LAUSR

Immune checkpoint control is one of several mechanisms that negatively influence the immune system and contribute to the development and progression of cancer. To enhance anti-tumor immune responses in patients with advanced solid tumors, we employ a novel autologous cancer cell therapy, APN401, which allows transient and highly specific silencing of Casitas B-lineage lymphoma-b (Cbl-b) in patients’ peripheral mononuclear cells (PBMCs). Cbl-b is an E3 ubiquitin protein ligase that plays a central role in both innate and adaptive immune responses. Here we present two patients with advanced, metastatic solid tumors: one patient diagnosed with appendix carcinoma, and one patient diagnosed with head and neck squamous cell carcinoma (HNSCC). Both showed stable disease (SD) during treatment with APN401. In an open-label, multicenter Phase Ib trial, two increasing dose levels of APN401 were evaluated in patients with advanced solid tumors. Using invIOs’s closed cell-processing platform - Enhancement Platform for immune Cells (EPiC) - patients’ PBMCs were purified from leukapheresis products and subsequently transfected with a small interfering ribonucleic acid (siRNA) to specifically block Cbl-b expression. The entire manufacturing process required less than six hours, and the drug product could be reinfused on the same day. The trial evaluated safety and clinical outcomes, as well as the activity and potency of the drug product. Additionally, various biomarkers were analyzed in patients’ peripheral blood, which was collected prior to each treatment cycle. Two patients, one with appendix carcinoma and one with HNSCC, showed stable disease after repeated APN401 treatments at the lowest and/or intermediate dose levels. Subsequent drug product analyses revealed increased IL-2 levels and elevated CD8/CD4 ratios, suggesting potential cytotoxic efficacy. In stimulation assays with HLA class I-restricted viral or tumor antigens, increased IFN-γ levels were detected and served as surrogate markers for improved immunity and tumor reactivity. 10X genomics and TCR clonotyping revealed clonal expansion of T cell subsets throughout the course of the treatment. Taken together, these initial results indicate that APN401, a novel personalized cancer cell therapy based on targeted silencing of Cbl-b in PBMCs, may be a safe and effective immunotherapy for solid tumors. This cell therapy will be further evaluated as a monotherapy along with potential combinations in clinical trials in various solid tumors. Ethics approval: The clinical trial was approved by the Medical University of Vienna institution’s independent Ethics Committee, approval number 1778/2020. Citation Format: Mario Kuttke, Alexander Dohnal, Andreas Tanzmann, Beate Pribitzer, Felix Batrina, Stefan Bunka, Sophia Spagl, Manuela Branka, Sarah Bischof, Kathrin Thell, Maria Urban, Hannes Muehleisen, Bernhard Peball, Bianca Gapp, Angela Halfmann, Markus Raderer, Gerald Prager, Thorsten Fuereder, Romana Gugenberger, Nina Worel. Case report: APN401, a novel cancer therapy using Cbl-b silenced autologous PBMCs, induced stable disease in two patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB187.