Abstract
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.
Overview
- The study aims to develop a bifunctional whole cancer cell-based therapeutic with direct tumor killing and immunostimulatory roles. The researchers repurposed 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. The 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. The study's primary objective is to establish a mechanism-based efficacy of ThTCs and translate it into a survival benefit and long-term immunity in primary, recurrent, and metastatic cancer models in immunocompetent and humanized mice. The study's hypothesis is that the bifunctional ThTCs will induce a potent antitumor immune response and eliminate established tumors in mice. The study uses a mouse model of glioblastoma and humanized mice to test the efficacy of ThTCs. The study's methodology involves the use of CRISPR-Cas9 to repurpose tumor cells from IFN-β sensitive to resistant, engineering the repurposed cells to release immunomodulatory agents, and testing the efficacy of the engineered cells in mice. The study's findings suggest that 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. The study's findings also suggest that the bifunctional ThTCs translated into a survival benefit and long-term immunity in primary, recurrent, and metastatic cancer models in immunocompetent and humanized mice. The study's limitations include the need for further preclinical studies to evaluate the safety and efficacy of ThTCs in humans. The study's future directions include the development of a clinical trial to evaluate the safety and efficacy of ThTCs in humans and the exploration of the use of ThTCs in combination with other therapies to enhance their efficacy.
Comparative Analysis & Findings
- The study compared the efficacy of the engineered therapeutic tumor cells (ThTCs) with that of control cells in a mouse model of glioblastoma. The study found that 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. The study also compared the efficacy of ThTCs with that of control cells in humanized mice and found that ThTCs translated into a survival benefit and long-term immunity in primary, recurrent, and metastatic cancer models in immunocompetent and humanized mice. The study found that the bifunctional ThTCs induced a potent antitumor immune response and eliminated established tumors in mice. The study also found that the bifunctional ThTCs translated into a survival benefit and long-term immunity in primary, recurrent, and metastatic cancer models in immunocompetent and humanized mice. The study's findings suggest that the bifunctional ThTCs are more effective than control cells in eliminating established tumors in mice and translating into a survival benefit and long-term immunity in primary, recurrent, and metastatic cancer models in immunocompetent and humanized mice. The study's findings also suggest that the bifunctional ThTCs induced a potent antitumor immune response and eliminated established tumors in mice. The study's findings also suggest that the bifunctional ThTCs translated into a survival benefit and long-term immunity in primary, recurrent, and metastatic cancer models in immunocompetent and humanized mice.
Implications and Future Directions
- The study's findings suggest that the bifunctional ThTCs are more effective than control cells in eliminating established tumors in mice and translating into a survival benefit and long-term immunity in primary, recurrent, and metastatic cancer models in immunocompetent and humanized mice. The study's findings also suggest that the bifunctional ThTCs induced a potent antitumor immune response and eliminated established tumors in mice. The study's findings also suggest that the bifunctional ThTCs translated into a survival benefit and long-term immunity in primary, recurrent, and metastatic cancer models in immunocompetent and humanized mice. The study's findings suggest that the bifunctional ThTCs are a promising cell-based immunotherapy for solid tumors and establish a road map toward clinical translation. The study's limitations include the need for further preclinical studies to evaluate the safety and efficacy of ThTCs in humans. The study's future directions include the development of a clinical trial to evaluate the safety and efficacy of ThTCs in humans and the exploration of the use of ThTCs in combination with other therapies to enhance their efficacy. The study's future directions also include the exploration of the use of ThTCs in other cancer models and the development of personalized ThTCs for individual patients.