Doctoral thesis

Chimeric Antigen Receptor T (CAR-T) cells represent a groundbreaking approach in immunotherapy, where a patient’s own T cells are genetically modified to recognize and destroy cancer cells. This therapy has shown remarkable success in treating certain hematological cancers. However, its efficacy against solid tumors remains limited, partly due to the dysfunction CAR-T cells experience within the tumor microenvironment.

The primary goal of this project is to address this challenge by identifying the molecular mechanisms underlying CAR-T cell dysfunction in solid tumors and developing innovative strategies to enhance their therapeutic efficacy. To achieve this, the intrinsic mechanisms of T cells responsible for dysfunction will be investigated. Using CRISPRCas9 technology, previously identified candidate genes will be disrupted, and their impact on CAR-T cell functionality will be analyzed. This investigation will provide insights into how these genes contribute to cellular dysfunction and how their ablation could restore antitumor activity. Additionally, the potential to pharmacologically modulate the expression of these candidate genes using existing drugs will be assessed. This strategy aims to determine whether the combined use of pharmacological agents and CAR-T cells can enhance the therapy’s efficacy against solid tumors. Finally, the potential of candidate genes to serve as integration sites for therapeutic transgenes will be explored. This approach would enable the localized expression of therapeutic agents directly within the tumor microenvironment while simultaneously addressing CAR-T cell dysfunction.

The outcomes of this project have the potential to overcome critical barriers in the treatment of solid tumors. By developing innovative strategies to enhance CAR-T cell performance, this research represents a significant step toward more effective and targeted therapies, ultimately expanding the options available for cancer patients.