TNF receptor superfamily-based targeted cancer immunotherapy

Various proteins belonging to the “Tumor Necrosis Factor ligand superfamily” (TNFSF) are currently tested for treating cancer because they can induce “programmed cell death” (also known as apoptosis) in cancer cells. Unfortunately, therapies using these proteins or not very tumor-selective and may be accompanied by serious side effects. The research presented in the thesis of Yuan He focuses on the development of novel tumor-seeking variants thereof that selectively induce apoptosis in cancer cells resulting in viewer side-effects. In particular, a fully novel bispecific antibody-based strategy is described for selectively inducing apoptosis in melanoma cancer cells, a very dangerous and usually difficult to treat form of skin cancer. Also, two new so-called TRAIL fusion proteins are described in which a therapeutic antibody fragment is fused to the pro-apoptotic protein TRAIL. These new TRAIL fusion proteins were designed to selectively bind to cancer cells and then locally help the immune system to fight the cancer cells more effectively. Finally, to address possible safety issues, a new two-step targeting strategy was developed for delivering TRAIL and other therapeutic proteins to cancer lesions. In principle, this new two-step approach may allow for remotely controlling the biological activity of a cancer-fighting fusion protein in case unwanted toxicity occurs.