Bifunctional cancer cell-based vaccine concomitantly drives direct tumor killing and antitumor immunity.
Kok-Siong ChenClemens ReinshagenThijs A Van SchaikFilippo RossignoliPaulo BorgesNatalia Claire MendoncaReza AbdiBrennan G SimonDavid A ReardonHiroaki WakimotoKhalid ShahPublished in: Science translational medicine (2023)
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.
Keyphrases
- immune response
- dendritic cells
- growth factor
- crispr cas
- papillary thyroid
- herpes simplex virus
- cell death
- squamous cell carcinoma
- high fat diet induced
- small cell lung cancer
- toll like receptor
- cell proliferation
- squamous cell
- genome editing
- signaling pathway
- type diabetes
- induced apoptosis
- adipose tissue
- highly efficient
- single cell
- mesenchymal stem cells
- small molecule
- binding protein
- insulin resistance
- inflammatory response
- childhood cancer
- metal organic framework
- lymph node metastasis
- protein kinase
- monoclonal antibody
- oxidative stress