Factors associated with durable EFS in adult B-cell ALL patients achieving MRD-negative CR after CD19 CAR T-cell therapy

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Baseline platelet count, lactate dehydrogenase, and lymphodepletion regimen impact EFS in patients in MRD-negative CR after CD19 CAR T-cell. Allogeneic HCT after CD19 CAR T-cell therapy is well tolerated and may improve EFS.

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Most cited references 14

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CD22-CAR T Cells Induce Remissions in CD19-CAR Naïve and Resistant B-ALL

Terry Fry, Nirali Shah, Rimas Orentas … (2017)

Chimeric antigen receptor (CAR) T-cells targeting CD19 mediate potent effects in relapsed/refractory pre-B cell acute lymphoblastic leukemia (B-ALL) but antigen loss is a frequent cause of resistance to CD19-targeted immunotherapy. CD22 is also expressed on most B-ALL and usually retained following CD19 loss. We report results from a phase I trial testing a novel CD22-CAR in twenty-one children and adults, including 17 previously treated with CD19-directed immunotherapy. Dose dependent anti-leukemic activity was observed with complete remission in 73% (11/15) of patients receiving ≥ 1 × 106 CD22-CART cells/kg, including 5/5 patients with CD19dim/neg B-ALL. Median remission duration was 6 months. Relapses were associated with diminished CD22 site density that likely permitted escape from killing by CD22-CART cells. These results are the first to eastablish the clinical activity of a CD22-CAR in pre-B cell ALL, including in leukemia resistant to anti-CD19 immunotherapy, demonstrating comparable potency to CD19-CART at biologically active doses in B-ALL. They also highlight the critical role played by antigen density in regulating CAR function. (Funded by NCI Intramural Research Program)

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Intent to treat leukemia remission by CD19CAR T cells of defined formulation and dose in children and young adults

Catherine Lindgren, Assaf P. Oron, Daniel Li … (2017)

Publisher's Note: There is an [Related article:] Inside Blood Commentary on this article in this issue. Defined-composition manufacturing platform of CD19 CAR T cells contributes to >90% intent-to-treat complete remission rate. Uniformity of durable persistence of CAR T cells and mitigation of antigen escape are key aspects for further optimization. Transitioning CD19-directed chimeric antigen receptor (CAR) T cells from early-phase trials in relapsed patients to a viable therapeutic approach with predictable efficacy and low toxicity for broad application among patients with high unmet need is currently complicated by product heterogeneity resulting from transduction of undefined T-cell mixtures, variability of transgene expression, and terminal differentiation of cells at the end of culture. A phase 1 trial of 45 children and young adults with relapsed or refractory B-lineage acute lymphoblastic leukemia was conducted using a CD19 CAR product of defined CD4/CD8 composition, uniform CAR expression, and limited effector differentiation. Products meeting all defined specifications occurred in 93% of enrolled patients. The maximum tolerated dose was 10 6 CAR T cells per kg, and there were no deaths or instances of cerebral edema attributable to product toxicity. The overall intent-to-treat minimal residual disease–negative (MRD − ) remission rate for this phase 1 study was 89%. The MRD − remission rate was 93% in patients who received a CAR T-cell product and 100% in the subset of patients who received fludarabine and cyclophosphamide lymphodepletion. Twenty-three percent of patients developed reversible severe cytokine release syndrome and/or reversible severe neurotoxicity. These data demonstrate that manufacturing a defined-composition CD19 CAR T cell identifies an optimal cell dose with highly potent antitumor activity and a tolerable adverse effect profile in a cohort of patients with an otherwise poor prognosis. This trial was registered at www.clinicaltrials.gov as #NCT02028455.

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A transgene-encoded cell surface polypeptide for selection, in vivo tracking, and ablation of engineered cells.

Xiuli Wang, Wen-Chung Chang, ChingLam W Wong … (2011)

An unmet need in cell engineering is the availability of a single transgene encoded, functionally inert, human polypeptide that can serve multiple purposes, including ex vivo cell selection, in vivo cell tracking, and as a target for in vivo cell ablation. Here we describe a truncated human EGFR polypeptide (huEGFRt) that is devoid of extracellular N-terminal ligand binding domains and intracellular receptor tyrosine kinase activity but retains the native amino acid sequence, type I transmembrane cell surface localization, and a conformationally intact binding epitope for pharmaceutical-grade anti-EGFR monoclonal antibody, cetuximab (Erbitux). After lentiviral transduction of human T cells with vectors that coordinately express tumor-specific chimeric antigen receptors and huEGFRt, we show that huEGFRt serves as a highly efficient selection epitope for chimeric antigen receptor(+) T cells using biotinylated cetuximab in conjunction with current good manufacturing practices (cGMP)-grade anti-biotin immunomagnetic microbeads. Moreover, huEGFRt provides a cell surface marker for in vivo tracking of adoptively transferred T cells using both flow cytometry and immunohistochemistry, and a target for cetuximab-mediated antibody-dependent cellular cytotoxicity and in vivo elimination. The versatility of huEGFRt and the availability of pharmaceutical-grade reagents for its clinical application denote huEGFRt as a significant new tool for cellular engineering.

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Author and article information

Journal

Title: Blood

Publisher: American Society of Hematology

ISSN (Print): 0006-4971

ISSN (Electronic): 1528-0020

Publication date Created: April 11 2019

Publication date (Print): April 11 2019

Volume: 133

Issue: 15

Pages: 1652-1663

Affiliations

[1 ]Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA;

[2 ]Department of Medicine, University of British Columbia, Vancouver, BC, Canada;

[3 ]Juno Therapeutics, Seattle, WA; and

[4 ]Department of Laboratory Medicine and

[5 ]Department of Medicine, University of Washington, Seattle, WA

Article

DOI: 10.1182/blood-2018-11-883710

PMC ID: 6460418

PubMed ID: 30728140

SO-VID: 90004cd0-de84-4639-8f17-0ad44277f847

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Factors associated with durable EFS in adult B-cell ALL patients achieving MRD-negative CR after CD19 CAR T-cell therapy

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CRISPR/Cas9 editing in human blood

Most cited references 14

CD22-CAR T Cells Induce Remissions in CD19-CAR Naïve and Resistant B-ALL

Intent to treat leukemia remission by CD19CAR T cells of defined formulation and dose in children and young adults

A transgene-encoded cell surface polypeptide for selection, in vivo tracking, and ablation of engineered cells.

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Cited by 147

Most referenced authors 867