CAR T-cells for T-cell malignancies: challenges in distinguishing between therapeutic, normal, and neoplastic T-cells

Alcantara, Marion; Tesio, Melania; June, Carl H.; Houot, Roch

doi:10.1038/s41375-018-0285-8

Cited by 108 publications

(108 citation statements)

References 73 publications

(10 reference statements)

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“…The percent lysis values observed for K562 cells were more than two times higher compared to NK-92 cells at 25:1 to 100:1 effector:target ratios. The results in Figure 2 demonstrate that NK-92 are in fact susceptible to NK cell mediated lysis, which might well explain the rather weak outcome of the "first-in-man clinical trial" conducted by Tang et al with CD33-CAR NK-92 cells, as well as the findings that CAR-T-cells in general seem to be superior to CAR NK-92 cells (7,16). The human NK-like leukemia cell line YT, another potential cell line for adoptive immunotherapies, was not sensitive at all (Figure 2), an observation that now makes the YT cell line more attractive for adoptive immunotherapies compared to NK-92 cells.…”

Section: Discussionmentioning

confidence: 88%

Human NK-92 Cells Function as Target Cells for Human NK Cells – Implications for CAR NK-92 Therapies

et al. 2020

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Background/Aim: Recent studies indicate that chimeric antigen receptor (CAR)-T-cells seem to be superior to CAR modified NK-92 cells. One, at least partial, explanation to this discrepancy has been addressed herein, by having NK-92 cells as target cells in cytotoxicity reactions using peripheral blood mononuclear cells. Materials and Methods: A time-resolved fluorometric assay (TDA-labeled NK-92 or K562 as target cells) was used for measuring the cytotoxic activity of blood mononuclear cells (PBMC). Results: The cytotoxic capacity of the NK-92 cells was initially demonstrated by their ability to efficiently kill K562 cells. Interestingly, having PBMC as effector cells rendered the very same NK-92 cells sensitive to NK-cell mediated cytolysis. A 1:100 target:effector ratio gave 34.1% lysis compared to 72.2% lysis for K562 cells. Incubating PBMC for longer times (24 up to 48 h) potentiated their NK-activity against NK-92 cells even more, reaching a level close to that obtained with K562 cells. Conclusion: This study pinpoints a severe problem that has to be considered in future immune-based cancer therapies with NK-92 as well as CAR-transduced NK-92 cells.

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Section: Discussionmentioning

confidence: 88%

Human NK-92 Cells Function as Target Cells for Human NK Cells – Implications for CAR NK-92 Therapies

et al. 2020

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“…We found only a few cases (8/117) reporting B-cell aplasia, not exactly matching the frequency described in available scientific evidence [17,29]. It may depend on the fact that B-cell aplasia is not properly considered as an adverse event, but rather as an expected one unless it became prolonged, leading to hypogammaglobulinemia; in addition, our findings could be due the appropriate use of immunoglobulin replace as supportive care for children with B-cell aplasia [30,31]. Moreover, recently, B-cell aplasia has been included as uncommon adverse drug reaction (frequency ranked ≥1/1000 to <1/100) in the last updated Summary of the Product Characteristics (SPC) of tisagenlecleucel (updated on 1 April 2020), likely suggesting a low frequency of occurrence or a challenging identification as adverse event.…”

Section: Discussionmentioning

confidence: 54%

Tisagenlecleucel in Children and Young Adults: Reverse Translational Research by Using Real-World Safety Data

et al. 2020

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Tisagenlecleucel has revolutionized the pharmacological approach of relapsed or refractory B-cell acute lymphoblastic leukaemialeukaemia in paediatrics. The safety profile of tisagenlecleucel still needs to be better defined. The aim of this study was a post-marketing evaluation of the safety of tisagenlecleucel through the analysis of the Eudravigilance database with focus on the paediatric population. From 2017 to 2020, one third of Individual Case Safety Reports referring to tisagenlecleucel (117/364) have been collected in paediatrics, on average nine year-old boys. Overall, 92% of the638 adverse events were serious and caused or prolonged hospitalisation. A total of 55 adverse events presented a fatal outcome, mainly due to progression of malignant neoplasm (N = 10; 18.2%), recurrence of acute lymphocytic leukaemia (N = 6; 10.9%) or occurrence of acute lymphocytic leukaemia (N = 5; 9.1%). Cytokine release syndrome was commonly reported after tisagenlecleucel infusion (54/638), followed by pyrexia (45/638) and hypotension (27/638). Only 18/638 events referred to neurotoxicity, none of them resulted in death. More than one third of cases (41/117) were suggestive of therapeutic failure. This first post-marketing analysis confirms pre-approval evidence of the safety profile of tisagenlecleucel in paediatrics. Since only a few years of marketing is available, further followed-up studies need to be performed to investigate longer-term safety of tisagenlecleucel.

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“…This problem can lead to the "autophase killing" of CAR-T cells, while CAR-T cells targeting normal T cells may lead to severe infection in patients. 434 Therefore, reducing the side effects of CAR-T cells in T-NHLs has become the focus of research. Moreover, using CRISPR/Cas9 gene-editing technology, generating CAR-T cells (also known as UCART7) that lack CD7 and TCR alpha-chain expression could target CD7 + T-cell malignancies and reduce mutual attacks between CAR-T cells.…”

Section: Car-t Therapy In Lymphomamentioning

confidence: 99%

Advances in targeted therapy for malignant lymphoma

Wang

Qin

Huo

et al. 2020

Sig Transduct Target Ther

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The incidence of lymphoma has gradually increased over previous decades, and it ranks among the ten most prevalent cancers worldwide. With the development of targeted therapeutic strategies, though a subset of lymphoma patients has become curable, the treatment of refractory and relapsed diseases remains challenging. Many efforts have been made to explore new targets and to develop corresponding therapies. In addition to novel antibodies targeting surface antigens and small molecular inhibitors targeting oncogenic signaling pathways and tumor suppressors, immune checkpoint inhibitors and chimeric antigen receptor T-cells have been rapidly developed to target the tumor microenvironment. Although these targeted agents have shown great success in treating lymphoma patients, adverse events should be noted. The selection of the most suitable candidates, optimal dosage, and effective combinations warrant further investigation. In this review, we systematically outlined the advances in targeted therapy for malignant lymphoma, providing a clinical rationale for mechanism-based lymphoma treatment in the era of precision medicine.Signal Transduction and Targeted Therapy (2020) 5:15; https://doi.

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CAR T-cells for T-cell malignancies: challenges in distinguishing between therapeutic, normal, and neoplastic T-cells

Cited by 108 publications

References 73 publications

Human NK-92 Cells Function as Target Cells for Human NK Cells – Implications for CAR NK-92 Therapies

Human NK-92 Cells Function as Target Cells for Human NK Cells – Implications for CAR NK-92 Therapies

Tisagenlecleucel in Children and Young Adults: Reverse Translational Research by Using Real-World Safety Data

Advances in targeted therapy for malignant lymphoma

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