Intent-to-treat leukemia remission by CD19 CAR T cells of defined formulation and dose in children and young adults

Gardner, Rebecca; Finney, Olivia; Annesley, Colleen; Brakke, Hannah; Summers, Corinne; Leger, Kasey J.; Bleakley, Marie; Brown, Christopher; Mgebroff, Stephanie; Kelly-Spratt, Karen S.; Hoglund, Virginia; Lindgren, Catherine; Oron, Assaf P.; Li, Daniel; Riddell, Stanley R.; Park, Julie R.; Jensen, Michael C.

doi:10.1182/blood-2017-02-769208

Cited by 883 publications

(1,014 citation statements)

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“…Another strategy is the use of inhibitory CARs (iCAR) consisting of an antigen recognition domain and the intracellular domain of an immune checkpoint molecule such as PD-1 or CTLA-4 [63]. Other groups have incorporated genes for targeted ablation of CAR T cells in the case of severe CRS such as herpes simplex virus thymidine kinase (HSVtk) for ablation using ganciclovir [64], inducible caspase 9 (iCasp9) for ablation using small-molecule AP1903 [65], or epidermal growth factor receptor (EGFR) for ablation using cetuximab [32].…”

Section: Discussionmentioning

confidence: 99%

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Cellular Immunotherapy in B-Cell Malignancy

Schwarzbich¹,

Witzens‐Harig²

2017

Oncol Res Treat

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In recent years, cellular immunotherapy in B-cell malignancies has been driven by adoptive transfer of genetically engineered T cells expressing chimeric antigen receptors (CARs). CARs consist of a single chain variable fragment (scFv) of a monoclonal antibody, a spacer domain, a transmembrane domain, an intracellular signaling domain, and additional costimulatory domains. The bulk of clinical data available is on CD19-targeting CAR T cells for the treatment of B-cell acute lymphocytic leukemia (B-ALL), chronic lymphocytic leukemia, and B-cell non-Hodgkin lymphoma. Results so far have been promising with impressive rates and depth of remission especially among B-ALL patients. However, CAR T-cell therapy is a complex multi-step process, and clinical trials so far differ profoundly in CAR construct used, gene transfer method, composition of the cellular product, lymphodepletion, and CAR T-cell dose used. Randomized trials will be needed to conclusively evaluate the implications of these differences. The treatment concept is associated with significant neurotoxicity and potentially lethal cytokine release syndrome, both of which require specific management. Improvements in CAR design may help to overcome toxicity, the effects of an immunosuppressive microenvironment, and tumor escape by development of antigen-negative clones. This review will explain the mechanism of action, summarize the clinical experience with this treatment modality so far, and explore future developments in the field.

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Section: Discussionmentioning

confidence: 99%

“…The largest datasets available are on pediatric and adult B-ALL. These patients generally respond very well: Deep and persisting remissions can be achieved in 70-93% of patients [31,32]. Those durable complete remissions (CRs) correlate with the persistence of CAR T cells and sustained B-cell depletion.…”

Section: Clinical Outcomes and Adverse Eventsmentioning

confidence: 99%

Cellular Immunotherapy in B-Cell Malignancy

Schwarzbich¹,

Witzens‐Harig²

2017

Oncol Res Treat

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“…1,15 However, in the recent report by Gardner et al, the median persistence of functional CD19 CAR T cells was only 3 months. 4 This study used a CAR T construct with a 41BB co-stimulatory domain and EGFR surface tag, and additionally the CAR product consisted of a defined CD4/CD8 composition in efforts to improve CAR activity. 16 While the investigators reported a CR rate of 93%, they noted 18 relapses among the 40 patients who achieved remission, with an estimated 1-year EFS of 40%.…”

