Navigating the path of Cancer Immunotherapeutics: Novel Targets and Innovative Development Tools

The development of immune checkpoint (IC) inhibitors is an undeniable revolutionary milestone within the immuno-oncology field. Throughout this thesis, we explore novel IC-based therapies and develop research tools to accelerate their development and overcome the still lack of clinical benefit in a wide range of patients.
The lack of response of many patients to current IC inhibitors (ICIs) suggests that cancer cells might exploit a different set of inhibitory regulators to silence anticancer immunity. Identification of such immune checkpoints could enable their therapeutic targeting within the tumor microenvironment. In this regard, this thesis describes the discovery and pre-clinical validation of CD24, a molecule with potential checkpoint activity in B-cell lymphoma, and report the development of Fc-less bi-specific antibody derivatives to increase on-target/on-tumor effects upon CD24 targeted treatment. Further, the study of antigen-specific T cell responses is becoming increasingly important to predict the efficacy of ICIs. Thus, in this thesis, we describe the development of a luminescence-based assay (“E7-TCR method”) for the rapid in vitro study of antigen-specific immune responses in the context of immunoregulatory checkpoints and therapeutics, and apply it to the study of VISTA, as a potential immune regulator in cancer innate immunity. Finally, antibody-based therapies, such as ICIs, require a rational design and optimization of the antibody molecule format itself. In this thesis, we also report on a sensing technology based on an in-house biosensing platform using Whispering-Gallery Modes (WGMs) to assess antibody binding characteristics and provide useful information for the characterization and improvement of antibody-based cancer immunotherapeutics.