Novel targeted strategies for cancer (immuno) therapy

In recent decades, conventional cytotoxic cancer treatment modalities have gradually been complemented with (and sometimes replaced by) novel and more tumor-selective approaches, including various forms of cancer immunotherapy. Important advancements have been made in the field of immune checkpoint inhibition (ICI) strategies using antagonistic antibodies. Nevertheless, cancer cells may escape ICI by producing large amounts of very small (30–150 nm) extracellular vesicles called Tumor-derived EXosomes (TEX). TEX were shown to expose large amounts of the inhibitory immune checkpoint molecule CD73. Intriguingly, the currently used conventional (monospecific) immune checkpoint-blocking antibodies fail to inhibit TEX-exposed CD73. Therefore, we constructed and preclinically evaluated the novel bispecific antibody (bsAb) CD73xEpCAM. BsAb CD73xEpCAM showed unique capacity to selectively block TEX-exposed CD73 and may be useful as an alternative or complementary approach for cancer immunotherapy.
Cancer vaccines represent another promising form of cancer immunotherapy. Typically, cancer vaccines critically rely on targetable and immunogenic cancer-specific mutation-based neoepitopes, which are extremely rare. In this thesis, we demonstrated for the first time that cancer-specific transcription-induced chimeric RNAs can be exploited to produce a cell-free cancer vaccine that induces potent CD8+ T cell-mediated anticancer immunity. Our novel approach may be particularly useful for the development of cancer vaccines to treat malignancies with a low mutational burden or without mutation-based antigens.
Finally, we pre-clinically evaluated the potential of using a growth hormone-releasing hormone receptor (GHRH-R) antagonistic peptide ‘MIA-602’ to treat refractory malignancies, such as gastric and esophageal cancers.