Section: Current Challengesmentioning

confidence: 99%

“…5 Subsequent results in CLL have been heterogeneous; but in ALL and non-Hodgkin's lymphoma (NHL), high CR rates have been noted across trials utilizing second generation CARs. [1][2][3][4]12,14 However, the durability of response varies between studies, and has been difficult to determine since many patients subsequently proceeded to transplant. Additionally, a similar toxicity pattern of CRS and neurotoxicity has been noted across trials.…”

Section: Introductionmentioning

confidence: 99%

“…Response rates up to 90% have been reported for patients with refractory B-lineage acute lymphoblastic leukemia (ALL). [1][2][3][4] Much has been learned since the excitement of the first reported case using CAR T cell therapy for the successful treatment of a patient with multiply relapsed chronic lymphocytic leukemia (CLL). 5 Pre-clinical and clinical trials are underway in other malignancies, including multiple myeloma, acute myeloid leukemia, and solid tumors.…”

Section: Introductionmentioning

confidence: 99%

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Debate: Transplant is Still Necessary in the Era of Targeted Cellular Therapy for ALL

Kebriaei

2019

Clinical Lymphoma Myeloma and Leukemia

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Clinical Predictors of Neurotoxicity After Chimeric Antigen Receptor T-Cell Therapy

Rubin

Jarrah

et al. 2020

JAMA Neurol

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IMPORTANCE Chimeric antigen receptor (CAR) T-cell therapy for relapsed or refractory hematologic malignant neoplasm causes severe neurologic adverse events ranging from encephalopathy and aphasia to cerebral edema and death. The cause of neurotoxicity is incompletely understood, and its unpredictability is a reason for prolonged hospitalization after CAR T-cell infusion.OBJECTIVE To identify clinical and laboratory parameters predictive of neurotoxicity and to develop a prognostic score associated with its risk. DESIGN, SETTING, AND PARTICIPANTSThis single-center diagnostic/prognostic accuracy study was conducted at Brigham and Women's Hospital/Dana Farber Cancer Institute from April 2015 to February 2020. A consecutive sample of all patients undergoing CAR T-cell therapy with axicabtagene ciloleucel for relapsed or refractory lymphoma were assessed for inclusion (n = 213). Patients who had previously received CAR T cells or who were treated for mantle cell lymphoma were excluded (n = 9). Patients were followed up for a minimum of 30 days from the date of CAR T-cell infusion. MAIN OUTCOMES AND MEASURESThe primary outcomes were measures of performance (accuracy, sensitivity, specificity, area under the curve) of a diagnostic tool to predict the occurrence of CAR-associated neurotoxicity, as graded by the Common Terminology Criteria for Adverse Events criteria. RESULTSTwo hundred four patients (127 men [62.2%]; mean [SD] age, 60.0 [12.1] years) were included in the analysis, of which 126 (61.8%) comprised a derivation cohort and 78 (38.2%), an internal validation cohort. Seventy-three patients (57.9%) in the derivation cohort and 45 patients (57.7%) in the validation cohort experienced neurotoxicity. Clinical and laboratory values obtained early in admission were used to develop a multivariable score that can predict the subsequent development of neurotoxicity; when tested on an internal validation cohort, this score had an area under the curve of 74%, an accuracy of 77%, a sensitivity of 82%, and a specificity of 70% (positive:negative likelihood ratio, 2.71:0.26). CONCLUSIONS AND RELEVANCEThe score developed in this study may help predict which patients are likely to experience CAR T-cell-associated neurotoxicity. The score can be used for triaging and resource allocation and may allow a large proportion of patients to be discharged from the hospital early.

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Intent-to-treat leukemia remission by CD19 CAR T cells of defined formulation and dose in children and young adults

Abstract: Publisher's Note: There is an Inside Blood Commentary on this article in this issue.

Cited by 883 publications

References 20 publications

Cellular Immunotherapy in B-Cell Malignancy

Cellular Immunotherapy in B-Cell Malignancy

Debate: Transplant is Still Necessary in the Era of Targeted Cellular Therapy for ALL

Clinical Predictors of Neurotoxicity After Chimeric Antigen Receptor T-Cell Therapy

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