Abstract
AIMS: To determine whether using a pH-sensitive peptide (CBX-15) for antigen-independent targeting of MMAE to tumors induced anti-tumor efficacy via direct and immunological mechanisms in the rat tumor model. METHODS: CBX-15 was assessed for its ability to kill tumor cells and induce immunogenic cell death (ICD) in female Fischer rats bearing syngeneic 13762 mammary adenocarcinoma tumors via in vivo and ex vivo functional assays. RESULTS: CBX-15 demonstrated efficacy, safety and anti-tumor immunologic memory, demonstrated by the ability of both CBX-15-cured and vaccinated rats to reject further tumor challenge. Responding rats exhibited the induction of ICD-induced immunomodulatory activity, including recognition of tumor cells ex vivo, recruitment of TILs and increases in memory CD4(+) T lymphocytes in the bone marrow. CONCLUSION: CBX-15 eradicates tumors by a combination of both direct cytotoxic action of MMAE as well as through the induction of ICD, the latter of which results in long term anti-tumor immunological memory. To our knowledge, this is the first work demonstrating both anti-tumor efficacy and induction of long-term anti-tumor immune memory by a tumor-selective drug in the rat, the species used for preclinical toxicological evaluation. This study provides a strong justification for exploring combination therapies with CBX-15 and other immunomodulators.