Targeting the inside out: New antigens for TCR T cell therapy

The adoptive transfer of T cells gene-engineered with antigen-specific receptors, such as chimeric antigen receptors (CARs) or T cell receptors (TCRs), has demonstrated its feasibility and therapeutic potential for the treatment of cancer. However, several challenges must be addressed to make this therapy amendable for larger patient populations. These challenges include the need for new targets homogeneously expressed in solid cancers, the prevention of treatment-related toxicities, both on-target and off-target, the complex manufacturing requirements, and the low efficacy and durability in solid tumors.

This thesis addresses two critical challenges in adoptive T cell therapy: the development of new technologies for TCR T cell therapies and the identification of targets suitable for large patient cohorts.

Part I of this thesis describes the development of new technologies for TCR T cell therapies and outlines the necessary steps to isolate and select safe, effective TCRs for clinical application. Part II presents three novel targets for T cell therapies aimed at treating solid tumors that are currently beyond the reach of existing approaches. The corresponding TCRs show strong potential for clinical development, offering new treatment options for these challenging tumor types. The discovery workflow described in this thesis provides a robust framework for identifying additional targets and TCRs, thereby broadening the therapeutic scope of adoptive cell therapy (ACT).