Abstract 3519: Bioengineering enucleated cell vehicles for targeted delivery of Interleukin 12 to metastatic tumors

Abstract

Abstract Metastatic triple negative breast cancer (TNBC) includes poor prognoses and limited effective therapies. Metastasis is the major barrier to durable clinical responses as many patients appear cured of their disease, yet return to clinic with recurrences from dormant micro-metastases. Immune activating agents, such as Interleukin 12 (IL-12) have attracted attention as anti-cancer adjuvants due to their ability to elicit systemic anti-cancer immunity. Although targeting distributed metastases can be accomplished by intravenous (IV) administration, administration of IL-12 into patient vasculature is highly inefficient due to its short half-life and poor toxicity profile. There is a major unmet need to develop biocompatible carriers that improve targeted delivery of IL-12 by specifically homing to metastatic lesions. Mesenchymal stem cells (MSCs) are considered ideal biodelivery vehicles as they display innate tumor-trophism and can deliver biomolecules specifically to systemic metastases. However, major issues need to be addressed before MSCs can be used to deliver IL-12 to patients: MSC tumor homing needs to be improved, and unmodified MSCs can engraft and contribute to tumor growth and metastasis, raising legitimate safety concerns. To address these major limitations, our laboratory developed a MSC-derived biodelivery vehicle with enhanced homing abilities to deliver biomolecules directly to tumors. Our approach involved using scRNA-seq to identify chemoattractant receptor/ligand pairs (CXCR4/CXCL12, CCR2/CCL2) and endothelial adhesion molecules (PSGL-1/P-E-Selectins) that mediate leukocyte homing and extravasation. We then lentivirally expressed these receptors in MSCs and removed nuclei using Ficoll gradient ultracentrifugation. These bioengineered enucleated MSCs (termed Cargocytes™) have a defined lifespan (4 days) and robustly home to TNBC. This is an important breakthrough as TNBC-trophic Cargocytes can be scaled for clinical applications and are safe for in vivo use as described in our recent publication (Nature Biomedical Engineering, in press). By using syngeneic mouse models of metastatic TNBC, we have observed IV-injected Cargocytes robustly extravasate and precisely home to metastatic lung nodules, suggesting Cargocytes act as remarkable biodelivery vehicles. Indeed, the tumor-trophism of Cargocytes includes both integrating into large macro-metastases and homing to broadly distributed micro-metastases. Cargocytes effectively produce and deliver high doses of IL-12 to mouse TNBC, which induces strong immune activation in tumors. This immune activation involved a potent anti-metastatic response, evidencing strong therapeutic efficacy. These findings suggest Cargocyte-delivered IL-12 could constitute a safe, potent, and highly specific anti-metastatic therapy for TNBC and other metastatic cancers sharing similar chemoattractant profiles. Citation Format: Jeffrey White, Huawei Wang, Flavia Franco Da Cunha, Maureen Ruchhoeft, Richard Klemke. Bioengineering enucleated cell vehicles for targeted delivery of Interleukin 12 to metastatic tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3519.