Journal Article

Bispecific anti-CD20, anti-CD19 CAR T cells for relapsed B cell malignancies: a phase 1 dose escalation and expansion trial

Schneider, Dina, Krueger, Winfried, Zhu, Fenlu, Hamadani, Mehdi, Dropulić, Boro, Johnson, Bryon D., Shah, Nirav N., Cunningham, Ashley, Hari, Parameswaran, Keever-Taylor, Carolyn A., Worden, Andrew A., Kadan, Michael J., Fenske, Timothy S., Szabo, Aniko, Orentas, Rimas, Yim, Sharon

2020

Overview

Chimeric antigen receptor (CAR) T cells targeting CD19 are a breakthrough treatment for relapsed, refractory B cell malignancies 1 – 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 × 10 5 –2.5 × 10 6 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 × 10 6 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 × 10 6 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. A new bispecific CAR T cell product targeting the CD20 and CD19 antigens demonstrates an excellent safety profile and high clinical efficacy in patients with B cell non-Hodgkin lymphoma and chronic lymphocytic leukemia.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/250/251 / 631/67/1990/283 / 631/67/1990/291 / Adult / Aged / Antigens / Antigens, CD19 - immunology / Antigens, CD20 - immunology / B cells / Biomedical and Life Sciences / Biomedicine / Cancer Research / CD19 antigen / CD20 antigen / Chimeric antigen receptors / Chronic lymphocytic leukemia / Cryopreservation / Diseases / Dose-Response Relationship, Immunologic / Down-regulation / Effectiveness / Feasibility / Female / Health aspects / Health services / Humans / Immunotherapy / Immunotherapy, Adoptive - methods / Infectious Diseases / Letter / Leukemia / Leukemia, B-Cell - immunology / Leukemia, B-Cell - pathology / Leukemia, B-Cell - therapy / Lymphatic leukemia / Lymphocyte Count / Lymphocytes / Lymphocytes T / Lymphoma / Lymphoma, B-Cell - immunology / Lymphoma, B-Cell - pathology / Lymphoma, B-Cell - therapy / Male / Malignancy / Manufacturing / Metabolic Diseases / Methods / Middle Aged / Molecular Medicine / Neurosciences / Neurotoxicity / Non-Hodgkin's lymphoma / Onsite / Patients / Physiological aspects / Receptors, Antigen, T-Cell - immunology / Receptors, Chimeric Antigen - immunology / Recurrence / Relapse / T cells / T-Lymphocytes - cytology / T-Lymphocytes - immunology / T-Lymphocytes - metabolism / T-Lymphocytes - transplantation / Toxicity