Allogeneic responses in ASC and other hypoimmune cell therapies

• Autores: Irene Zamora Marmol
• Directores de la Tesis: Alvaro Avivar Valderas (dir. tes.), Mariano Andrés García Arranz (dir. tes.)
• Lectura: En la Universidad Autónoma de Madrid ( España ) en 2025
• Idioma: inglés
• Tribunal Calificador de la Tesis: Javier García Casado (presid.), María José Calzada García (secret.), Francesco Maria Dazzi (voc.), Elena Núñez Gómez (voc.), Beatriz González Gálvez (voc.)
• Programa de doctorado: Programa de Doctorado en Biociencias Moleculares por la Universidad Autónoma de Madrid
• Materias:
  • Ciencias de la vida
    • Biología celular
    • Inmunología
• Enlaces
  • Tesis en acceso abierto en: Biblos-e Archivo
• Resumen

  • Cell therapy is a rapidly advancing research field, gaining increasing attention due to its potential for treating a wide range of diseases, particularly in regenerative medicine and immunotherapy. Mesenchymal Stromal Cells (MSC) and induced pluripotent stem cells (iPSC) are two of the most promising cell types in this area, offering opportunities for both allogeneic and autologous therapies. MSC are attractive due to their potent immunomodulatory and regenerative properties, while iPSC offer the unique advantage of being able to differentiate into virtually any cell type, allowing patient-specific treatment design. Despite these promising advances, one of the key challenges in the clinical translation of these therapies is understanding their interactions with the host immune system. In this context, it is crucial for research units to develop robust immunogenicity assays to 1) to understand how cell products interact with the immune system, including evaluating their efficacy, survival after administration, and mechanisms of action, and 2) to provide researchers with the necessary tools to compare and select between potential cell therapy candidates based on their immune profile. The ultimate objective in all cases is to optimize therapeutic outcomes. This study explores different immunogenicity assays applied to Alofisel cell product, based on Adipose-derived Mesenchymal Stromal cells (ASC) and recently withdrawn from the market, as well as potential iPSC-derived products still in early investigation phases. For ASC-based therapy, we evaluated apoptosis levels following interaction with pre-activated Peripheral Blood Mononuclear Cells (PBMC) under varying conditions. This methodology was further applied to clinical investigations using Crohn's Disease (CD) patient samples from the ADMIRE-CDII clinical trial to assess immune-related outcomes. In addition, high throughput immunophenotype data from these studies was analysed using dimensionality reduction and clustering techniques to provide further insights into the effects of Alofisel on immune cell populations. On the iPSC front, iPSC-derived enteric neuronal progenitors (iENP) were analysed for PBMC activation and susceptibility to Natural Killer (NK) cell-mediated cytotoxicity, providing valuable data on their potential immunogenicity. Both ASC and iPSC/iENP related studies pose a challenge since these cells are hypoimmunogenic (low immunogenic), either inherently or as a result of genetic modifications. Overall, these approaches offer effective methods for studying the immune interactions of cell therapy products, allowing for better understanding and optimization of their clinical application. By refining immunogenicity assays, researchers can advance the development of cell therapies with improved efficacy and safety profiles