Abstract B141: Evaluation of antigen-agnostic anti-tumor activity and immunological memory induced by CBX-15 (alphalexTM-MMAE) in the rat syngeneic breast cancer model

Abstract

CBX-15 is a peptide-drug conjugate consisting of alphalexTM-monomethyl auristatin E (MMAE). The alphalexTM is a unique variant of pH-Low Insertion Peptide1 (pHLIP®) designed to target the low pH microenvironment of cancer cells, a universal feature of all rapidly growing tumors. The peptide of CBX-15 forms an alpha helix only in low pH conditions, resulting in unidirectional insertion of the peptide and delivery of MMAE across the cancer cell membrane, and avoidance of delivery to healthy tissues, including immune cells.  Efficacy and anti-tumor immunological memory induced by CBX-15 was evaluated in Fischer 344 rats bearing syngeneic 13762 mammary adenocarcinoma tumors. The development of anti-tumor immunological memory was examined in CBX-15-cured animals by in vivo/ex vivo rechallenge with live tumor cells and subsequent assessment of tumor rejection, cytokine release by T cells, tumor immune cell infiltration, and memory T cell composition of the bone marrow.  CBX-15 rapidly regressed rat tumors, resulting in complete responses while sparing healthy tissues such as bone marrow. Cured rats rejected live tumor rechallenge and exhibited a doubling of bone marrow-resident CD4 memory T cells 50 days post-dose. Splenocytes and lymph node suspensions derived from cured rats demonstrated formation of a Th1-mediated IFNƳ response when exposed ex vivo to tumor cells.   The ability of CBX-15 to induce immunogenic cell death was established by vaccinating syngeneic animals with CBX-15 treated tumor cells and subsequent tumor rechallenge, which demonstrated anti-tumor immunity induced by CBX-15.  These preclinical data demonstrate the anti-tumor efficacy of CBX-15 in the rat as well as the ability of CBX-15 to enhance tumor immunogenicity through immunogenic cell death by utilizing a universal pH-based tumor targeting mechanism.1 Wyatt LC et al. 2017. Applications of pHLIP Technology for Cancer Imaging and Therapy. Trends Biotech.

Citation Format: Sophia Gayle, Timothy Paradis, Qing Zhang, Laurie Tylaska, Connor Hagen, Theresa Pasqualini, Vishwas Paralkar. Evaluation of antigen-agnostic anti-tumor activity and immunological memory induced by CBX-15 (alphalexTM-MMAE) in the rat syngeneic breast cancer model [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B141.