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

// Lucas A. Horn 1,* , Nicholas G. Ciavattone 2,* , Ryan Atkinson 1 , Netsanet Woldergerima 1 , Julia Wolf 1 , Virginia K. Clements 1 , Pratima Sinha 1 , Munanchu Poudel 1 and Suzanne Ostrand-Rosenberg 1 1 Department of Biological Sciences, University of Maryland Baltimore County, Baltimore, MD, USA 2 Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, MD, USA * These authors contributed equally to this project Correspondence to: Suzanne Ostrand-Rosenberg, email: // Keywords : tumor-induced immune suppression, checkpoint inhibitor blockade, T cell activation, solid tumors, cancer immunotherapy Received : April 21, 2017 Accepted : July 26, 2017 Published : August 03, 2017 Abstract 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.