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Cancer Research Is Leading the Way
Published in Rebecca A. Krimins, Learning from Disease in Pets, 2020
Bruton’s tyrosine kinase (BTK) is a crucial enzyme for B-cell differentiation, proliferation, and survival (Pal Singh, Dammeijer, and Hendriks 2018). In the context of B-cell malignancies, including NHL, inhibition of BTK alters cytokine signaling resulting in decreased proliferation and impaired cell migration (Pal Singh, Dammeijer, and Hendriks 2018). The earliest evidence in support of clinical efficacy of BTK inhibitors was generated in a comparative oncology trial in canines with spontaneous lymphoma (Honigberg et al. 2010). This particular trial was unique in that there were no suitable mouse models to utilize for preclinical efficacy evaluation, as mouse models of B-cell lymphoma had impaired B-cell receptor signaling that was dissimilar to humans and canines (Thamm 2019). Thus, the canine lymphoma trial was the first in vivo study to demonstrate proof-of-concept that BTK inhibition could lead to measurable antitumor responses in lymphoma (Honigberg et al. 2010). Additionally, this study was critical for the development of pharmacodynamic assays used in subsequent human clinical trials to ensure adequate drug exposures (Honigberg et al. 2010). The results of this canine oncology trial directly informed human clinical trials, leading to FDA approval for ibrutinib use in several B-cell malignancies (Thamm 2019).
Mucosal manifestations of immunodeficiencies
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Scott Snapper, Jodie Ouahed, Luigi D. Notarangelo
X-linked agammaglobulinemia (XLA) results from mutations of the Bruton's tyrosine kinase (BTK) gene. BTK is located on the X chromosome and regulates signaling through the pre-B-cell receptor (pre-BCR) and the BCR. BTK deficiency results in a block at the pro-B to pre-B cell stage in B-cell differentiation in the bone marrow. Accordingly, patients with XLA have a severe reduction or absence of circulating B cells, associated with profound deficiency of all immunoglobulin isotypes. A similar phenotype can also be observed in patients with autosomal recessive forms of agammaglobulinemia, due to mutations of the mu (μ) heavy-chain gene; of the Igα, Igβ, and V pre-B components of the pre-BCR; or of the adaptor molecule B-cell linker protein, which is also involved in pre-BCR-mediated signaling.
Primary immunodeficiency diseases
Published in Gabriel Virella, Medical Immunology, 2019
John W. Sleasman, Gabriel Virella
This condition is associated with absent B cells and results from a mutation in Bruton's tyrosine kinase (BTK) located on Xq21.2-22. Multiple mutations within these loci lead to the common phenotype of arrested B-cell development in the bone marrow. There are other rare forms of congenital agammaglobulinemia that appear in infancy but are inherited as autosomal recessive traits associated with deletions/mutations in genes encoding parts of either the Vλ region or of the Cμ heavy-chain region.
Immunosuppressive tumor microenvironment modulation by chemotherapies and targeted therapies to enhance immunotherapy effectiveness
Published in OncoImmunology, 2022
Robby Barnestein, Loïck Galland, Laura Kalfeist, François Ghiringhelli, Sylvain Ladoire, Emeric Limagne
Another interesting point to highlight concerns Bruton’s tyrosine kinase (BTK) inhibitors. BTK plays a crucial role in oncogenic pathways and is notably known for its involvement in B cell malignancies. Therefore, BTK inhibitors have emerged including ibrutinib, which can inhibit phosphorylation of BTK and efficiently reduce the phosphorylation of the receptor tyrosine kinases ErbB1, ErbB2 and ErbB3, thereby suppressing AKT and MAPK signaling in ErbB2-positive BC cell lines.141 Dubovsky et al. suggested that ibrutinib may also enhance the antitumor immune response by modulating the Th1/Th2 CD4+ T cell ratio.142 Treatment of mice bearing EMT-6 mammary tumors with ibrutinib resulted in a reduced frequency of MDSCs in both the spleen and tumor.143 Varikuti et al. demonstrated that ibrutinib was able to deplete and reprogram MDSCs to mature DCs, which boosts antitumor Th1 immune response and improves infiltration of cytotoxic T lymphocytes due to enhanced tumor-derived antigen presentation to CD8+ T cells.144 A combination of immunotherapy and ibrutinib was shown to suppress tumor growth in preclinical models of TNBC.145 However, a phase 1/2 clinical trial reported limited antitumor activity with a combination of ibrutinib-immunotherapy (durvalumab).146
Cost-effectiveness analysis of KTE-X19 CAR T therapy versus real-world standard of care in patients with relapsed/refractory mantle cell lymphoma post BTKi in England
Published in Journal of Medical Economics, 2022
Svenja Petersohn, Gilles Salles, Michael Wang, Jim Wu, Sally W. Wade, Claire L. Simons, Craig Bennison, Rubina Siddiqi, Weimin Peng, Ioana Kloos, Gab Castaigne, Georg Hess
Current treatment options for MCL in the UK are defined by the British Society for Haematology and National Institute for Health and Care Excellence (NICE) which have established a clear treatment pathway for patients receiving first and second-line treatment for MCL2,3. In the first line, patients are recommended to receive a high-dose cytarabine regimen followed when possible by an autologous stem cell transplant (auto-SCT) with or without rituximab maintenance2,4. Patients who are not eligible for auto-SCT will instead receive immunochemotherapy with or without rituximab2,3. Patients who are refractory or relapse are eligible to receive treatment with Bruton tyrosine kinase inhibitor (BTKi) ibrutinib3,4. Current treatment options for higher subsequent relapses are not well established. The use of alternative immunochemotherapy to that adopted in the first line, but also treatment with venetoclax and lenalidomide, commonly results in inferior response and rapid progression4–7.
Cardiotoxicity of BTK inhibitors: ibrutinib and beyond
Published in Expert Review of Hematology, 2022
Bradley W. Christensen, Vlad G Zaha, Farrukh T. Awan
Bruton’s tyrosine kinase (BTK) is a cytoplasmic protein tyrosine kinase that plays a critical role in B-cell development and function [1]. Mutations in the BTK gene located on the X chromosome were initially implicated in the development of X-linked agammaglobulinemia, a primary humoral immunodeficiency characterized by B-cell arrest at the pro-B cell stage and lack of immunoglobulin production [2,3]. Further studies have demonstrated that BTK operates at the crossroads of multiple B-cell signaling pathways (Figure 1). Its most well-described role is as a downstream effector of antigen-dependent B-cell receptor (BCR) signaling. Upon stimulation of the BCR, BTK is phosphorylated by the src-family kinase LYN. In turn, BTK phosphorylates phospholipase C-γ2 (PLC- γ2) and triggers the release of intracellular calcium and the activation of transcription factors involved in B-cell differentiation, proliferation, and survival [4–6]. In addition to its role in the BCR pathway, BTK also mediates CD40, Fc receptors, Toll-like receptors, and chemokine receptor pathway signaling (Figure 1) [7–10]. Given its central contribution to a diverse array of intracellular processes within the B-cell program, it is unsurprising that aberrations in BTK signaling have been implicated in a wide spectrum of autoimmune, immunologic, and malignant conditions in humans [7,11–15].