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
Links to Fileshttps://doi.org/10.18632/oncotarget.19865
MetadataShow full item record
Horn, Lukas A.
Ciavattone, Nicholas G.
Clements, Virginia K.
Type of Work17 pages
Citation of Original PublicationHorn, 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.
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.
Attribution 3.0 United States
SubjectsPDL1⁺ solid tumors
Bi-specific T cell engagers (BiTEs)
Programmed Death 1 (PD1) pathway-mediated immune suppression
tumor-induced immune suppression
checkpoint inhibitor blockade
T cell activation
Bi-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.
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Except where otherwise noted, this item's license is described as This 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.
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