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

Tu, Sanfang; Huang, Rui; Guo, Zhenling; Deng, Lan; Song, Chaoyang; Zhou, Xuan; Yue, Chunyan; Zhang, Lenghe; He, Yanjie; Yang, Jilong; Zhao, Liang; Du, Junyan; Cao, Peihua; Li, Yuchen; Chang, Lung‐Ji; Li, Yuhua

doi:10.1002/ajh.25630

Cited by 15 publications

(18 citation statements)

References 10 publications

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“…In this study, 67% of patients had an objective response, which was consistent with previously reported results. The results of this trial and our previous trial prove the effectiveness and potential of our 4th-generation CAR-T cells (18). In addition, CD27, a costimulatory molecule, is not inferior to 4-1BB, OX40 and ICOS.…”

Section: Discussionsupporting

confidence: 63%

“…The individualized CAR-T cells were produced as previously described (18). Briefly, peripheral blood mononuclear cells of eligible participants were obtained through apheresis and transported to Geno-Immune Medical Institute, Shenzhen, China, where the CAR-T product was manufactured.…”

Section: Manufacture and Infusionmentioning

confidence: 99%

“…In the previous study of our center, it was found that compared with patients with low tumor burden, leukemia patients with higher tumor burden are less likely to achieve remission after 4SCAR19 infusion, and are accompanied by a higher probability of relapse/progression (18). Therefore, take the prognosis of patients into consideration, we administered bridging chemotherapy to seven patients with high tumor burden in this trial.…”

Section: Characteristic Of Patientsmentioning

confidence: 99%

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Phase I Trial of Fourth-Generation Anti-CD19 Chimeric Antigen Receptor T Cells Against Relapsed or Refractory B Cell Non-Hodgkin Lymphomas

Zhou

Wang

et al. 2020

Front. Immunol.

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BackgroundThe administration of second- or third-generation anti-CD19 chimeric antigen receptor (CAR) T cells has remarkably improved the survival of patients with relapsed or refractory B cell malignancies. However, there are limited clinical results from fourth-generation CAR-T cell therapy, and the factors affecting response rate and survival have not been fully determined.MethodsLymphoma patients with progression or relapse after intensive treatments, including hematopoietic stem cell transplantation, and life expectancy >2 months were enrolled in the study. Peripheral lymphocytes were collected through apheresis, and magnetically selected T cells were lentivirally transduced with a 4th-generation CAR featuring an anti-CD19 CAR and the iCasp9 suicide switch (4SCAR19). The patients received 4SCAR19 T cell infusion after approximately seven days of expansion and a conditioning regimen comprising cyclophosphamide/fludarabine. The efficacy, safety, and risk factors were evaluated.ResultsA total of 21 patients with relapsed/refractory B cell non-Hodgkin lymphoma were enrolled and received 4SCAR19 T cell infusions at a median dose of 8.9×105 CAR-T cells/kg. The overall response rate was 67% [95% confidence interval (CI), 43 to 85], with 43% of patients achieving a complete response and 24% having a partial response. The overall and complete response rates were 58 and 33% in the diffuse large B-cell lymphoma (DLBCL) group and 78 and 56% in the non-DLBCL group, respectively. The median overall survival was 23.8 months (95% CI, not reached), with a median follow-up of 13.7 months. Factors affecting overall survival were International Prognostic Index (IPI), disease type, and remission status after CAR-T cell treatment. The most common adverse events of grade 3 or 4 during treatment were neutropenia (76%), leukopenia (71%), and thrombocytopenia (29%). The incidence of cytokine release syndrome (CRS) was 14%, and all cases were grade 1. One patient developed grade 3 neurotoxicity. No deaths were attributed to infusion of 4SCAR19 T cells, CRS, or neurotoxicity.ConclusionsIn this study, patients with relapsed or refractory B cell non-Hodgkin’s lymphoma who received 4SCAR19 T cell therapy had durable responses and few of adverse events. The IPI model is suitable for evaluating the prognosis of patients receiving CAR-T cell therapy.Trial registrationChinese Clinical Trial Registry (http://www.chictr.org.cn): ChiCTR-OOC-16007779.

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Section: Discussionsupporting

confidence: 63%

Section: Manufacture and Infusionmentioning

confidence: 99%

Section: Characteristic Of Patientsmentioning

confidence: 99%

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Phase I Trial of Fourth-Generation Anti-CD19 Chimeric Antigen Receptor T Cells Against Relapsed or Refractory B Cell Non-Hodgkin Lymphomas

Zhou

Wang

et al. 2020

Front. Immunol.

