Senescent cancer cell-derived nanovesicle as a personalized therapeutic cancer vaccine

Abstract

Cancer: Turning tumors into vaccinesTherapeutic vaccines derived from tumor cells could provide a personalized strategy for training the immune system to find and destroy cancer. Past efforts to develop such vaccines have been hampered by the challenge of identifying tumor-specific proteins that elicit a strong immune response. To overcome this, Byung-Soo Kim and colleagues at Seoul National University pursued a strategy in which they subjected tumor cells to chemical treatments that halted proliferation and stimulated production of immunity-activating signaling molecules. The cells were then broken up into membrane-encased fragments filled with tumor-derived biomolecules. Mice dosed with such vaccines, which carry a diverse mix of antigens, showed a potent anti-cancer response, resulting in tumor cell death and significantly improved survival. By treating cells from patient biopsies in this fashion, clinicians could potentially derive potent, individually tailored tumor vaccines. The development of therapeutic cancer vaccines (TCVs) that provide clinical benefits is challenging mainly due to difficulties in identifying immunogenic tumor antigens and effectively inducing antitumor immunity. Furthermore, there is an urgent need for personalized TCVs because only a limited number of tumor antigens are shared among cancer patients. Several autologous nanovaccines that do not require the identification of immunogenic tumor antigens have been proposed as personalized TCVs. However, these nanovaccines generally require exogenous adjuvants (e.g., Toll-like receptor agonists) to improve vaccine immunogenicity, which raises safety concerns. Here, we present senescent cancer cell-derived nanovesicle (SCCNV) as a personalized TCV that provides patient-specific tumor antigens and improved vaccine immunogenicity without the use of exogenous adjuvants. SCCNVs are prepared by inducing senescence in cancer cells ex vivo and subsequently extruding the senescent cancer cells through nanoporous membranes. In the clinical setting, SCCNVs can be prepared from autologous cancer cells from the blood of liquid tumor patients or from tumors surgically removed from solid cancer patients. SCCNVs also contain interferon-gamma and tumor necrosis factor-alpha, which are expressed during senescence. These endogenous cytokines act as adjuvants and enhance vaccine immunogenicity, avoiding the need for exogenous adjuvants. Intradermally injected SCCNVs effectively activate dendritic cells and tumor-specific T cells and inhibit primary and metastatic tumor growth and tumor recurrence. SCCNV therapy showed an efficacy similar to that of immune checkpoint blockade (ICB) therapy and synergized with ICB. SCCNVs, which can be prepared using a simple and facile procedure, show potential as personalized TCVs.