLC tumors were enhanced following combined MYXV/anti-PD-1 at 60 days post treatment. In our GEM model, MYXV alone results in a statistically significant prolongation of survival compared to both PBS and cisplatin treated animals. To determine the effect of MYXV delivered by intratumoral injection we utilized patient derived xenografts (PDX) and newly developed subcutaneous syngeneic tumor models for SCLC in immunocompetent mice. Following MYXV treatment in PDX tumors we observed extensive necrosis and persisting virus detected 10 days post treatment. In our immunocompetent subcutaneous syngeneic tumor model, MYXV is cleared by 7 days, which is consistent with clearance following intrapulmonary MYXV delivery in our GEM model. This was accompanied by extensive necrosis, reduction in tumor volume, increased infiltrating immune cells, and induction of de novo endogenous tumor specific antibody responses. In conclusion, we demonstrate the potential for MYXV as an oncolytic virotherapy for SCLC, with selective infection leading to enhanced anti-tumor immune responses.
Citation Format: Patrick Kellish, Connor Hartzell, Daniil Shabashvili, Masmudur M. Rahman, Maria V. Guijarro, Akbar Nawab, Grant McFadden, Frederic J. Kaye, Maria Zajac-Kaye. Priming immunity against SCLC with oncolytic virotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1465.