Chimeric antigen receptor T cells for sustained remissions in leukemia

Abstract

Background: Relapsed acute lymphoblastic leukemia (ALL) is difficult to treat despite the availability of aggressive therapies. Chimeric antigen receptor-modified T cells targeting CD19 may overcome many limitations of conventional therapies and induce remission in patients with refractory disease.

Methods: We infused autologous T cells transduced with a CD19-directed chimeric antigen receptor (CTL019) lentiviral vector in patients with relapsed or refractory ALL at doses of 0.76×10(6) to 20.6×10(6) CTL019 cells per kilogram of body weight. Patients were monitored for a response, toxic effects, and the expansion and persistence of circulating CTL019 T cells.

Results: A total of 30 children and adults received CTL019. Complete remission was achieved in 27 patients (90%), including 2 patients with blinatumomab-refractory disease and 15 who had undergone stem-cell transplantation. CTL019 cells proliferated in vivo and were detectable in the blood, bone marrow, and cerebrospinal fluid of patients who had a response. Sustained remission was achieved with a 6-month event-free survival rate of 67% (95% confidence interval [CI], 51 to 88) and an overall survival rate of 78% (95% CI, 65 to 95). At 6 months, the probability that a patient would have persistence of CTL019 was 68% (95% CI, 50 to 92) and the probability that a patient would have relapse-free B-cell aplasia was 73% (95% CI, 57 to 94). All the patients had the cytokine-release syndrome. Severe cytokine-release syndrome, which developed in 27% of the patients, was associated with a higher disease burden before infusion and was effectively treated with the anti-interleukin-6 receptor antibody tocilizumab.

Conclusions: Chimeric antigen receptor-modified T-cell therapy against CD19 was effective in treating relapsed and refractory ALL. CTL019 was associated with a high remission rate, even among patients for whom stem-cell transplantation had failed, and durable remissions up to 24 months were observed. (Funded by Novartis and others; CART19 ClinicalTrials.gov numbers, NCT01626495 and NCT01029366.).

Figures

Figure 1. Probability of Event-free and Overall Survival at 6 Months

Panel A shows the time to an event after infusion of CTL019. Events were relapse (in seven patients), no response (in three patients), and the myelodysplastic syndrome (in one patient). Tick marks indicate the time of data censoring at the last follow-up or on the date of initiation of alternative therapy (in four patients). The curve in Panel B shows overall survival. Data were censored at the time of the last follow-up. In both panels, dashed lines represent 95% confidence intervals.

Figure 2. Persistence of CTL019

Panel A shows the results of detection of CTL019-positive T cells detected by means of flow cytometry in peripheral-blood samples. “Confirmed negative” was defined as the first of two consecutive negative measurements (7 to 5×109 total cells (3×105 to 1×108 cells per kilogram of body weight) was achieved in all treated patients (see Table S2 in the Supplementary Appendix). A split-dose strategy was used to determine safety with 0.1×108 to 1×108 cells per kilogram infused over 1 to 3 days (5×108 to 50×108 cells in patients who weighed 50 kg or more). The transduction efficiency ranged from 5.5 to 45.3%; this yielded a dose of 0.76 to 20.6×106 CTL019 cells per kilogram.

Figure 3. B-Cell Aplasia

Panel A shows the results of testing to detect the percentage of CD19-positive lymphocytes in peripheral-blood samples by means of flow cytometry. Patients 1 through 25 were participants in the pediatric trial (which included children and young adults 5 to 22 years of age), and Patients 26 through 30 were participants in the adult trial (which included patients 26 to 60 years of age). Negative results were defined as less than 3% of lymphocytes that were positive for CD19. An outlier sample (Patient 16 at month 3) with 4% CD19-positive lymphocytes was discrepant with the measurements on clinical flow cytometry (

Figure 4. Correlates of the Cytokine-Release Syndrome

Panel A shows peak levels of interleukin-6 in the first 28 days after infusion of CTL019 cells in patients with severe cytokine-release syndrome as compared with patients with cytokine-release syndrome that was not severe. Severe cytokine-release syndrome was defined as hypotension requiring the use of two or more vasopressors or respiratory failure requiring mechanical ventilation. Panel B shows the severity of cytokine-release syndrome according to the baseline disease burden in bone marrow after chemotherapy and before infusion (in the pediatric trial only). Solid circles indicate complete remission, open circles no response, and horizontal lines medians.