Targeting T-cell malignancies using anti-CD4 CAR NK-92 cells

Abstract

// Kevin G. Pinz 1, * , Elizabeth Yakaboski 1, * , Alexander Jares 3 , Hua Liu 3 , Amelia E. Firor 1 , Kevin H. Chen 1 , Masayuki Wada 1 , Huda Salman 4 , William Tse 5 , Nabil Hagag 4 , Fengshuo Lan 4 , Elaine Lai-Han Leung 2 , Xun Jiang 1, 2 and Yupo Ma 1, 2, 3 1 iCell Gene Therapeutics LLC, Research & Development Division, Long Island High Technology Incubator, Stony Brook, NY 11790, USA 2 State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau SAR, China 3 Department of Pathology, Stony Brook Medicine, Stony Brook University Medical Center, Stony Brook, NY 11794, USA 4 Department of Internal Medicine, Stony Brook Medicine, Stony Brook University Medical Center, Stony Brook, NY 11794, USA 5 Division of Hematology and Medical Oncology, James Graham Brown Cancer Center, University of Louisville Health Sciences Center, Louisville, KY 40202, USA * These authors have contributed equally to this work Correspondence to: Xun Jiang, email: sue.jiang@icellgene.com Yupo Ma, email: yupo.ma@icellgene.com Keywords: NK cells; immunotherapy; T-cell malignancies; chimeric antigen receptors Received: September 12, 2017     Accepted: October 25, 2017     Published: November 22, 2017 ABSTRACT Peripheral T-cell lymphomas (PTCLs) are a group of very aggressive non-Hodgkin’s lymphomas (NHLs) with poor prognoses and account for a majority of T-cell malignancies. Overall, the standard of care for patients with T-cell malignancies is poorly established, and there is an urgent clinical need for a new approach. As demonstrated in B-cell malignancies, chimeric antigen receptor (CAR) immunotherapy provides great hope as a curative treatment regimen. Because PTCLs develop from mature T-cells, these NHLs are commonly CD4 + , and CD4 is highly and uniformly expressed. Therefore, CD4 is an ideal target for PTCL CAR immunotherapy. To that effect, we created a robust third-generation anti-CD4 CAR construct (CD4CAR) and introduced it into clonal NK cells (NK-92). CD4CAR NK-92 cells specifically and robustly eliminated diverse CD4 + human T-cell leukemia and lymphoma cell lines (KARPAS-299, CCRF-CEM, and HL60) and patient samples ex vivo . Furthermore, CD4CAR NK-92 cells effectively targeted KARPAS-299 cells in vivo that modeled difficult-to-access lymphoma nodules, significantly prolonging survival. In our study, we present novel targeting of CD4 using CAR-modified NK cells, and demonstrate efficacy. Combined, our data support CD4CAR NK cell immunotherapy as a potential new avenue for the treatment of PTCLs and CD4 + T-cell malignancies.