Immune recovery in patients with mantle cell lymphoma receiving long-term ibrutinib and venetoclax combination therapy

Davis, Joanne E.; Handunnetti, Sasanka; Ludford-Menting, Mandy; Sharpe, Chia; Blombery, Piers; Anderson, Mary Ann; Roberts, Andrew W.; Seymour, John F.; Tam, Constantine S.; Ritchie, David; Koldej, Rachel

doi:10.1182/bloodadvances.2020002810

Cited by 15 publications

(8 citation statements)

References 48 publications

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“…In the study published on the long-term follow-up (median 26.7 months) of the phase-two registration trial of ibrutinib in this setting, the most frequent infections were observed in the upper respiratory and urinary tracts. The majority of infections were self-limiting, not supported by opportunistic pathogens and, above all, reduced over time [ 104 ]. Therefore, despite the progressive immunological dysfunction in CLL and MCL from initial diagnosis to a relapsed or refractory state, aggravated by chemotherapy, ibrutinib can improve the immune response over time in both diseases ( Table 1 ).…”

Section: Effects Of Targeted Therapy On Immune Functionsmentioning

confidence: 99%

Effects of B-Cell Lymphoma on the Immune System and Immune Recovery after Treatment: The Paradigm of Targeted Therapy

Mancuso

Mattana

Carlisi

et al. 2022

IJMS

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B-cell lymphoma and lymphoproliferative diseases represent a heterogeneous and complex group of neoplasms that are accompanied by a broad range of immune regulatory disorder phenotypes. Clinical features of autoimmunity, hyperinflammation, immunodeficiency and infection can variously dominate, depending on the immune pathway most involved. Immunological imbalance can play a role in lymphomagenesis, also supporting the progression of the disease, while on the other hand, lymphoma acts on the immune system to weaken immunosurveillance and facilitate immunoevasion. Therefore, the modulation of immunity can have a profound effect on disease progression or resolution, which makes the immune system a critical target for new therapies. In the current therapeutic scenario enriched by chemo-free regimens, it is important to establish the effect of various drugs on the disease, as well as on the restoration of immune functions. In fact, treatment of B-cell lymphoma with passive immunotherapy that targets tumor cells or targets the tumor microenvironment, together with adoptive immunotherapy, is becoming more frequent. The aim of this review is to report relevant data on the evolution of the immune system during and after treatment with targeted therapy of B-cell lymphomas.

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Section: Effects Of Targeted Therapy On Immune Functionsmentioning

confidence: 99%

Effects of B-Cell Lymphoma on the Immune System and Immune Recovery after Treatment: The Paradigm of Targeted Therapy

Mancuso

Mattana

Carlisi

et al. 2022

IJMS

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“…In recent studies, ICIs have demonstrated encouraging results when combined with hypomethylating agents (HMAs) in relapsed/refractory AML patients, particularly for those who were not exposed to HMA treatment, but most of the other clinical trials did not achieve a satisfactory response when using ICIs alone (15)(16)(17)(18)(19). One of the reasons for this discrepancy may be that the patients involved in those trials often experienced failure with multiple lines of conventional therapy, which could have a long-term impact on immunological fitness and clinical responses (20,21). Therefore, comparing the immune status of T cells in AML patients before and after chemotherapy may help determine which type of patient could benefit from novel immune therapies.…”

Section: Introductionmentioning

confidence: 99%

PD-1 and TIGIT Are Highly Co-Expressed on CD8+ T Cells in AML Patient Bone Marrow

Xu¹,

Yao²,

Zeng³

et al. 2021

Front. Oncol.

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Despite the great success of immune-checkpoint inhibitor (ICI) treatment for multiple cancers, evidence for the clinical use of ICIs in acute myeloid leukemia (AML) remains inadequate. Further exploration of the causes of immune evasion in the bone marrow (BM) environment, the primary leukemia site, and peripheral blood (PB) and understanding how T cells are affected by AML induction chemotherapy or the influence of age may help to select patients who may benefit from ICI treatment. In this study, we comprehensively compared the distribution of PD-1 and TIGIT, two of the most well-studied IC proteins, in PB and BM T cells from AML patients at the stages of initial diagnosis, complete remission (CR), and relapse-refractory (R/R) disease after chemotherapy. Our results show that PD-1 was generally expressed higher in PB and BM T cells from de novo (DN) and R/R patients, while it was partially recovered in CR patients. The expression of TIGIT was increased in the BM of CD8+ T cells from DN and R/R patients, but it did not recover with CR. In addition, according to age correlation analysis, we found that elderly AML patients possess an even higher percentage of PD-1 and TIGIT single-positive CD8+ T cells in PB and BM, which indicate greater impairment of T cell function in elderly patients. In addition, we found that both DN and R/R patients accumulate a higher frequency of PD-1+ and TIGIT+ CD8+ T cells in BM than in corresponding PB, indicating that a more immunosuppressive microenvironment in leukemia BM may promote disease progression. Collectively, our study may help guide the combined use of anti-PD-1 and anti-TIGIT antibodies for treating elderly AML patients and pave the way for the exploration of strategies for reviving the immunosuppressive BM microenvironment to improve the survival of AML patients.

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“…More recently it has been reported that long-term treatment with ibrutinib significantly restored T-cell proliferative ability, degranulation, and cytokine secretion in peripheral blood samples from patients with CLL [ 24 ]. We have also demonstrated that long-term exposure to ibrutinib in vivo may return the T cell function of patients with advanced mantle cell lymphoma (MCL) to that of healthy donors [ 25 ]. Overall, this improved T cell fitness following ibrutinib therapy may in turn be able to be exploited to improve the generation and efficacy of subsequent adoptive CAR-T cell therapy in CLL [ 26 ] or other B cell malignancies including MCL [ 27 ].…”

Section: Introductionmentioning

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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Immune recovery in patients with mantle cell lymphoma receiving long-term ibrutinib and venetoclax combination therapy

Cited by 15 publications

References 48 publications

Effects of B-Cell Lymphoma on the Immune System and Immune Recovery after Treatment: The Paradigm of Targeted Therapy

Effects of B-Cell Lymphoma on the Immune System and Immune Recovery after Treatment: The Paradigm of Targeted Therapy

PD-1 and TIGIT Are Highly Co-Expressed on CD8+ T Cells in AML Patient Bone Marrow

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

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