Guizhi Zhu
Associate Professor, University of Michigan
Engineer and deliver peptide-based proteolysis-targeting vaccines (PROTAX) for cancer immunotherapy
Abstract
Synthetic long peptide (SLP) vaccines hold great potential to improve the tumor therapeutic efficacy of immune checkpoint blockade (ICB). However, current SLP vaccines elicit limited T cell responses pivotal for tumor immunotherapy. Here, we present SLP-based proteolysis-targeting vaccines (PROTAX) that facilitate antigen proteolytic processing and cross-presentation to potentiate T cell responses for robust ICB combination immunotherapy of tumors. PROTAX are modular conjugates of SLP antigens, E3 ligase-binding ligands, and linkers. In antigen-presenting cells (APCs), PROTAVs bind to E3 ligases to rapidly ubiquitinate PROTAV antigens, thereby facilitating antigen proteolytic processing by proteasome and promoting antigen cross-presentation to T cells. In mice, when co-delivered with bi-adjuvants activating cyclic-GMP-AMP synthase (cGAS) and Toll-like receptor 9 (TLR9) using lipid nanoparticles (LNPs), PROTAVs promoted the quantity and quality of CD8+ T cells against monovalent or multivalent SLP antigens. Combining PROTAX and ICB remodels tumor immune microenvironment. As a result, the combination of PROTAX with ICB promotes the complete regression rates of murine melanoma and human papillomavirus (HPV)-associated tumors, and eradicates 50%-100% ICB-resistant large tumors (300 mm3) in HPV-associated tumors, B16F10 melanoma, and SM1 Braf(V600E) allograft melanoma, and significantly promoted the tumor therapeutic efficacy of chemically-induced autochthonous Braf(V600E) melanoma in a genetically engineered mouse model. Overall, PROTAX represent a simple and broadly applicable platform for robust tumor combination immunotherapy.
Bio
Dr. Guizhi Zhu is currently Ara Garo Paul Associate Professor at University of Michigan – Ann Arbor. He received BS degree in Biotechnology from Nankai University, PhD degree in Biomedical Sciences from the University of Florida, followed by a postdoc training on drug delivery and bioimaging at the National Institute of Biomedical Imaging and Bioengineering (NIBIB) of NIH. His multidisciplinary research group (https://www.guizhizhu.org/) studies the engineering and delivery of nucleic acid and peptide therapeutics and vaccines for the treatment and prophylaxis of cancer, infectious diseases, autoimmune diseases, and genetic diseases. He has published over 100 peer-reviewed papers. He has received prestigious awards, including 2022 Oligonucleotide Pharmaceutical Society (OTS) Young Investigator Award and 2022 American Association of Pharmaceutical Scientists (AAPS) Emerging Leader Award.