In a phase I clinical trial, 12 patients (11 with T cell leukemia/lymphoma and 1 with CD7+ AML) were treated with RD13-01 – a healthy donor-derived CAR T product with CD7 and TCRs knocked out (to reduce fratricide), HLA-II ablated (RFX5 KO) and an NK cell inhibitory receptor added(to reduce allo-rejection), and γc knocked in (to enhance IL-2 production). No DLTs, GvHD, or neurotoxicity were observed. Low-grade CRS was common, and viral reactivation was observed in several patients. 9 of 11 (81%) of patients showed an OR, with 7/11 (63.6%) achieving CR or CRi. At a median follow-up of 10.5 months, several patients remained in remission, some of which were durable.
Contributed by Lauren Hitchings
ABSTRACT: Chimeric antigen receptor (CAR)-T cell therapy against T cell malignancies faces major challenges including fratricide between CAR-T cells and product contamination from the blasts. Allogeneic CAR-T cells, generated from healthy donor T cells, can provide ready-to-use, blast-free therapeutic products, but their application could be complicated by graft-versus-host disease (GvHD) and host rejection. Here we developed healthy donor-derived, CD7-targeting CAR-T cells (RD13-01) with genetic modifications to resist fratricide, GvHD and allogeneic rejection, as well as to potentiate antitumor function. A phase I clinical trial (NCT04538599) was conducted with twelve patients recruited (eleven with T cell leukemia/lymphoma, and one with CD7-expressing acute myeloid leukemia). All patients achieved pre-set end points and eleven proceeded to efficacy evaluation. No dose-limiting toxicity, GvHD, immune effector cell-associated neurotoxicity or severe cytokine release syndrome (grade_³_3) were observed. 28 days post infusion, 81.8% of patients (9/11) showed objective responses and the complete response rate was 63.6% (7/11, including the patient with AML). 3 of the responding patients were bridged to allogeneic hematopoietic stem cell transplantation. With a median follow-up of 10.5 months, 4 patients remained in complete remission. Cytomegalovirus (CMV) and/or Epstein-Barr virus (EBV) reactivation was observed in several patients, and one died from EBV-associated diffuse large B-cell lymphoma (DLBCL). Expansion of CD7-negative normal T cells was detected post infusion. In summary, we present the first report of a Phase I clinical trial using healthy donor-derived CD7-targeting allogeneic CAR-T cells to treat CD7(+) hematological malignancies. Our results demonstrated the encouraging safety and efficacy profiles of the RD13-01 allogeneic CAR-T cells for CD7(+) tumors.
Author Info: (1) Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China. 1313016@zju.edu.cn. Liangzhu Laboratory,
Author Info: (1) Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China. 1313016@zju.edu.cn. Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, Zhejiang, China. 1313016@zju.edu.cn. Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, China. 1313016@zju.edu.cn. Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, Zhejiang, China. 1313016@zju.edu.cn. (2) Nanjing Bioheng Biotech Co., Ltd, Nanjing, Jiangsu, China. Department of Hematology, Ruian people's Hospital, Wenzhou, Zhejiang, China. (3) Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China. Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, Zhejiang, China. Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, China. Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, Zhejiang, China. (4) Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China. Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, Zhejiang, China. Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, China. Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, Zhejiang, China. (5) Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China. Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, Zhejiang, China. Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, China. Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, Zhejiang, China. (6) Nanjing Bioheng Biotech Co., Ltd, Nanjing, Jiangsu, China. (7) Department of Hematology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China. (8) Laboratory of Stem Cell Transplantation, Ningbo First Hospital, Ningbo, Zhejiang, China. (9) Nanjing Bioheng Biotech Co., Ltd, Nanjing, Jiangsu, China. (10) Nanjing Bioheng Biotech Co., Ltd, Nanjing, Jiangsu, China. (11) Nanjing Bioheng Biotech Co., Ltd, Nanjing, Jiangsu, China. (12) Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China. Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, Zhejiang, China. Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, China. Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, Zhejiang, China. (13) Nanjing Bioheng Biotech Co., Ltd, Nanjing, Jiangsu, China. (14) Nanjing Bioheng Biotech Co., Ltd, Nanjing, Jiangsu, China. (15) Nanjing Bioheng Biotech Co., Ltd, Nanjing, Jiangsu, China. (16) Nanjing Bioheng Biotech Co., Ltd, Nanjing, Jiangsu, China. (17) Nanjing Bioheng Biotech Co., Ltd, Nanjing, Jiangsu, China. (18) Nanjing Bioheng Biotech Co., Ltd, Nanjing, Jiangsu, China. (19) Nanjing Bioheng Biotech Co., Ltd, Nanjing, Jiangsu, China. (20) Nanjing Bioheng Biotech Co., Ltd, Nanjing, Jiangsu, China. (21) Nanjing Bioheng Biotech Co., Ltd, Nanjing, Jiangsu, China. (22) Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China. Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, Zhejiang, China. Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, China. Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, Zhejiang, China. (23) Department of Hematology, Ruian people's Hospital, Wenzhou, Zhejiang, China. (24) Nanjing Bioheng Biotech Co., Ltd, Nanjing, Jiangsu, China. (25) Nanjing Bioheng Biotech Co., Ltd, Nanjing, Jiangsu, China. (26) Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China. dongrui-wang@zju.edu.cn. Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, Zhejiang, China. dongrui-wang@zju.edu.cn. Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, China. dongrui-wang@zju.edu.cn. Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, Zhejiang, China. dongrui-wang@zju.edu.cn. (27) Nanjing Bioheng Biotech Co., Ltd, Nanjing, Jiangsu, China. jiangtao.ren@bioheng.com. (28) Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China. huanghe@zju.edu.cn. Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, Zhejiang, China. huanghe@zju.edu.cn. Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, China. huanghe@zju.edu.cn. Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, Zhejiang, China. huanghe@zju.edu.cn.
