Circulating Extracellular Vesicles Induce Chimeric Antigen Receptor T Cell Dysfunction in Chronic Lymphocytic Leukemia (CLL)

Cox, Michelle J.; Lucien-Matteoni, Fabrice; Sakemura, Reona; Boysen, Justin C.; Kim, Young S.; Hansen, Michael J.; Roman, Claudia Manriquez; Tapper, Erin E.; Crotts, Sydney B.; Schick, Kendall J.; Hefazi, Mehrdad; Horvei, Paulina; Ruff, Michael W.; Kay, Neil E.; Kenderian, Saad S.

doi:10.1016/j.bbmt.2019.12.137

Cited by 5 publications

(6 citation statements)

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“…This exhaustion phenotype has been described more frequently in T cells located in secondary lymphoid organs than in those circulating in peripheral blood (33). In addition, extracellular vesicles secreted by CLL cells induce phenotypic, functional and transcriptional dysfunction in chimeric antigen receptor (CAR) T cells, leading to their exhaustion (117). Moreover, the exhausted CD8 + T cells in patients with CLL express high levels of inhibitory molecules such as CD160, PD-1 and TIGIT (91).…”

Section: Cd160 Expression In the Cll Tumor Microenvironmentmentioning

confidence: 99%

CD160 receptor in CLL: Current state and future avenues

et al. 2022

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CD160 is a glycosylphosphatidylinositol (GPI)-anchored cell surface glycoprotein expressed on cytotoxic natural killer (NK) cells and T-cell subsets. It plays a crucial role in the activation of NK-cell cytotoxicity and cytokine production. It also modulates the immune system and is involved in some pathologies, such as cancer. CD160 is abnormally expressed in B-cell chronic lymphocytic leukemia (CLL) but not expressed in normal B lymphocytes. Its expression in CLL enhances tumor cell proliferation and resistance to apoptosis. CD160 is also a potential prognostic marker for the detection of minimal residual disease (MRD) in CLL, which is important for the clinical management of CLL, the prevention of disease relapse, and the achievement of complete remission. In this review, we present an overview of CD160 and its involvement in the pathophysiology of CLL. We also discuss its use as a prognostic marker for the assessment of MRD in CLL.

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Section: Cd160 Expression In the Cll Tumor Microenvironmentmentioning

confidence: 99%

CD160 receptor in CLL: Current state and future avenues

et al. 2022

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“…Furthermore, it was recently elucidated that CLL cells can directly impair CAR T-cell function and induce an exhausted phenotype through the release of plasma extracellular vesicles. 91 Thus, a meaningful role for CAR T-cell therapy in CLL may rely on the ability of current and/or future therapies to successfully target the TME and improve T-cell fitness in patients with CLL, prior to the CAR T-cell treatment, during preparation of the product, and after its administration.…”

Section: Cll-induced T-cell Dysfunc-mentioning

confidence: 99%

Targeting the tumor microenvironment in chronic lymphocytic leukemia

Svanberg

Janum²,

Patten

et al. 2021

haematol

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The tumor microenvironment (TME) plays an essential role in the development, growth, and survival of the malignant B-cell clone in chronic lymphocytic leukemia (CLL). Within the proliferation niches of lymph nodes, bone marrow, and secondary lymphoid organs, a variety of phenotypically and functionally altered cell types, including T cells, natural killer cells, monocytes/macrophages, endothelial and mesenchymal stroma cells, provide crucial survival signals, along with CLL-cellinduced suppression of antitumor immune responses. The B-cell receptor pathway plays a pivotal role in mediating the interaction between CLL cells and the TME. However, an increasing number of additional components of the multifactorial TME are being discovered. Although the majority of therapeutic strategies employed in CLL hitherto have focused on targeting the leukemic cells, emerging evidence implies that modulation of microenvironmental cells and CLL-TME interactions by novel therapeutic agents significantly affect their clinical efficacy. Thus, improving our understanding of CLL-TME interactions and how they are affected by current therapeutic agents may improve and guide treatment strategies. Identification of novel TME interactions may also pave the road for the development of novel therapeutic strategies targeting the TME. In this review, we summarize current evidence on the effects of therapeutic agents on cells and interactions within the TME. With a growing demand for improved and personalized treatment options in CLL, this review aims at inspiring future exploration of smart drug combination strategies, translational studies, and novel therapeutic targets in clinical trials.

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“…Patients with CLL express high levels of CLL derived extracellular vesicles containing programmed death ligand-1 (PDL-1), resulting in impaired antigen specific CAR-T proliferation. 50 Ibrutinib administered prior to or concurrently with CAR T may reverse T-cell dysfunction in CLL via inhibition of IL-2 inducible T-cell kinase, resulting in improved CAR T expansion and decreased expression of inhibitory molecules, such as programmed cell death-1 (PD-1). 51 Furthermore, concurrent ibrutinib reduces proinflammatory cytokines which may reduce CRS.…”

Section: Chronic Lymphocytic Leukemiamentioning

confidence: 99%

Advances in CAR T Therapy for Hematologic Malignancies

Freyer

Porter

2020

Pharmacotherapy

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The introduction of chimeric antigen receptor T‐cell (CAR T) therapy has resulted in a paradigm shift in the management of relapsed/refractory B‐cell malignancies. Patients with acute lymphoblastic leukemia and non‐Hodgkin’s lymphoma who had exhausted all meaningful treatment options now have an opportunity for long‐term remission and possibly cure. CAR T is rapidly expanding into the treatment paradigm for multiple myeloma with approvals expected in the near future. CAR T for chronic lymphocytic leukemia may not be far behind, while CAR T studies in Hodgkin lymphoma and acute myeloid leukemia are ongoing. Such therapeutic success brings challenges in toxicity management related to cytokine release syndrome and immune effector cell–associated neurotoxicity syndrome. Our understanding of these unique syndromes is evolving, with predictive models and additional treatment strategies on the horizon. This review aims to summarize the progress of CAR T therapeutics within malignant hematology thus far and highlight ongoing advances in the field.

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Circulating Extracellular Vesicles Induce Chimeric Antigen Receptor T Cell Dysfunction in Chronic Lymphocytic Leukemia (CLL)

Cited by 5 publications

References 0 publications

CD160 receptor in CLL: Current state and future avenues

CD160 receptor in CLL: Current state and future avenues

Targeting the tumor microenvironment in chronic lymphocytic leukemia

Advances in CAR T Therapy for Hematologic Malignancies

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