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Bispecific Anti-CD20/Anti-CD19 CAR T Cells for Patients With Relapsed B-Cell Malignancies


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In a single-institution phase I dose-escalation and -expansion trial reported as a letter in Nature Medicine, Shah et al found that treatment with tandem bispecific anti-CD20/anti-CD19 4-1BB–CD3ζ lentiviral (LV20.19) chimeric antigen receptor (CAR) T cells produced high response rates in adult patients with relapsed B-cell non-Hodgkin lymphoma or chronic lymphocytic leukemia.

Study Details

In the study, a total of 26 eligible patients enrolled between October 2017 and July 2019 at Froedtert Hospital and Medical College of Wisconsin Grace Clinic underwent apheresis for LV20.19 CAR T-cell production. Cell manufacturing was performed on site (using the CliniMACS Prodigy system) and was set at 14 days, with the aim of infusing noncryopreserved LV20.19 CAR T cells. During dose-escalation, CAR T-cell doses ranged from 2.5 × 105  to 2.5 × 106 cells/kg.

Key Findings

No dose-limiting toxicities were observed during dose escalation, with a dose of 2.5 × 106 cells/kg being selected for the expansion phase.

A total of 22 patients received the target infusion dose of LV20.19 CAR T cells, with 3 receiving 2.5 × 105 cells/kg, 3 receiving 7.5 × 105 cells/kg, and 16 receiving 2.5 × 106 cells/kg. A total of 15 (68%) received noncryopreserved infusions.

“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.”
— Shah et al

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Cytokine-release syndrome was observed in 14 patients (64%) and was grade 3 or 4 in 1 (5%). Neurotoxicity occurred in seven patients (32%) and was grade 3 or 4 in three (14%). Median time to cytokine-release syndrome was 5 days (range = 0­–13 days) and median time to neurotoxicity was 6 days (range = 0–13 days).

Among the 22 evaluable patients, 18 (82%) achieved response at day 28, with complete response observed in 14 (64%). Response at day 28 was observed in 10 of 11 patients with diffuse large B-cell lymphoma, 4 of 7 with mantle cell lymphoma, 3 of 3 with chronic lymphocytic leukemia, and 1 of 1 with follicular lymphoma.

The response rate at day 28 was numerically higher among patients receiving noncryopreserved CAR T cells vs for those receiving CAR T cells after thawing (93% vs 57%, P = .08).

Among the 16 patients who received 2.5 × 106 cells/kg, response at day 28 was observed in 14 (88%), with complete response in 12 (75%). Response was observed in all 12 patients who received 2.5 × 106 cells/kg with noncryopreserved infusion, with complete response in 11 (92%).

Among patients with complete response by day 28, median duration of response was not reached, with median follow-up of 10.1 months. Among those with partial response, median duration of response was 2.3 months. Median overall survival among all patients was 20.3 months. Patients with a response by day 28 had a peak in CAR T-cell numbers in peripheral blood between days 7 and 12, with numbers declining to low or undetectable levels by day 90.

Among 13 patients who had no response or progressed after an initial response (n = 9), biopsy showed that all retained CD19 expression. No difference was observed between mean expression of CD19 (P = .76) or CD20 (P = 1.0) on tumor cells at baseline vs at relapse.

The investigators concluded: “On-site manufacturing and infusion of noncryopreserved 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.”

Nirav N. Shah, MD, of the BMT & Cellular Therapy Program, Division of Hematology & Oncology, Medical College of Wisconsin, Milwaukee, is the corresponding author for the Nature Medicine article.

Disclosure: The study was supported by the Midwest Athletes Against Childhood Cancer (MACC) Fund, Children’s Wisconsin Foundation, Lentigen Technology, Drive for the Cure Foundation, and Froedtert & Medical College of Wisconsin Cancer Center. For full disclosures of the study authors, visit nature.com.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
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