Characteristics of anti-CLL1 based CAR-T therapy for children with relapsed or refractory acute myeloid leukemia: the multi-center efficacy and safety interim analysis

Article

作者: Hu, Zhengbin ; He, Yingyi ; Li, Guangchao ; Zhou, Zhao ; Zheng, Yongwei ; Bu, Chaoke ; Ding, Wen ; Luo, Min ; Zhang, Hui ; Li, Chunfu ; Peng, Zhiyong ; Pei, Kunlin

C-type lectin-like molecule-1 (CLL1) is preferentially expressed on acute myeloid leukemia (AML) stem cells and AML blasts, which can be considered as AML-associated antigen. Anti-CLL1-based CAR-T cells exhibited effective tumor-killing capacity in vitro and in AML-bearing mouse model. In this report, eight children with relapsed or refractory AML (R/R-AML) were recruited for a phase 1/2 clinical trial of autologous anti-CLL1 CAR-T cell immunotherapy. The objectives of this clinical trial were to evaluate the safety and the preliminary efficacy of anti-CLL1 CAR-T cell treatment. Patients received one dose of autologous anti-CLL1 CAR-T cells after lymphodepletion conditioning. After CAR-T treatment, patients developed grade 1-2 cytokine release syndrome (CRS) but without any lethal events. 4 out of 8 patients achieved morphologic leukemia-free state (MLFS) and minimal residual disease (MRD) negativity, 1 patient with MLFS and MRD positivity, 1 patient achieved complete remission with incomplete hematologic recovery (CRi) but MRD positivity, 1 patient with partial remission (PR), and 1 patient remained at stable disease (SD) status but had CLL1-positive AML blast clearance. These results suggested that anti-CLL1-based CAR-T cell immunotherapy can be considered as a well-tolerated and effective option for treating children with R/R-AML.

2020-09-01·Toxicological Sciences2区 · 医学

Nonclinical Safety Assessment of AMG 553, an Investigational Chimeric Antigen Receptor T-Cell Therapy for the Treatment of Acute Myeloid Leukemia

2区 · 医学

Article

作者: Hensley, Kelly ; Yan, Qinghong ; Goldstein, Rebecca ; Li, Chi-Ming ; Brooks, Benjamin ; Hernandez, Rocio ; Frank, Brendon ; Lebrec, Herve ; Boyle, Michael ; Arvedson, Tara ; Adams, Gregor ; Karbowski, Christine ; Homann, Oliver ; Wang, Xiaoting ; Kim, Kei

AbstractFeline McDonough Sarcoma-like tyrosine kinase 3 (FLT3), a tyrosine-protein kinase involved in hematopoiesis, is detectable on the cell surface of approximately 80% of leukemia isolates from adult patients with acute myeloid leukemia (AML). AMG 553 is an investigational chimeric antigen receptor (CAR) T-cell immunotherapy for the treatment of AML. FLT3 expression analysis and in vitro and in vivo studies were leveraged to evaluate the nonclinical safety of AMG 553. Cynomolgus monkeys administered autologous anti-FLT3 CAR T cells demonstrated no evidence of CAR T-cell-mediated toxicity, expansion, or persistence, likely due to restricted cell surface FLT3 protein expression in healthy animals. This highlights the limited value of such in vivo studies for safety assessment of the CAR T-cell modality when directed against a target with restricted expression. To complement these studies and directly evaluate the potential toxicities of eliciting T-cell-mediated cytotoxicity against cells with surface expression of FLT3 protein in vivo, data from cynomolgus monkey toxicology studies with 2 bispecific T-cell engager molecules targeting FLT3 were leveraged; findings were consistent with the targeted killing of bone marrow cells expressing cell surface FLT3. Potential AMG 553-induced cytotoxicity was assessed against a wide range of normal human primary cells and cell lines; cytotoxicity was observed against FLT3-positive AML cell lines and a percentage of primary bone marrow CD34+ cells. In conclusion, the nonclinical safety data suggest that AMG 553 can target FLT3 protein on AML cells, whereas only affecting a percentage of normal hematopoietic stem and progenitor cells, supporting clinical development.

Nature Medicine

Cytokine-mediated CAR T therapy resistance in AML

Article

作者: Fisher, Han R. ; Loken, Michael R ; Farooki, Saamia N. ; Hexner, Elizabeth O ; Frost, Benjamin F ; Loren, Alison W. ; Perl, Alexander E ; Porter, David L. ; McCurdy, Shannon R ; Fisher, Han R ; Luger, Selina M ; Rogal, Walter ; Gaymon, Avery L. ; Fraietta, Joseph A. ; Loren, Alison W ; Fraietta, Joseph A ; June, Carl H ; Aplenc, Richard ; Mellors, Patrick W. ; Hwang, Wei-Ting ; Brogdon, Jennifer L ; Mellors, Patrick W ; Perl, Alexander E. ; Gaymon, Avery L ; Gill, Saar I ; Brogdon, Jennifer L. ; Loken, Michael R. ; Luger, Selina M. ; Siegel, Don L. ; Bhagwat, Anand S ; Bhagwat, Anand S. ; McCurdy, Shannon R. ; Stadtmauer, Edward A. ; Frey, Noelle ; Torres, Leonel ; Farooki, Saamia N ; Stadtmauer, Edward A ; Hexner, Elizabeth O. ; Siegel, Don L ; Porter, David L ; Shestova, Olga ; Frazee, Diane ; Frost, Benjamin F. ; Martin, Mary Ellen ; June, Carl H. ; Shestov, Maksim ; Gill, Saar I. ; Plesa, Gabriela

Acute myeloid leukemia (AML) is a rapidly progressive malignancy without effective therapies for refractory disease. So far, chimeric antigen receptor (CAR) T cell therapy in AML has not recapitulated the efficacy seen in B cell malignancies. Here we report a pilot study of autologous anti-CD123 CAR T cells in 12 adults with relapsed or refractory AML. CAR T cells targeting CD123⁺ cells were successfully manufactured in 90.4% of runs. Cytokine release syndrome was observed in 10 of 12 infused individuals (83.3%, 90% confidence interval 0.5-0.97). Three individuals achieved clinical response (25%, 90% confidence interval 0.07-0.53). We found that myeloid-supporting cytokines are secreted during cell therapy and support AML blast survival via kinase signaling, leading to CAR T cell exhaustion. The prosurvival effect of therapy-induced cytokines presents a unique resistance mechanism in AML that is distinct from any observed in B cell malignancies. Our findings suggest that autologous CART manufacturing is feasible in AML, but treatment is associated with high rates of cytokine release syndrome and relatively poor clinical efficacy. Combining CAR T cell therapies with cytokine signaling inhibitors could enhance immunotherapy efficacy in AML and achieve improved outcomes (ClinicalTrials.gov identifier: NCT03766126 ).

100 项与 Autologous EGFR-CAR T cells(Sun Yat-Sen University) 相关的药物交易

登录后查看更多信息