CD3xPDL1 bi-specific T cell engager (BiTE) simultaneously activates T cells and NKT cells, kills PDL1⁺ tumor cells, and extends the survival of tumor-bearing humanized mice

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dc.contributor.authorHorn, Lukas A.
dc.contributor.authorCiavattone, Nicholas G.
dc.contributor.authorAtkinson, Ryan
dc.contributor.authorWoldergerima, Netsanet
dc.contributor.authorWolf, Julia
dc.contributor.authorClements, Virginia K.
dc.contributor.authorSinha, Pratima
dc.contributor.authorPoudel, Munanchu
dc.contributor.authorOstrand-Rosenberg, Suzanne
dc.date.accessioned2018-04-17T18:30:16Z
dc.date.available2018-04-17T18:30:16Z
dc.date.issued2017
dc.description.abstractBi-specific T cell engagers (BiTEs) activate T cells through CD3 and target activated T cells to tumor-expressed antigens. BiTEs have shown therapeutic efficacy in patients with liquid tumors; however, they do not benefit all patients. Anti-tumor immunity is limited by Programmed Death 1 (PD1) pathway-mediated immune suppression, and patients who do not benefit from existing BiTES may be non-responders because their T cells are anergized via the PD1 pathway. We have designed a BiTE that activates and targets both T cells and NKT cells to PDL1⁺ cells. In vitro studies demonstrate that the CD3xPDL1 BiTE simultaneously binds to both CD3 and PDL1, and activates healthy donor CD4⁺ and CD8⁺ T cells and NKT cells that are specifically cytotoxic for PDL1⁺ tumor cells. Cancer patients’ PBMC are also activated and cytotoxic, despite the presence of myeloid-derived suppressor cells. The CD3xPDL1 BiTE significantly extends the survival time and maintains activated immune cell levels in humanized NSG mice reconstituted with human PBMC and carrying established human melanoma tumors. These studies suggest that the CD3xPDL1 BiTE may be efficacious for patients with PDL1⁺ solid tumors, in combination with other immunotherapies that do not specifically neutralize PD1 pathway-mediated immune suppression.en_US
dc.description.urihttps://doi.org/10.18632/oncotarget.19865en_US
dc.format.extent17 pagesen_US
dc.genrejournal articlesen_US
dc.identifierdoi:10.13016/M2B853K9M
dc.identifier.citationHorn, L.A., N.G. Ciavattone, R. Atkinson, N. Woldergerima, J. Wolf, V.K. Clements, P. Sinha, M. Poudel, and S. Ostrand-Rosenberg, 2017. CD3xPDL1 bi-specific T cell engager (BiTE) simultaneously activates T cells and NKT cells, kills PDL1+ tumor cells, and extends the survival of tumor-bearing humanized mice. Oncotarget 8: 57964-57980.en_US
dc.identifier.urihttp://hdl.handle.net/11603/8777
dc.language.isoen_USen_US
dc.publisherOncotargeten_US
dc.relation.isAvailableAtThe University of Maryland, Baltimore County (UMBC)
dc.relation.ispartofUMBC Biological Sciences Department Collection
dc.relation.ispartofUMBC Faculty Collection
dc.relation.ispartofUMBC Student Collection
dc.rightsThis item may be protected under Title 17 of the U.S. Copyright Law. It is made available by UMBC for non-commercial research and education. For permission to publish or reproduce, please contact the author.
dc.rightsAttribution 3.0 Unported (CC BY 3.0)*
dc.rights.urihttps://creativecommons.org/licenses/by/3.0/*
dc.subjectPDL1⁺ solid tumorsen_US
dc.subjectBi-specific T cell engagers (BiTEs)en_US
dc.subjectliquid tumorsen_US
dc.subjectProgrammed Death 1 (PD1) pathway-mediated immune suppressionen_US
dc.subjectCD3xPDL1 BiTEen_US
dc.subjectimmunotherapiesen_US
dc.subjecttumor-induced immune suppressionen_US
dc.subjectcheckpoint inhibitor blockadeen_US
dc.subjectT cell activationen_US
dc.subjectsolid tumorsen_US
dc.subjectcancer immunotherapyen_US
dc.titleCD3xPDL1 bi-specific T cell engager (BiTE) simultaneously activates T cells and NKT cells, kills PDL1⁺ tumor cells, and extends the survival of tumor-bearing humanized miceen_US
dc.typeTexten_US

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