To reduce the risk of antigen escape and demonstrate the feasibility of on-site manufacturing (CliniMACS Prodigy), Shah et al. generated a bispecific CD19-CD20 4-1BB-CD3ζ CAR vector and manufactured product for 26 patients over 14 days. At or above the target cell dose, CRS and neurotoxicity were limited and manageable, and 82% of patients responded (64% CR). Cryopreserved infusion product appeared less effective than fresh. Manufacturing success for patients previously treated with CAR products was low and showed very limited in vivo expansion. All non-responding or relapsing patients continued to express CD19.
Contributed by Ed Fritsch
ABSTRACT: Chimeric antigen receptor (CAR) T cells targeting CD19 are a breakthrough treatment for relapsed, refractory B cell malignancies1-5. Despite impressive outcomes, relapse with CD19- disease remains a challenge. We address this limitation through a first-in-human trial of bispecific anti-CD20, anti-CD19 (LV20.19) CAR T cells for relapsed, refractory B cell malignancies. Adult patients with B cell non-Hodgkin lymphoma or chronic lymphocytic leukemia were treated on a phase 1 dose escalation and expansion trial (NCT03019055) to evaluate the safety of 4-1BB-CD3ζ LV20.19 CAR T cells and the feasibility of on-site manufacturing using the CliniMACS Prodigy system. CAR T cell doses ranged from 2.5 x 105-2.5 x 106 cells per kg. Cell manufacturing was set at 14 d with the goal of infusing non-cryopreserved LV20.19 CAR T cells. The target dose of LV20.19 CAR T cells was met in all CAR-naive patients, and 22 patients received LV20.19 CAR T cells on protocol. In the absence of dose-limiting toxicity, a dose of 2.5 x 106 cells per kg was chosen for expansion. Grade 3-4 cytokine release syndrome occurred in one (5%) patient, and grade 3-4 neurotoxicity occurred in three (14%) patients. Eighteen (82%) patients achieved an overall response at day 28, 14 (64%) had a complete response, and 4 (18%) had a partial response. The overall response rate to the dose of 2.5 x 106 cells per kg with non-cryopreserved infusion (n = 12) was 100% (complete response, 92%; partial response, 8%). Notably, loss of the CD19 antigen was not seen in patients who relapsed or experienced treatment failure. In conclusion, on-site manufacturing and infusion of non-cryopreserved LV20.19 CAR T cells were feasible and therapeutically safe, showing low toxicity and high efficacy. Bispecific CARs may improve clinical responses by mitigating target antigen downregulation as a mechanism of relapse.
Author Info: (1) BMT & Cellular Therapy Program, Division of Hematology & Oncology, Medical College of Wisconsin, Milwaukee, WI, USA. nishah@mcw.edu. (2) BMT & Cellular Therapy Program, Divisio
Author Info: (1) BMT & Cellular Therapy Program, Division of Hematology & Oncology, Medical College of Wisconsin, Milwaukee, WI, USA. nishah@mcw.edu. (2) BMT & Cellular Therapy Program, Division of Hematology & Oncology, Medical College of Wisconsin, Milwaukee, WI, USA. (3) Lentigen, a Miltenyi Biotec company, Gaithersburg, MD, USA. (4) BMT & Cellular Therapy Program, Division of Hematology & Oncology, Medical College of Wisconsin, Milwaukee, WI, USA. (5) Division of Biostatistics, Medical College of Wisconsin, Milwaukee, WI, USA. (6) BMT & Cellular Therapy Program, Division of Hematology & Oncology, Medical College of Wisconsin, Milwaukee, WI, USA. (7) Lentigen, a Miltenyi Biotec company, Gaithersburg, MD, USA. (8) Lentigen, a Miltenyi Biotec company, Gaithersburg, MD, USA. (9) Lentigen, a Miltenyi Biotec company, Gaithersburg, MD, USA. (10) BMT & Cellular Therapy Program, Division of Hematology & Oncology, Medical College of Wisconsin, Milwaukee, WI, USA. (11) Department of Pathology, Medical College of Wisconsin, Milwaukee, WI, USA. (12) BMT & Cellular Therapy Program, Division of Hematology & Oncology, Medical College of Wisconsin, Milwaukee, WI, USA. (13) BMT & Cellular Therapy Program, Division of Hematology & Oncology, Medical College of Wisconsin, Milwaukee, WI, USA. (14) Lentigen, a Miltenyi Biotec company, Gaithersburg, MD, USA. boro.dropulic@miltenyi.com. (15) Lentigen, a Miltenyi Biotec company, Gaithersburg, MD, USA. Department of Pediatrics, University of Washington School of Medicine, Ben Towne Center for Childhood Cancer Research, Seattle, WA, USA. (16) BMT & Cellular Therapy Program, Division of Hematology & Oncology, Medical College of Wisconsin, Milwaukee, WI, USA.
