Paradis Timothy, Zhang Qing, Tylaska Laurie, Hagen Connor, Pasqualini Theresa, Paralkar Vishwas, Gayle Sophia
Department of Biology, Cybrexa Therapeutics, New Haven, CT, USA.
Immunotherapy. 2025 May;17(7):501-512. doi: 10.1080/1750743X.2025.2510189. Epub 2025 Jun 3.
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.
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 and 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 , 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.
在大鼠肿瘤模型中，确定使用pH敏感肽（CBX-15）将单甲基澳瑞他汀E（MMAE）非抗原依赖性靶向肿瘤是否通过直接和免疫机制诱导抗肿瘤疗效。
通过细胞毒性和功能测定，评估CBX-15对携带同基因13762乳腺腺癌肿瘤的雌性Fischer大鼠杀伤肿瘤细胞和诱导免疫原性细胞死亡（ICD）的能力。
CBX-15表现出疗效、安全性和抗肿瘤免疫记忆，CBX-15治疗组和接种组大鼠均有能力排斥进一步的肿瘤攻击，这证明了上述结论。有反应的大鼠表现出ICD诱导的免疫调节活性，包括肿瘤细胞识别、肿瘤浸润淋巴细胞募集以及骨髓中记忆性CD4 T淋巴细胞增加。
CBX-15通过MMAE的直接细胞毒性作用以及ICD的诱导来根除肿瘤，后者导致长期抗肿瘤免疫记忆。据我们所知，这是第一项在大鼠（用于临床前毒理学评估的物种）中证明肿瘤选择性药物具有抗肿瘤疗效并诱导长期抗肿瘤免疫记忆的研究。本研究为探索CBX-15与其他免疫调节剂的联合疗法提供了有力依据。
