@article{f25f516ce83d4a7799860e8d6d936751,
title = "T cell receptor-targeted immunotherapeutics drive selective in vivo HIV- And CMV-specific T cell expansion in humanized mice",
abstract = "To delineate the in vivo role of different costimulatory signals in activating and expanding highly functional virus-specific cytotoxic CD8+ T cells, we designed synTacs, infusible biologics that recapitulate antigen-specific T cell activation signals delivered by antigen-presenting cells. We constructed synTacs consisting of dimeric Fc-domain scaffolds linking CD28- or 4-1BB-specific ligands to HLA-A2 MHC molecules covalently tethered to HIV- or CMV-derived peptides. Treatment of HIV-infected donor PBMCs with synTacs bearing HIV- or CMV-derived peptides induced vigorous and selective ex vivo expansion of highly functional HIV- and/or CMV-specific CD8+ T cells, respectively, with potent antiviral activities. Intravenous injection of HIV- or CMV-specific synTacs into immunodeficient mice intrasplenically engrafted with donor PBMCs markedly and selectively expanded HIV-specific (32-fold) or CMV-specific (46-fold) human CD8+ T cells populating their spleens. Notably, these expanded HIV- or CMV-specific CD8+ T cells directed potent in vivo suppression of HIV or CMV infections in the humanized mice, providing strong rationale for consideration of synTac-based approaches as a therapeutic strategy to cure HIV and treat CMV and other viral infections. The synTac platform flexibility supports facile delineation of in vivo effects of different costimulatory signals on patient-derived virus-specific CD8+ T cells, enabling optimization of individualized therapies, including HIV cure strategies.",
author = "Mengyan Li and Garforth, {Scott J.} and O'Connor, {Kaitlyn E.} and Hang Su and Lee, {Danica M.} and Alev Celikgil and Chaparro, {Rodolfo J.} and Seidel, {Ronald D.} and Jones, {R. Brad} and Ravit Arav-Boger and Almo, {Steven C.} and Harris Goldstein",
note = "Funding Information: Conflict of interest: SCA, SJG, RDS, and RJC are coinventors of the SynTac technology, which was developed in the laboratory of SCA, described in a pending patent application, “SynTac Polypeptides and Uses Thereof” (US patent application 16/740,752), and licensed to Cue Biopharma. The use of synTacs for application in HIV is also patent pending with HG and SCA as coinventors and is described in “Precision Activation of HIV-Specific CTLs to Eliminate Reactivated Latent T Cells” (US patent application 16/603,306). SCA, RDS, and RJC are cofounders and stockholders of Cue Biopharma. RDS and RJC are employees of Cue Biopharma. SCA and HG received financial support from Cue Biopharma for previous research studies. Copyright: {\textcopyright} 2021, American Society for Clinical Investigation. Submitted: June 5, 2020; Accepted: October 5, 2021; Published: December 1, 2021. Reference information: J Clin Invest. 2021;131(23):e141051. https://doi.org/10.1172/JCI141051. Funding Information: We are grateful to Marina Caskey and Michel Nussenzweig (Rockefeller University) for providing HIV-seropositive donor PBMCs, Christina Ochsenbauer and John Kappes (University of Alabama at Birmingham) for providing the HIV-LucR construct, June Kan-Mitchell (University of Texas at El Paso) for providing the SL9-specific T cell clone, the NIH Tetramer Core Facility (contract number 75N93020D00005) for providing the HLA-A*0201 SL9 and pp65 tetramers, Melissa Fazzari for assistance in statistical analysis, and Saso Cemerski (Cue Biopharma) for his critical review of the manuscript. synTac technology was developed with support provided by the NIH (U01GM094665, U54GM094662 and R01CA198095 to SCA). This work was funded by the Price Family Foundation (to HG and SCA), the NIH (R01AI145024, R01DA044584, R01DA048609, and UM1AI126617 to HG, and R01CA198095 to SCA), the Charles Michael Chair in Autoimmune Diseases (to HG), and the Wollowick Family Foundation Chair in Multiple Sclerosis and Immunology (to SCA). Additional support was provided by Cores supported by the Einstein-Rockefeller-CUNY Center for AIDS Research, an NIH funded program (P30AI124414), and by the Einstein Macromolecular Therapeutics Development Facility and other Cores supported by the Albert Einstein Cancer Center, an NIH funded program (P30CA013330). Funding Information: We are grateful to Marina Caskey and Michel Nussenzweig (Rockefeller University) for providing HIV-seropositive donor PBMCs, Christina Ochsenbauer and John Kappes (University of Alabama at Birmingham)forprovidingtheHIV-LucRconstruct,JuneKan-Mitchell (University of Texas at El Paso) for providing the SL9-specific T cell clone, the NIH Tetramer Core Facility (contract number 75N93020D00005) for providing the HLA-A*0201 SL9 and pp65 tetramers, Melissa Fazzari for assistance in statistical analysis, and Saso Cemerski (Cue Biopharma) for his critical review of the manuscript. synTac technology was developed with support provided by the NIH (U01GM094665, U54GM094662 and R01CA198095 to SCA). This work was funded by the Price Family Foundation (to HG and SCA), the NIH (R01AI145024, R01DA044584, R01DA048609, and UM1AI126617 to HG, and R01CA198095 to SCA), the Charles Michael Chair in Autoimmune Diseases (to HG), and the Wollowick Family Foundation Chair in Multiple Sclerosis and Immunology (to SCA). Additional support was provided by Cores supported by the Einstein-Rockefeller-CUNY Center for AIDS Research, an NIH funded program (P30AI124414), and by the Einstein Macromolecular Therapeutics Development Facility and other Cores supported by the Albert Einstein Cancer Center, an NIH funded program (P30CA013330). Publisher Copyright: Copyright: {\textcopyright} 2021, American Society for Clinical Investigation.",
year = "2021",
month = dec,
day = "1",
doi = "10.1172/JCI141051",
language = "English (US)",
volume = "131",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "23",
}