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“…Age, performance status, previous allogeneic hematopoietic stem cell transplantation (HSCT) or blinatumomab treatment and the dose of infused CAR T cells did not show any significant effects on long-term survival [23,35]. However, in a clinical trial carried out in our department, we found that elderly patients were at an increased risk of disease relapse or progression, which requires a further study to confirm the relation between age and relapse risk [37].…”

Section: Predictive Factors For Positive Relapse In Clinical Practicementioning

confidence: 61%

Mechanisms underlying CD19-positive ALL relapse after anti-CD19 CAR T cell therapy and associated strategies

Nie

Chen

et al. 2020

Biomark Res

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Chimeric antigen receptor (CAR) T cell therapy, especially anti-CD19 CAR T cell therapy, has shown remarkable anticancer activity in patients with relapsed/refractory acute lymphoblastic leukemia, demonstrating an inspiring complete remission rate. However, with extension of the follow-up period, the limitations of this therapy have gradually emerged. Patients are at a high risk of early relapse after achieving complete remission. Although there are many studies with a primary focus on the mechanisms underlying CD19relapse related to immune escape, early CD19 + relapse owing to poor in vivo persistence and impaired efficacy accounts for a larger proportion of the high relapse rate. However, the mechanisms underlying CD19 + relapse are still poorly understood. Herein, we discuss factors that could become obstacles to improved persistence and efficacy of CAR T cells during production, preinfusion processing, and in vivo interactions in detail. Furthermore, we propose potential strategies to overcome these barriers to achieve a reduced CD19 + relapse rate and produce prolonged survival in patients after CAR T cell therapy.

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“…4SCAR T-cells can be depleted when uncontrollable toxicity is observed following CAR T-cell infusion. The details of the CART manufacturing process are as previously described (17). The safety and efficacy of 4SCAR T-cells have been demonstrated in patients with highly resistant B-cell lymphoma (18, 19).…”

Section: Introductionmentioning

confidence: 99%

CD19 and CD70 Dual-Target Chimeric Antigen Receptor T-Cell Therapy for the Treatment of Relapsed and Refractory Primary Central Nervous System Diffuse Large B-Cell Lymphoma

Zhou

Guo

et al. 2019

Front. Oncol.

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Background: The therapeutic efficacy of chimeric antigen receptor (CAR) T-cells targeting CD19 has been illustrated in the treatment of diffuse large B-cell lymphoma (DLBCL). However, there is a 21–35% relapse rate after anti-CD19 CAR T-cell induced remission. In addition, CAR T-cell therapy has severe adverse reactions, such as cytokine release syndrome (CRS) and CART-related encephalopathy syndrome (CRES). Because of the potential mortality associated with severe CRES, patients with primary central nervous system lymphoma (PCNSL) are usually excluded from clinical trials involving CAR T-cell therapy. Here, we report a case of refractory and relapsed primary central nervous system diffuse large B-cell lymphoma (PCNS-DLBCL).Case Presentation: The patient is a 67-year-old male who was diagnosed with PCNSL in 2011. He achieved complete remission (CR) after receiving 6 cycles of temozolomide and high-dose methotrexate. In December 2016, he experienced his first relapse and was treated with surgery and multicourse chemotherapy. He achieved CR again after the treatment. However, he experienced a second relapse in August 2017. MRI revealed a residual mass of 26 mm*35 mm*30 mm on the right side of the post-operative cavity and stale hemorrhage in the left basal ganglia. After confirming the expression of CD19 and CD70 in his tumor samples, the patient was given lymphodepletion chemotherapy followed by infusion of 4th generation CD19-CAR T-cells (4SCART19) and 4th generation CD70-CAR T-cells (4SCART70). One month later, the patient had symptomatic improvement, and brain MRI showed CR. Both CART19 and CART70 cells were detected in the 10th month after CAR T-cell infusion. Notably, neither CRS nor CRES occurred during treatment and follow-up. To date, the patient has maintained disease-free survival with more than 17 months of follow-up.Conclusions: The results of this study indicate that combination of CD19- and CD70-specific CAR T-cells may effectively target PCNSL and maintain disease-free survival without inducing CRS or CRES. Therefore, central nervous system lymphoma is not an absolute contraindication for dual-target CAR T-cell therapy.

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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

Cited by 15 publications

References 10 publications

Phase I Trial of Fourth-Generation Anti-CD19 Chimeric Antigen Receptor T Cells Against Relapsed or Refractory B Cell Non-Hodgkin Lymphomas

Phase I Trial of Fourth-Generation Anti-CD19 Chimeric Antigen Receptor T Cells Against Relapsed or Refractory B Cell Non-Hodgkin Lymphomas

Mechanisms underlying CD19-positive ALL relapse after anti-CD19 CAR T cell therapy and associated strategies

CD19 and CD70 Dual-Target Chimeric Antigen Receptor T-Cell Therapy for the Treatment of Relapsed and Refractory Primary Central Nervous System Diffuse Large B-Cell Lymphoma

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