Abstract 1419: Locoregional delivery with engineered stem cells modulates immunosuppressive tumor microenvironment in brain leptomeningeal metastasis

Abstract

Abstract Leptomeningeal metastasis (LM) is one of the severe disease conditions in brain metastasis (BM) and results in poor prognosis and reduction of quality of life. Immunotherapies such as anti-Programmed cell Death (PD)-1 antibodies have shown improved overall survival against non-small cell lung cancer (NSCLC).. However, the clinical benefit of patients with NSCLC derived LM is still limited due to poor penetration of therapeutic agents into the brain and cerebrospinal fluid (CSF) and lack of understanding of the tumor microenvironment in LM. In this study, we first developed immune-competent mouse models of LM which show significantly decreased immune cells and increased PD-1+ T cells in the tumor microenvironment as compared to primary NSCLC tumors, thus mimicking primary and LM NSCL in patients. Next, we explored the use of oncolytic herpes simplex virus (oHSV) that selectively replicate in tumor cells and illicit an antitumor effect via oncolysis and production of neoantigens for targeting LM NSCLC. Given that virus neutralization, and inefficient extravasation are the major barriers to the effective systemic delivery of oHSV to target metastatic tumor lesions in the brain, we utilized mesenchymal stem cells (SC) and created two population of mesenchymal SC types: one for loading oncolytic herpes simplex virus (oHSV) and another one, engineered with knockout of Nectin-1 receptor by CRISPR/Cas9 technique to be resistant to oHSV, for secreting single-chain variable fragment (scFv) anti-PD-1. We show that locoregional treatment improved therapeutic outcomes by inducing oHSV-mediated immunogenic cell death, and activation of anti-tumor T cell signaling in mouse NSCLC LM tumors. Our novel SCs based immunotherapeutic strategy provides a roadmap towards treatment of lung to brain leptomeningeal metastatic patients. Citation Format: Nobuhiko Kanaya, Waleed Seddiq, Kok-Siong Chen, Yoshinori Kajiwara, Lucia Moreno Lama, Shinji Kuroda, Toshiyoshi Fujiwara, Hiroaki Wakimoto, Khalid Shah. Locoregional delivery with engineered stem cells modulates immunosuppressive tumor microenvironment in brain leptomeningeal metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1419.