Ibrutinib for improved chimeric antigen receptor T‐cell production for chronic lymphocytic leukemia patients

Fan, Fuli; Yoo, Hyeon Joo; Stock, Sophia; Wang, Lei; Liu, Yibin; Schubert, Maria‐Luisa; Wang, Sanmei; Neuber, Brigitte; Hückelhoven‐Krauss, Angela; Gern, Ulrike; Schmitt, Anita; Müller‐Tidow, Carsten; Dreger, Peter; Schmitt, Michael; Sellner, Leopold

doi:10.1002/ijc.33212

Cited by 53 publications

(53 citation statements)

References 54 publications

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“…3 ). In this sense the less specific effects of ibrutinib are important for the observed T cell effects and may underpin the recent findings that ibrutinib improves the production of CAR-T cellsin patients with CLL previously treated with ibrutinib [ 26 ] and that ibrutinib supplementation during CAR-T production results in a greater cell yield with a more naïve-like phenotype and decreased expression of exhaustion markers [ 33 ]. Indeed, based on these findings a number of trials have been initiated utilising BTKi in combination with CAR-T administration in MCL (NCT04234061) and CLL (NCT03960840).…”

Section: Discussionmentioning

confidence: 99%

Ibrutinib protects T cells in patients with CLL from proliferation-induced senescence

et al. 2021

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Background The development of Bruton’s tyrosine kinase inhibitors (BTKi) for the treatment of chronic lymphocytic leukaemia (CLL) has provided a highly effective and relatively non-toxic alternative to conventional chemotherapy. Some studies have shown that BTKi can also lead to improvements in T cell immunity in patients despite in vitro analyses suggesting an immunosuppressive effect of BTKi on T cell function. Methods In this study, we examined both the in vitro effect and long-term in vivo effect of two clinically available BTKi, ibrutinib and zanubrutinib. Additional in vitro assessments were undertaken for a third BTKi, acalabrutinib. Immune subset phenotyping, cytokine secretion, T cell degranulation and proliferation assays were performed on peripheral blood mononuclear cells isolated from untreated CLL patients, and CLL patients on long-term (> 12 months) BTKi treatment. Results Similar to prior studies we observed that long-term BTKi treatment normalises lymphocyte subset frequency and reduces PD-1 expression on T cells. We also observed that T cells from patients taken prior to BTKi therapy showed an abnormal hyper-proliferation pattern typical of senescent T cells, which was normalised by long-term BTKi treatment. Furthermore, BTKi therapy resulted in reduced expression of the T cell exhaustion markers PD-1, TIM3 and LAG3 in late generations of T cells undergoing proliferation. Conclusions Collectively, these findings indicate that there are critical differences between the in vitro effects of BTKi on T cell function and the effects derived from long-term BTKi exposure in vivo. Overall long-term exposure to BTKi, and particularly ibrutinib, resulted in improved T cell fitness in part due to suppressing the abnormal hyper-proliferation of CLL T cells and the associated development of T cell senescence.

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Section: Discussionmentioning

confidence: 99%

Ibrutinib protects T cells in patients with CLL from proliferation-induced senescence

et al. 2021

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“…Ibrutinib decreased the expression of the immune checkpoint molecules PD-1 and CTLA-4 by CLL cells in vivo (Long et al, 2017). Ibrutinib was also shown to be effective in improving the yield and development of CAR-T cells in CLL patient samples, which has remained difficult compared with other B cell malignancies treated with CAR-T cells (Fan et al, 2021). All of these studies highlight the potential of ITK inhibition as a novel immunotherapeutic approach to cancer treatment.…”

Section: A Novel Immunotherapeutic Approachmentioning

confidence: 96%

Targeting ITK signaling for T cell-mediated diseases

2021

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The focus of this review is to examine the role of ITK signaling in multiple diseases and investigate the clinical potential of ITK inhibition. The diseases and potential interventions reviewed include T cell-derived malignancies as well as other neoplastic diseases, allergic diseases such as asthma and atopic dermatitis, certain infectious diseases, several autoimmune disorders such as rheumatoid arthritis and psoriasis, and finally the use of ITK inhibition in both solid organ and bone marrow transplantation recipients.

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“…CART cell generation with the showing of ibrutinib created enhanced cell viability and expansion of CLL patientderived CART cells. And ibrutinib enriched the mentioned cells with the less-differentiated naïve-like phenotype and declined expression of exhaustion markers (PD-1, TIM-3, and LAG-3) (35).…”

Section: Disscusionmentioning

confidence: 99%

Super-Enhancer Associated Nine-gene Prognostic Score Model for Prediction of Survival in Chronic Lymphoic Leukemia Patients

Liang

Yang

et al. 2021

Preprint

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BackgroundChronic lymphocytic leukemia (CLL) is a group of highly heterogeneous mature B cell malignancy with various disease courses and diagnoses. Super-enhancer(SE) is a novel concept drew in recent years which is a cluster of enhancers involved in cell differentiation and tumorigenesis ,and is one of the promising therapeutic targets for cancer therapy. Although there is a multitude of prognostic markers in CLL, insights into the role of super-enhancer(SE)-related risk indicators are still lacking.MethodsThe CLL-related super-enhancers in training database were processed by Lasso penalized Cox regression analysis to screen a nine-gene prognostic model. And the associations between all of the individual markers and OS of CLL were assessed by Cox regression analysis. Besides, in order to understand the connection between individual genes and selected disease characteristics, like IGHV mutation status, FISH abnormality, and ZAP70 expression level, we performed correlation analysis.ResultsA nine-gene prognostic model was screened, including TCF7, VEGFA, MNT, GMIP, SLAMF1, TNFRSF25, GRWD1, SLC6AC, and LAG3. A SE-related risk score was further constructed and the robust predictive performance with 5-year survival and time-to-treatment (TTT) area under the curve(AUC): 0.997 and 1.000 in the training database and 0.628 and 0.673 in the testing database, respectively. Besides, a high correlation was found between the risk score and known prognostic markers of CLL, including the mutational status of immunoglobulin variable region loci (IGHV), chromosomal abnormalities, and ZAP70 expression. Meantime, we noticed that the expression of TCF7, GMIP, SLAMF1, TNFRSF25, and LAG3 in CLL were different from healthy donors(P<0.01), moreover, the risk score and LAG3 level of matched pairs before and after treatment samples varied significantly, although these results were not completely consistent in different datasets. ConclusionTherefore, the SE-associated nine-gene prognostic model developed here may be used to predict the prognosis and assist in the risk stratification of CLL patients in the future.

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Ibrutinib for improved chimeric antigen receptor T‐cell production for chronic lymphocytic leukemia patients

Cited by 53 publications

References 54 publications

Ibrutinib protects T cells in patients with CLL from proliferation-induced senescence

Ibrutinib protects T cells in patients with CLL from proliferation-induced senescence

Targeting ITK signaling for T cell-mediated diseases

Super-Enhancer Associated Nine-gene Prognostic Score Model for Prediction of Survival in Chronic Lymphoic Leukemia Patients

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