The administration of inactivated tumor cells is known to induce a potent antitumor immune response; however, the efficacy of such an approach is limited by its inability to kill tumor cells before inducing the immune responses. Unlike inactivated tumor cells, living tumor cells have the ability to track and target tumors. Here, we developed a bifunctional whole cancer cell–based therapeutic with direct tumor killing and immunostimulatory roles. We repurposed the tumor cells from interferon-β (IFN-β) sensitive to resistant using CRISPR-Cas9 by knocking out the IFN-β–specific receptor and subsequently engineered them to release immunomodulatory agents IFN-β and granulocyte-macrophage colony-stimulating factor. These engineered therapeutic tumor cells (ThTCs) eliminated established glioblastoma tumors in mice by inducing caspase-mediated cancer cell apoptosis, down-regulating cancer-associated fibroblast-expressed platelet-derived growth factor receptor β, and activating antitumor immune cell trafficking and antigen-specific T cell activation signaling. This mechanism-based efficacy of ThTCs translated into a survival benefit and long-term immunity in primary, recurrent, and metastatic cancer models in immunocompetent and humanized mice. The incorporation of a double kill-switch comprising herpes simplex virus–1 thymidine kinase and rapamycin-activated caspase 9 in ThTCs ensured the safety of our approach. Arming naturally neoantigen-rich tumor cells with bifunctional therapeutics represents a promising cell-based immunotherapy for solid tumors and establishes a road map toward clinical translation.
Vasculogenic cell therapies have emerged as a powerful tool to increase vascularization and promote tissue repair/regeneration. Current approaches to cell therapies, however, rely mostly on progenitor cells, which pose significant risks (e.g., uncontrolled differentiation, tumorigenesis, and genetic/epigenetic abnormalities). Moreover, reprogramming methodologies used to generate induced endothelial cells (iECs) from induced pluripotent stem cells rely heavily on viral vectors, which pose additional translational limitations. This work describes the development of engineered human extracellular vesicles (EVs) capable of driving reprogramming-based vasculogenic therapies without the need for progenitor cells and/or viral vectors. EVs are derived from primary human dermal fibroblasts (HDFs), and are engineered to pack transcription factor genes/transcripts of ETV2, FLI1, and FOXC2 (EFF). In addition to EFF, the engineered EVs are also loaded with transcripts of angiogenic factors (e.g., VEGF-A, VEGF-KDR, FGF2). In vitro and in vivo studies indicate that such EVs effectively transfected HDFs and drive direct conversions towards iECs within 714 days. Finally, wound healing studies in mice indicate that engineered EVs lead to improved wound closure and vascularity. Altogether, these results show the potential of engineered human vasculogenic EVs to drive direct reprogramming processes of somatic cells towards iECs, and facilitate tissue repair/regeneration.
The administration of inactivated tumor cell lysate is known to induce a potent antitumor immune response, however, their therapeutic efficacy as shown in Phase I-III clinical trials is limited. This could be attributed to the lack of direct cytotoxic effect on tumor cells and the inability to trigger a strong antitumor immune response. Unlike inactivated tumor cells, living tumor cells possess a unique potential to home to and self-target tumors. Therefore, repurposing the tumor cells’ self-homing property and natural source of neoantigens is advantageous for self-targeted cancer immunotherapy. In this study, we developed a genetically engineered living whole cancer cell-based therapeutic with direct tumor killing and immunostimulatory roles. We switched the tumor cells from death ligands sensitive to resistant using CRISPR/Cas9 and subsequently engineered them to release dual cell killing and immunomodulatory agents. These engineered therapeutic tumor cells (ThTC) eliminated established tumor and activating antitumor immune cell trafficking and antigen-specific T cell activation signaling. This mechanism-based efficacy of ThTC translated into a marked survival benefit and long-term immunity in primary, recurrent, and metastatic cancer models in immunocompromised, immunocompetent and humanized mice. Arming naturally neoantigen-rich tumor cells with multidisciplinary therapeutics represents promising cell-based immunotherapy for solid tumors and establishes a roadmap towards clinical translation. Citation Format: Kok-Siong Chen, Natalia Claire Mendonca, Paulo Borges, Khalid Shah. Developing a self-targeted cancer immunotherapy using engineered whole tumor cell-based vaccine [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 698.
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