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• W2971878912 abstract "Genetically transduced chimeric antigen receptor (CAR) T-cells targeting CD19 represent a revolutionary immunotherapy in the field of B-lineage malignancies. They have been reported to induce an 83-93% response rate in patients with refractory/relapsed (R/R) B-cell acute lymphoblastic leukemia (ALL).1 Despite the great success of CAR T-cell therapy, some obstacles to the widespread clinical application of this treatment exist, such as the time-consuming, expensive manufacturing process1, 2 and severe adverse reactions, including cytokine release syndrome (CRS) and CAR T-cell-related encephalopathy syndrome (CRES).3 In 2013, the National Cancer Institute initially developed a simplified process for the production of anti-CD19 CAR T-cells.4 Recently, most existing T-cell engineering protocols reduce the T-cell ex vivo culture time to 11-17 days.4-6 However, up to 18.5% of enrolled patients reportedly fail to receive CAR T-cell therapy, due to disease progression before CAR T-cell release or manufacturing issues.5, 7 Thus, further simplifying the manufacturing process in a manner that retains the potent anti-leukemia efficacy and safety of this therapy is critical. Here, we report that fourth-generation CAR T-cells cultured ex vivo for 7 days resulted in a manufacturing success rate of 100% in 25 adult R/R ALL patients, and a 92% objective response rate. More importantly, no case of neurotoxicity of any grade, or severe CRS occurred. From May 23, 2016, to 19 January 192 019, a total of 25 adult patients with R/R CD19-positive ALL were recruited and infused with CD19-specific CAR T-cells. The median age was 36 years (range 18 to 67 years). Of these patients, six had previously undergone hematopoietic stem cell transplantation (HSCT), and 16 had high-risk cytogenetic ALL subtypes. Most of the patients had been heavily pretreated, with 15 (60%) undergoing more than four courses of prior chemotherapy. Peripheral blood mononuclear cells were collected through apheresis, and T- cells were purified by CD3 beads, and activated by anti-CD3/CD28 antibody. Lentiviral CAR with the signaling domains CD28/CD27/CD3ζ- iCasp9 was transduced into the activated T-cells (Figure S1A,B). Detailed information is described in the Supplementary Methods. Before CAR T-cell infusion, all but one patient underwent lymphocyte depletion with the fludarabine plus cyclophosphamide regimen. A total of nine (36%) patients had a high disease burden, that is, 50% or more blasts in bone marrow, seven of whom received bridging chemotherapy before lymphocyte depletion. All patients successfully produced CAR T-cells with a median dose of 7.133 × 105/kg (range, 8.631 × 104/kg to 4.219 × 106/kg) (Table S1). As expected, reducing the ex vivo culture time of T-cells resulted in less differentiation, resulting in a higher percentage of naïve-like T-cells as well as central memory T-cells (Figure S1C). The participants were monitored for CAR T-cells by real-time quantitative PCR once per week for the first 28 days, and some patients were then monitored approximately once per month. Various levels of CAR T-cells could be detected in all patients, indicating that the CAR T-cells expanded well in vivo. CAR T-cells were still detectable up to 11 months after infusion in one patient, who maintained disease-free survival (DFS) for 16 months (Figure S1D). The level of peak CAR T-cell expansion had no marked influence on the status of minimal residual disease (MRD)-negative complete remission (CR), or the incidence of CRS (Figure S1E,F). A total of 23 (92%) patients achieved an objective response, including 20 (80%) with MRD- negative CR, two (8%) with MRD-positive CR, and one (4%) with a partial response (Figure 1A). Two patients with Philadelphia chromosome-positive ALL did not respond, one of whom was confirmed to have a T315I mutation. Three patients received a second infusion of CAR T-cells at three to 7 months after initial treatment due to disease progression (patient five) or relapse (patients three and nine), but none of these patients showed an objective response. To determine the predictive factors for MRD-negative remission, a correlation analysis of patient characteristics, disease status and CAR T-cell properties was performed. Patients with a lower disease burden had a greater likelihood of achieving MRD-negative remission (P = .04) (Figure S2). We found that MRD-negative remission was not correlated with age, the number of prior treatments, disease status, Philadelphia chromosome status, HSCT before CAR T-cell therapy, or CAR T-cell expansion characteristics. Notably, the dose of infused CAR T-cells did not affect the clinical response, and doses less than 5 × 105/kg had the same efficacy as the higher doses (Figure S2). A total of 12 patients (48%) experienced CRS. Of these patients, 10 had grade 1 CRS and two developed grade 2 CRS, but no instances of grade 3 or higher CRS occurred (Figure 1B). All the symptoms of CRS were reversible, and well controlled with supportive care alone (n = 11), or with tocilizumab (n = 1). No patients needed steroids for CRS management. Risk factor analysis was performed to predict the risk of CRS (Figure S3). Notably, the patients who received high-dose CAR T-cell infusion, that is, at a dose greater than 5 × 105/kg, had a higher incidence of CRS than patients infused with a dose less than 5 × 105/kg (P = .041), although no cases of severe CRS were observed in either group. Furthermore, no cases of CRES of any grade were noted. The serum cytokine concentrations of interleukin (IL)-2, IL-4, IL-6, IL-10, tumor necrosis factor-α, interferon-γ and IL-17A did not increase significantly after CAR T-cell infusion (Figure S4). No patients suffered from definite GVHD