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.
