Chapter 2 B Lymphocytes in Cancer Immunology

Abstract The role of B lymphocytes in the pathogenesis and treatment of cancer has not received as much attention as the role of T cells. However, most patients with solid tumors harbor circulating antitumor antibodies and most tumors contain a population of infiltrating B cells implying an association between oncogenic events and B-cell activation. B-cell immunity can be beneficial by providing antibody-mediated protection from oncogenic viruses or a source of recombinant tumor-specific antibodies that can be used in combination with chemotherapeutic regimens. However, activation of B cells may also be detrimental to an effective antitumor response. Tumor-reactive antibodies and B cells often recognize antigens that are generated during the unscheduled apoptotic and necrotic death processes, which accompany tumor progression and may be involved in wound-healing processes that promote tumor growth and impair protective T-cell responses. Therefore, methods to eliminate autoreactive B cells, or switch them to a B effector-1 (Be-1) phenotype that amplifies Th1/Tc1-type T-cell responses, which are typically associated with effective antitumor responses, may improve the clinical outcomes of T-cell-mediated immunotherapies. Possible strategies include the administration of B-celldepleting monoclonal antibodies, use of targeted B-cell stimulatory agents such as Toll-like Receptor agonists, and adoptive transfer of large numbers of ex vivo generated tumor-reactive Be-1 cells

Risk and safety requirements for diagnostic and therapeutic procedures in allergology : World Allergy Organization Statement

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Persistent janus kinase‐signaling in chronic lymphocytic leukemia patients on ibrutinib: Results of a phase I trial

Abstract Methods to deepen clinical responses to ibrutinib are needed to improve outcomes for patients with chronic lymphocytic leukemia (CLL). This study aimed to determine the safety and efficacy of combining a janus kinase (JAK)‐inhibitor with ibrutinib because JAK‐mediated cytokine‐signals support CLL cells and may not be inhibited by ibrutinib. The JAK1/2 inhibitor ruxolitinib was prescribed to 12 CLL patients with abnormal serum beta‐2 microglobulin levels after 6 months or persistent lymphadenopathy or splenomegaly after 12 months on ibrutinib using a 3 + 3 phase 1 trial design (NCT02912754). Ibrutinib was continued at 420 mg daily and ruxolitinib was added at 5, 10, 15, or 20 mg BID for 3 weeks out of five for seven cycles. The break was mandated to avoid anemia and thrombocytopenia observed with ruxolitinib as a single agent in CLL. The combination was well‐tolerated without dose‐limiting toxicities. Cyclic changes in platelets, lymphocytes, and associated chemokines and thrombopoietic factors were observed and partial response criteria were met in 2 of 12 patients. The results suggest that JAK‐signaling helps CLL cells persist in the presence of ibrutinib and ruxolitinib with ibrutinib is well‐tolerated and may be a useful regiment to use in combination therapies for CLL

Low Density Lipoproteins Amplify Cytokine-signaling in Chronic Lymphocytic Leukemia Cells

Recent studies suggest there is a high incidence of elevated low-density lipoprotein (LDL) levels in Chronic Lymphocytic Leukemia (CLL) patients and a survival benefit from cholesterol-lowering statin drugs. The mechanisms of these observations and the kinds of patients they apply to are unclear. Using an in vitro model of the pseudofollicles where CLL cells originate, LDLs were found to increase plasma membrane cholesterol, signaling molecules such as tyrosine-phosphorylated STAT3, and activated CLL cell numbers. The signaling effects of LDLs were not seen in normal lymphocytes or glycolytic lymphoma cell-lines but were restored by transduction with the nuclear receptor PPARδ, which mediates metabolic activity in CLL cells. Breakdown of LDLs in lysosomes was required for the amplification effect, which correlated with down-regulation of HMGCR expression and long lymphocyte doubling times (LDTs) of 53.6 ± 10.4 months. Cholesterol content of circulating CLL cells correlated directly with blood LDL levels in a subgroup of patients. These observations suggest LDLs may enhance proliferative responses of CLL cells to inflammatory signals. Prospective clinical trials are needed to confirm the therapeutic potential of lowering LDL concentrations in CLL, particularly in patients with indolent disease in the “watch-and-wait” phase of management