Abstract CT174: Bladder cancer therapy with Alpha1H: From preclinical development to successful Phase II trials
Authors: Hien Tran, Antonín Brisuda, Ines Ambite, Marek Babjuk, Catharina Svanborg
Journal: Cancer Research (2025)

Abstract Alpha-lactalbumin is the most abundant protein in human milk and is crucial for the survival of the offspring. Native alpha-lactalbumin acts as a substrate specifier in the lactose synthase complex and without lactose, milk cannot be expressed, due to high viscosity. When partially unfolded, human alpha-lactalbumin gains the ability to kill tumor cells and immature cells, by forming oleic acid complexes. HAMLET (Human alpha-lactalbumin made lethal to tumor cells) kills a wide range of malignant cells in vitro and maintains this activity in vivo in patients with skin papillomas and bladder cancer in human. In addition, HAMLET has striking effects on human glioblastomas in a rat xenograft model. After convection-enhanced delivery, HAMLET diffuses throughout the brain, selectively killing tumor cells and controlling tumor progression without apparent tissue toxicity. Alpha1H (Alpha1-oleate), formed by a synthetic, alpha-helical peptide comprising the N-terminal 39 amino acids of alpha-lactalbumin and the fatty acid oleic acid, have shown therapeutic efficacy in tumor cells, cancer animal models and clinical studies. Bladder cancer was established, by intravesical instillation of MB49 cells on day 0 and the treatment group received five instillations of alpha1-oleate (1.7-17 mM) on days 3 to 11. A dose-dependent reduction in tumor size, bladder size and bladder weight were recorded in the alpha1-oleate treated group, compared to sham-treated mice. Tumor markers Ki-67, Cyclin D1 and VEGF were inhibited in a dose-dependent manner, as was the expression of cancer-related genes. Remarkably, toxicity for healthy tissue was not detected in alpha1-oleate-treated, tumor-bearing mice or healthy mice or rabbits, challenged with increasing doses of the active complex.In a single center, placebo controlled, double blinded Phase I/II interventional clinical trial of non-muscle invasive bladder cancer, all primary end points of safety and efficacy of alpha1-oleate treatment are reached, as evaluated in an interim analysis. Intra-vesical instillations of alpha1-oleate triggers massive shedding of tumor cells and the tumor size is reduced but no drug-related side effects are detected (primary endpoints). Shed cells contain alpha1-oleate, treated tumors show evidence of apoptosis and the expression of cancer-related genes is inhibited (secondary endpoints). The results are especially encouraging for bladder cancer, where therapeutic failures and high recurrence rates create a great, unmet medical need. FDA has granted fast track designation for its drug candidate Alpha1H for the treatment of non-muscle invasive bladder cancer. Citation Format: Hien Tran, Antonín Brisuda, Ines Ambite, Marek Babjuk, Catharina Svanborg. Bladder cancer therapy with Alpha1H: From preclinical development to successful Phase II trials [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT174.