SCIENCE TRANSLATIONAL MEDICINE
4 Jan 2023
Vol 15, Issue 677
AbstractThe 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.
Turning tumors into turncoatsInactivated tumor cells have been previously investigated for their anti-cancer ability and have only shown limited clinical benefit. To overcome this, Chen et al. have engineered living tumor cells to secrete interferon beta (IFNB) and granulocyte-macrophage colony-stimulating factor (GM-CSF) to both target tumors and alter the tumor microenvironments. These engineered therapeutic tumor cells (ThTCs) induced improved survival and long-term immunity in glioblastoma humanized mice. In addition, Chen et al. incorporated a double kill-switch to prevent secondary tumor initiation to provide an effective and safe therapy that warrants further investigation. —DH
FYI: Dr. Timothy Cripe