Targeting T-cell malignancies using anti-CD4 CAR NK-92 cells
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Kevin G. Pinz1,*, Elizabeth Yakaboski1,*, Alexander Jares3, Hua Liu3, Amelia E. Firor1, Kevin H. Chen1, Masayuki Wada1, Huda Salman4, William Tse5, Nabil Hagag4, Fengshuo Lan4, Elaine Lai-Han Leung2, Xun Jiang1,2 and Yupo Ma1,2,3
1iCell Gene Therapeutics LLC, Research & Development Division, Long Island High Technology Incubator, Stony Brook, NY 11790, USA
2State 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
3Department of Pathology, Stony Brook Medicine, Stony Brook University Medical Center, Stony Brook, NY 11794, USA
4Department of Internal Medicine, Stony Brook Medicine, Stony Brook University Medical Center, Stony Brook, NY 11794, USA
5Division 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
Xun Jiang, email: email@example.com
Yupo Ma, email: firstname.lastname@example.org
Keywords: NK cells; immunotherapy; T-cell malignancies; chimeric antigen receptors
Received: September 12, 2017 Accepted: October 25, 2017 Published: November 22, 2017
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.
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