Abstract 1816: Locoregional delivery with gene edited and engineered stem cells modulates unique immune profiling in leptomeningeal metastasis

Abstract

Abstract Patients with advanced melanoma have a high propensity to metastasize to the brain and numerous investigational treatments with targeted agents have shown modest response in melanoma brain metastatic patients. Leptomeningeal metastasis (LM) is one of the severe disease conditions in brain metastasis. Recently, phase I/II clinical studies with immune-checkpoint inhibitors (ICIs) are promising however the clinical benefit of patients with LM is limited mainly due to poor penetration of anti-PD-1 antibodies into the brain and cerebrospinal fluid. Therefore, there is an urgent need to develop innovative therapies for such tumors. Oncolytic herpes simplex virus (oHSV) that selectively replicate in tumor cells and illicit an antitumor effect via oncolysis and production of neoantigens are among the recently approved promising therapies for primary melanoma patients. However, 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 first established and characterized PTEN deficient metastatic melanoma tumor model and show that brain metastatic tumors are more immunosuppressive compared to primary melanoma and therefore mimics the clinical settings. Next, we developed a multimodal approach by creating tumor-tropic allogeneic twin (T) stem cells (SC): one for producing oncolytic herpes simplex virus (oHSV) and the other one engineered with CRISPR/Cas9 mediated knockout of Nectin 1 (N1) receptor (N1KO) to acquire resistance to oHSV and releasing immunomodulators. Utilizing mouse models of brain metastatic PTEN deficient melanomas, we show that locoregional delivery of twin stem cells releasing oHSV and cytokine, GM-CSF (TSC-G) activated dendritic cell and T cell-mediated immune responses in both syngeneic and patient derived-humanized mouse models. Importantly, our strategy exhibited greater therapeutic efficacy when compared with the existing oncolytic viral therapeutic approaches. Moreover, the use of SC-oHSV with SCN1KO releasing both GM-CSF and single-chain variable fragment (scFv) anti-PD-1 (TSC-G/P) effectively suppressed immunosuppressive PTEN deficient LM. Our findings provide a novel allogeneic SC based immunotherapeutic strategy against melanomas and a roadmap towards clinical application particularly for leptomeningeal disease. Citation Format: Nobuhiko Kanaya, Kok Siong Chen, Yoshinori Kajiwara, Waleed Seddiq, Thijs A. van Schaik, Touraj Aligholipour Farzani, Paulo Borges, Shah Khalid. Locoregional delivery with gene edited and engineered stem cells modulates unique immune profiling in leptomeningeal metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1816.