Antitumor efficacy of BAFF-R targeting CAR T cells manufactured under clinic-ready conditions
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ORIGINAL ARTICLE
Antitumor efficacy of BAFF‑R targeting CAR T cells manufactured under clinic‑ready conditions Zhenyuan Dong1 · Wesley A. Cheng1 · D. Lynne Smith1 · Brian Huang1 · Tiantian Zhang1 · Wen‑Chung Chang2 · Xiuli Wang2 · Stephen J. Forman2 · Larry W. Kwak1 · Hong Qin1 Received: 6 April 2020 / Accepted: 16 May 2020 © The Author(s) 2020
Abstract B-cell malignancies can potentially be cured by CD19 chimeric antigen receptor (CAR) T-cell therapy. Although clinical response rates can be up to 93% in acute lymphoblastic leukemia, treatment-related antigen loss and lack of therapeutic persistence contribute to disease relapse. These shortcomings of current CAR T-cell therapy indicate the need for biologically relevant target selection and for improving the efficacy and persistence of the CAR T cells, which we have addressed by developing a novel B-cell activating factor receptor (BAFF-R) CAR T-cell therapy with improved therapeutic persistence. BAFF-R is a B-cell survival receptor and highly expressed in B-cell malignancies. We developed a prototype CAR T cell that efficiently and specifically eliminated BAFF-R expressing human B-cell tumors in several xenogeneic mouse models, including models of CD19 antigen loss. We proceeded with translational development and validation of BAFF-R CAR T cells produced under current good manufacturing practices (cGMP). cGMP-grade BAFF-R CAR T cells underwent in vitro and in vivo validation in established models to confirm that the potency and efficacy of our original research modeling was replicated. Food and Drug Administration required release testing was performed to ensure our BAFF-R CAR T cells meet specifications for new drug products. Completing and exceeding these requirements, the data fully support the initiation of a first-in-human Phase 1 trial for BAFF-R-positive relapsed/refractory (r/r) B-ALL. Keywords CAR T cell therapy · Acute lymphoblastic leukemia · GMP production · BAFF-R
Introduction Chimeric antigen receptor (CAR) T-cell therapy has matured with the recent Food and Drug Administration (FDA) approval of CD19 CAR T cells marking a new era in cancer immunotherapy. This has curative potential for patients with B-cell malignancies, particularly acute lymphoblastic Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00262-020-02614-8) contains supplementary material, which is available to authorized users. * Hong Qin [email protected] 1
Toni Stephenson Lymphoma Center, Department of Hematology and Hematopoietic Cell Transplantation, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA
Center for CAR T Cell Therapy, Department of Hematology and Hematopoietic Cell Transplantation, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA
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leukemia (ALL) where response (CR) rates of 62–93% were observed [1]. Encouraging results have also been seen in recent clinical trials in non-Hodgkin lymphoma (NHL) patients (CR 23–55%) [2]. However, the potential of CD19 CAR T cells to treat B-cell
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