Journal Article

623 Immuno-STATs: Leveraging protein engineering to expand and track antigen-specific T cells in vivo

Li, Mengyan, Cheloha, Ross, Ploegh, Hidde, Celikgil, Alev, Kolifrath, Stephen, Duddempudi, Phaneendra, Garforth, Scott, Almo, Steven, Dearling, Jason, Chaparro, Rodolfo, Seidel, Ronald, O’Connor, Kaitlyn, Mesyngier, Maia, Goldstein, Harris, Rashidian, Mohammad, Zeigler, Stad, Zeyang, Ella, Packard, Alan, Woodham, Andrew

2020

Overview

BackgroundImmunotherapies are highly promising and effective strategies for the treatment of cancer; however, continuing challenges persist, including 1) untargeted global immune modulation, resulting in serious side effects; 2) lack of therapeutics capable of in vivo expansion of tumor-specific T cells; 3) inability to visualize in vivo tumor-specific T cell responses; and 4) lack of flexible platforms to rapidly and efficiently explore new therapeutic strategies and immune-escape mechanisms. To address these challenges, we developed a novel class of precision biologics to treat cancer, autoimmune diseases and infectious diseases. We describe a modular platform constructed around an Fc-based covalent pMHC dimer, referred to as synTac (artificial synapse for T cell activation; also termed Immuno-STATs for Selective Targeting and Alteration of T cells), which selectively delivers different cargoes, including costimulatory, coinhibitory or cytokine signals and other modalities to primary T cells of defined specificity. The inherent modularity supports broad applications. Changing the encoded peptide enables targeting of different T cell specificities to address different diseases, while altering the cargo allows for evaluation of different co-modulatory mechanisms or the delivery of mechanistically informative probes.MethodsSortase A-mediated enzymatic coupling supported site-specific and stoichiometric installation of positron emission tomography (PET)-active radiolabels on synTacs to visualize the in vivo localization of antigen-specific T cells. The NSG humanized mouse model allowed for the evaluation of synTacs/Immuno-STATs to drive the in vivo antigen-specific expansion of human CD8 T cells.ResultsUsing radiolabeled synTacs/Immuno-STATs loaded with the appropriate peptides, we employed positron emission tomography to localize human papillomavirus (HPV16)-specific CD8 T cells to implanted HPV16-positive tumors in mice, as well as influenza A virus (IAV)-specific CD8 T cells in the lungs of IAV-infected mice. In vivo administration of HIV- and CMV-specific synTacs/Immuno-STATs to immunodeficient mice intrasplenically engrafted with human donor PBMCs resulted in the marked and selective expansion of HIV-specific and CMV-specific human CD8 T cells populating their spleens, respectively.ConclusionsWe demonstrate the remarkable flexibility of the synTacs/Immuno-STAT platform for addressing a broad range of applications, including the first report of the in vivo imaging of antigen-specific CD8 T cell populations and in vivo antigen-selective expansion of human CD8 T cells. These results suggest that, in addition to broad therapeutic applications, synTac/Immuno-STATs may provide prognostic/diagnostic information. Most notably, these results demonstrate the presence of synTacs/Immuno-STAT biologics in the tumor or infected tissues where they can elicit T cell restimulation and expansion necessary for target killing and enhanced therapeutic efficacy.

• Publisher: BMJ Publishing Group LTD,BMJ Publishing Group
• Subject: Antigens / Immunotherapy / Lymphocytes / Synapses / Tomography