among the four patients who received a donor-derived CAR T-cell infusion, and no patients died of infection. With a median follow-up duration of 291 days, the median DFS was 257 days, and the median overall survival (OS) was 267 days (Figure 1C,D). At the time of the last follow-up, seven patients had disease relapse, including two patients with CD19-negative relapse and five patients with CD19-positive relapse (Figure 1E). At 180 days after infusion, the cumulative incidence of relapse was 29.4%, the cumulative OS rate was 60%, and the cumulative DFS rate was 55%. Risk factor analysis was also performed to predict the risk of disease progression or relapse. Elderly patients showed a higher likelihood of disease relapse or progression (P = .049), and the probability of these events occurring in patients with a high tumor burden was also relatively high (P < .001) (Figure S5). The DFS and OS rates among patients who achieved MRD-negative CR were significantly superior to those among patients who did not achieve MRD-negative CR (P < .001) (Figure S6A,B). Among 22 patients who achieved CR, 14 did not receive further treatment, while eight patients underwent allo-HSCT at a median of 45 (range 20 to 125) days post-remission. Among 14 patients who did not undergo HSCT, five relapsed post-CR (245 days, 211 days, 90 days, 61 days and 56 days). Among the eight patients who underwent HSCT, only two patients relapsed, one at 100 days and one at 226 days post-HSCT. Both had experienced secondary relapse and had a higher disease burden before CAR T-cell infusion. Patients who underwent HSCT after CAR T-cell infusion tended to have better DFS and OS than patients who were only observed for follow-up; however, statistical significance was not reached (P = .23, P = .20) (Figure S6C,D). In addition, long-term survival was not correlated with the dose of CAR T-cell infusion (Figure S6E,F). Reducing the ex vivo culture time resulted in a seven-day fourth-generation CAR T-cell production process in our study, and 80% of the patients achieved MRD-negative CR, demonstrating the potent anti-tumor efficacy in vivo. Correlation analysis showed that an infusing dose greater than or less than 5 × 105/kg had no effect on the clinical response or survival. However, a higher dose was associated with a higher incident risk of CRS, suggesting that a dose of less than 5 × 105/kg is safer and may be more acceptable. Interestingly, in contrast to the concern that less differentiated CAR T-cells may result in severe toxicity,8 in our study, there were no cases of severe CRS or CRES. This may be attributable to the low infusion dose of CAR T-cells, the nature of the CAR construct, and bridging chemotherapy before infusion in the patients with a high tumor burden. The median dose of CAR T-cells in this study is lower than the required dose in most reported trials.7, 9 Zhitao Ying et al found that altering the structure of CAR T-cells can result in lower levels of cytokines and thus enhance safety while retaining potent cytolytic activity.10 We observed that the levels of cytokines in serum did not increase significantly after CAR T-cell infusion, which also contributed to controlling CRS. The observed efficacy and safety in our study revealed the potential feasibility of this shortened ex vitro culture combining with the improved clinical treatment strategies. Although the patients who underwent HSCT after CAR T-cell infusion tended to have longer survival, statistical significance was not reached, which may be due to the limited sample size. In summary, our study indicated that reducing the ex vivo culture time of fourth-generation CAR T-cells in adult patients with R/R ALL is feasible and promising; however, further research and a longer follow-up period are needed. The authors would like to thank all members of the study team, the patients and their families. The authors declare that they have no potential conflict of interests. This work was supported by research funds from the Natural Science Foundation of Guangdong Province, China (No. 2018B030311042), the Science and Technology Planning Project of Guangdong Province, China (No.2017A020215183), the Major Program for Health Medical Collaborative Innovation of Guangzhou, China (No.201704020216), the Frontier Research Program of Guangzhou Regenerative Medicine and Health Guangdong Laboratory, China (No.2018GZR110105014), and the Startup Project for Clinical Trials of Southern Medical University, China (No.LC2016ZD027), Science and Technology Planning Technical Research Project of Shenzhen (JCYJ20170413154349187, JCYJ20170817172416991, JCYJ20170817172541842, and KQTD20140630143254906). S.T. and R.H. managed the patients and wrote the manuscript. Z.G. collected the data. LD revised the manuscript. C.S., X.Z. and C.Y. contributed to patient management. L.Z. produced the figures and Table. Y.H. participated in the registration of the clinical research. J.Y. and Z.L. were responsible for clinical trial recruitment and data revision. J.D. performed flow cytometry detection and bone marrow cell morphology detection. P.C. was responsible for the statistical analysis. Y.S.L. produced CAR T-cells. L.C. designed the study and guided CAR T-cell production. Y.H.L. contributed to the study design and manuscript writing. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article." @default.
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• W2971878912 date "2019-10-02" @default.
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• W2971878912 title "Shortening the ex vivo culture of CD19‐specific CAR T‐cells retains potent efficacy against acute lymphoblastic leukemia without CAR T‐cell‐related encephalopathy syndrome or severe cytokine release syndrome" @default.
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