Anti-CMV T cell redirection and targeted immune checkpoint inhibition as novel cancer immunotherapies

In this thesis of Isabel Britsch, the objective was to design novel targeted strategies aimed at overcoming resistance mechanisms in cancer cells and restoring anticancer immunity in patients who are unresponsive and/or ineligible for current treatment regimens.

The goal was to develop immunological strategies that effectively eliminate cancer cells while mitigating the risk of immune-related adverse events (irAEs).In the first part therapies that can redirect anti-cytomegalovirus (CMV) CD8-positive T cells to selectively target and eliminate cancer cells are explores and investigated. In this respect, anti- anti-cytomegalovirus T cells hold significant promise due to their high abundance in CMV-seropositive subjects, their propensity to increase with age, and their maintenance of excellent effector functions.In the second part the focus shifts to overcoming resistance caused by cancer cell-exposed immune checkpoints. We identified a previously unknown direct inhibitory effect of CD47 on T cell-mediated elimination of cancer cells. 

Additionally, the development of a novel series of bispecific antibodies was described. These antibodies selectively block immune checkpoints CD47 and CD73. They do so in a tumor-specific manner. This is achieved by directing them towards Epidermal Growth Factor Receptor (EGFR) or Epithelial Cell Adhesion Molecule (EpCAM)-overexpressing cancer cells.
Both approaches show promising results, appear to reduce side effects and may be applicable to a broader group of cancer patients who do not respond to current treatment regimens.