Target selection for CAR-T therapy

Wei, Jianshu; Xiao, Han; Jiang, Bo; Han, Weidong

doi:10.1186/s13045-019-0758-x

Cited by 145 publications

(122 citation statements)

References 60 publications

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“…Therefore, the application of CD22 CAR-T cells could be a promising treatment strategy. [32][33][34] Alternatively, CAR engineering could be used to enhance the affinity of the scFv activity against tumor cells with low antigen density. It indicates that by altering the affinity of EGFR and/or HER2 CARs, it is possible to recognize as low levels of antigens as expressed on a normal tissue.…”

Section: Discussionmentioning

confidence: 99%

Point mutation inCD19facilitates immune escape of B cell lymphoma from CAR-T cell therapy

Zhang

Chen

Tian

et al. 2020

J Immunother Cancer

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BackgroundTumor relapse due to mutation in CD19 can hinder the efficacy of chimeric antigen receptor (CAR)-T cell therapy. Herein, we focused on lymphoma patients whose B cells exhibited a point mutation in CD19 of B cells after CAR-T cell infusion.MethodsThe CAR-T and CD19+ B cells from peripheral blood or bone marrow were assessed using flow cytometry. Genome sequencing was conducted to identify the molecular characteristics of CAR-T and CD19+ B cells from pre-relapse and postrelapse samples. CD19 in CARs comprising single chain fragments variable (scFV) antibody with FMC63 or 21D4 was constructed. The cytotoxic efficacy of CAR-T cells was also evaluated via in vitro and in vivo experiments.ResultsA patient with high-grade B cell lymphoma exhibited complete response, but the lymphoma relapsed in her left breast at 6 months after CD19 CAR (FMC63)-T cell infusion. A mutation was found in exon 3 of CD19 (p.163. R-L) in malignant B cells of the patient. In two lymphoma patients who exhibited resistance to CAR-T cell therapy, a mutation was detected in exon 3 of CD19 (p.174. L-V). Functional analysis revealed that FMC63 CAR-T cells exhibited antitumor ability against wild-type CD19+ cells but were unable to eradicate these two types of mutated CD19+ cells. Interestingly, 21D4 CAR-T cells were potentially capable of eradicating these mutated CD19+ cells and exhibiting high antitumor capacity against CD19+ cells with loss of exon 1, 2, or 3.ConclusionsThese findings suggest that point mutation can facilitate immune escape from CAR-T cell therapy and that alternative CAR-T cells can effectively eradicate the mutated B cells, providing an individualized therapeutic approach for lymphoma patients showing relapse.

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Section: Discussionmentioning

confidence: 99%

Point mutation inCD19facilitates immune escape of B cell lymphoma from CAR-T cell therapy

Zhang

Chen

Tian

et al. 2020

J Immunother Cancer

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“…In addition, the adenine base editor reduces PD-1 by changing the glycosylated residue in CAR-T cells, which could be used to augment CAR-T therapy [107]. In terms of the structure of CAR, a PD-1-CD28 fusion receptor is able to switch original inhibitory signals into activation signal and enhance cytokine release, proliferation, and cytotoxicity of CAR-T cells [121].…”

Section: Strategies Focused On the Bm Microenvironmentmentioning

confidence: 99%

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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“…Furthermore, in a recent genome-wide CRISPR gene-editing study, BCMA was not found among more than 90 genes essential for MM (14). These are properties which do not fit with the description of the "ideal" target for immunotherapy (15,16).…”

Section: Bcma: the Ideal MM Car Target?mentioning

confidence: 92%

Dual Targeting to Overcome Current Challenges in Multiple Myeloma CAR T-Cell Treatment

2020

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In the era of highly promising novel targeted-immunotherapy strategies for multiple myeloma (MM), the first series of clinical trials with CAR T-cells targeting the plasma cell-specific B-cell maturation antigen (BCMA) have shown excellent response rates. In the long-term, however, MM appears to escape the therapy likely due to initial low and heterogeneous expression or downregulation of BCMA expression. Several other molecules targeted by CAR T-cells in MM are expressed at high levels on MM cells, but many of these attractive targets are also expressed on various, sometimes vital non-malignant cells, posing major risks for on-target, off-tumor side effects. CAR T-cell therapy for MM therefore faces two urgent challenges: (i) improving the efficacy of BCMA CAR T-cells and (ii) establishing a MM-selectivity even when CAR T-cells are directed against not entirely MM-specific target antigens. In this review, we will outline the current attempts to tackle these challenges, with a specific focus on how dual CAR targeting might be applied to tackle both issues.

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Target selection for CAR-T therapy

Cited by 145 publications

References 60 publications

Point mutation inCD19facilitates immune escape of B cell lymphoma from CAR-T cell therapy

Point mutation inCD19facilitates immune escape of B cell lymphoma from CAR-T cell therapy

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

Dual Targeting to Overcome Current Challenges in Multiple Myeloma CAR T-Cell Treatment

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