Novel anti-CD3 chimeric antigen receptor targeting of aggressive T cell malignancies

// Kevin H. Chen 1,* , Masayuki Wada 1,* , Amelia E. Firor 1 , Kevin G. Pinz 1 , Alexander Jares 2 , Hua Liu 2 , Huda Salman 3 , Marc Golightly 2 , Fengshuo Lan 3 , Xun Jiang 1 and Yupo Ma 1,2,4 1 iCell Gene Therapeutics LLC, Research & Development Division, Long Island High Technology Incubator, Stony Brook, NY, USA 2 Department of Pathology, Stony Brook Medicine, Stony Brook, NY, USA 3 Department of Internal Medicine, Stony Brook Medicine, Stony Brook University Medical Center, Stony Brook, NY, USA 4 Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau, China * These authors have contributed equally to this work Correspondence to: Xun Jiang, email: // Yupo Ma, email: // Keywords : NK cells, immunotherapy, T cell malignancies, CD3CAR Received : May 29, 2016 Accepted : July 22, 2016 Published : August 02, 2016 Abstract Peripheral T-cell lymphomas (PTCLS) comprise a diverse group of difficult to treat, very aggressive non-Hodgkin’s lymphomas (NHLS) with poor prognoses and dismal patient outlook. Despite the fact that PTCLs comprise the majority of T-cell malignancies, the standard of care is poorly established. Chimeric antigen receptor (CAR) immunotherapy has shown in B-cell malignancies to be an effective curative option and this extends promise into treating T-cell malignancies. Because PTCLS frequently develop from mature T-cells, CD3 is similarly strongly and uniformly expressed in many PTCL malignancies, with expression specific to the hematological compartment thus making it an attractive target for CAR design. We engineered a robust 3 rd generation anti-CD3 CAR construct (CD3CAR) into an NK cell line (NK-92). We found that CD3CAR NK-92 cells specifically and potently lysed diverse CD3 + human PTCL primary samples as well as T-cell leukemia cells lines ex vivo. Furthermore, CD3CAR NK-92 cells effectively controlled and suppressed Jurkat tumor cell growth in vivo and significantly prolonged survival. In this study, we present the CAR directed targeting of a novel target - CD3 using CAR modified NK-92 cells with an emphasis on efficacy, specificity, and potential for new therapeutic approaches that could improve the current standard of care for PTCLs.