Desarrollo traslacional de la inmunoterapia Celyvir: células progenitoras mesenquimales y virus oncolíticos para el tratamiento de tumores sólidos pediátricos

Abstract

Oncolytic virotherapy is an immunotherapy modality for cancer that involves the use of viruses designed to specifically target tumor cells without causing harm to healthy cells. However, oncolytic viruses do not exhibit tumor tropism, and their intravenous administration triggers an antiviral response from the patient, limiting effective antitumor efficacy. As a solution, the use of migratory cells capable of delivering oncolytic viruses to the tumor has been proposed. In line with this idea, Celyvir therapy was developed utilizing mesenchymal stem cells (MSCs) as carriers for the human oncolytic adenovirus ICOVIR-5. Celyvir therapy has reached clinical application through a compassionate use program and a first clinical trial involving pediatric patients with solid tumors. Overall, the clinical results showed an excellent safety and tolerance profile, with reported cases of clinical response, including complete remissions. However, further development of Celyvir therapy is still needed to enhance its antitumor effect, and a deeper understanding of its mechanism of action is required. The main objective of this Doctoral Thesis is the study, development, and optimization of the immunotherapy Celyvir. For this purpose, we have established preclinical models to investigate the mechanism of action of Celyvir, as well as different strategies for its optimization. In this regard, clinical findings indicated that Celyvir products manufactured with MSCs exhibiting lower pro-inflammatory responses after adenoviral infection provided better clinical responses in patients. Thus, we confirmed that the use of silent, less pro-inflammatory MSCs in Celyvir improved the antitumor efficacy of the treatment. Conversely, the production of a new oncolytic virus designed to induce a reduced pro-inflammatory response in infected MSCs did not improve the antitumor efficacy. Overall, these results improve our understanding of the mechanism of action of Celyvir therapy, and the variations studied in the treatment can be considered in ongoing clinical trials