评估 CBX-15（alphalex(TM)-MMAE）在大鼠中诱导的抗原非依赖性抗肿瘤活性及免疫记忆

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.

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.

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. Some targeted anti-cancer therapies can both directly kill tumor cells as well as indirectly produce anti-tumor activity by causing tumor cells to secrete molecules that result in activation of the immune system against the tumor, a mechanism called immunogenic cell death (ICD). CBX-15 is a novel pH-sensitive peptide-drug agent that targets the microtubule inhibiting drug MMAE universally to all solid tumors while avoiding delivery to healthy tissues. In the rat breast cancer model, CBX-15 demonstrates the ability to eradicate tumors by both direct cytotoxic activity as well as through ICD in a manner that is safe and avoids toxicity to healthy tissues. Furthermore, CBX-15 therapy allows for immune components to recognize and eliminate tumor cells long after CBX-15 treatment is ended. These data support the upcoming clinical trials of CBX-15 in combination with immunotherapy.