Lysosome-targeting chimeras degrading immune checkpoint proteins to enhance immunoradiotherapy of head and neck cancer

Project Summary Head and neck cancer (HNC) ranks the sixth most common cancer worldwide. Despite treatment advancements, there's an urgent need for more effective strategies to improve survival and quality of life for HNC patients. Carolyn Bertozzi group recently reported in Nature the groundbreaking protein degraders named lysosome- targeted chimeras (LYTACs), which have bispecific binding affinity that drives cell-surface endocytic receptors to drag membrane or extracellular oncogenic proteins to lysosomes for degradation. They have successfully targeted critical oncoproteins such as epidermal growth factor receptor and more. However, current degradation demonstration was limited to in vitro cancer cells, LYTACs' impact on immune cell modulation and their therapeutic potentials in HNC preclinical animal models remain unknown and require extensive evaluation before venturing to clinical trials. The bispecific targeting affinity of LYTACs, along with their antibody/protein nature, makes them ideal candidates for transformation into radiopharmaceuticals for immunoPET (immuno-positron emission tomography) imaging or internal radioimmunotherapy. However, this field has yet to be explored. My previous project has confirmed that eliminating immunosuppressive proteins is superior to the conventional blockade approach for eliciting better immunogenic responses in treating HNC. In ~200 HNC patient samples, we have confirmed substantial expression of LYTAC receptor CI-M6PR (cation-independent mannose-6- phosphate receptor). I collaborated with Prof Carolyn Bertozzi to develop the first LYTACs (based on CI-M6PR receptor) respectively targeting immunosuppressive proteins Galectin-1, Galectin-3 and Galectin-9 that are overexpressed in HNC. Theses LYTACs effectively degraded (~80%) their targets in human HNC cell, and the representative LYTAC targeting Galectin-1 (named G1M) significantly reduced T cell apoptosis to enhance immunotherapy. Additionally, G1M demonstrated excellent biocompatibility in mouse models. Building upon these promising results, in the proposed project, we will i) assess therapeutic efficacies (tumor & metastases inhibition, synergy with radiotherapy, in vivo immune responses, etc.) of these CI-M6PR-based LYTACs in humanized HNC tumor models (Aim 1, K99 Y1-Y2); ii) discover HNC-specific LYTAC receptors (since CI-M6PR is not HNC specific) and construct corresponding LYTAC degraders to broaden LYTACs' applicability in treating HNC. (Aim 2, R00 Y3-Y4); iii) develop radionuclide-LYTAC conjugates for internal radioimmunotherapy of HNC to improve the metastases and reoccurrence control (Aim 3, R00 Y4-Y5). We hope that this study will contribute to expediting the clinical translation of LYTACs as novel immune checkpoint degraders, which hold both promising clinical and commercial potential for improving treatments for HNC.