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    ABSTRACT: Over the past decade there have been significant advances in our understanding of the pathogenesis of CLL, which has been accompanied by an explosion in treatment options. While the combination of fludarabine, cyclophosphamide, and rituximab is the current frontline treatment of choice for fit patients, targeted therapies such ibrutinib, idelalisib, and ABT-199 are showing great promise in clinical trials. However, none of these drugs appear to curative, and allogeneic hematopoietic stem cell transplantation remains the only strategy that produces durable clinical remissions in otherwise poor risk disease. Immune reconstitution remains an enticing prospect in CLL, as malignant B cells should be particularly susceptible T-cell mediated attack. It has recently been demonstrated that the T-cell defect in CLL can be effectively overcome by both lenalidomide treatment and by adoptive transfer of chimeric antigen receptor T cells. A variety of other immunotherapies are in development, including CLL-vaccines, CD40 ligand therapies and monoclonal antibody immune checkpoint blockade. This review explores the nature of the immune defect in CLL and summarizes the recent developments in the immunotherapeutic field.
    Full-text · Article · Jan 2014 · Seminars in Hematology
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    ABSTRACT: Interview by Louise Rishton, Commissioning Editor Professor John Gribben is Chair of the International Workshop on non-Hodgkin Lymphoma and the Gordon Hamilton Fairley Chair of Medical Oncology at St. Bartholomew's Hospital, Bart's Cancer Institute, London, UK, a Cancer Research UK Centre of Excellence. His doctoral studies were performed at University College London, UK as the recipient of a Wellcome Trust Fellowship Award and he continued post-doctoral training with Professor Lee Nadler at the Dana-Farber Cancer Institute (Harvard Medical School, MA, USA). In 1992, Gribben was appointed to the Faculty at Harvard Medical School, where he remained as Associate Professor of Medicine and an Attending Physician at the Dana-Farber Cancer Institute and Brigham and Women's Hospital (MA, USA), until returning to London in 2005. Gribben is a founding member of the CLL Research Consortium, Associate Editor of Blood and was elected a Fellow of the Academy of Medical Science. His primary research interests include the immunotherapy of cancer (including stem cell transplantation), the identification of B-cell-tumor antigens and the detection and treatment of minimal residual disease in leukemia and lymphoma.
    Full-text · Article · Apr 2013 · Expert Review of Hematology
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    ABSTRACT: T-cell exhaustion, originally described in chronic viral infections, has recently been reported in solid and hematologic cancers. It is not defined whether exhaustion contributes to T-cell dysfunction observed in chronic lymphocytic leukemia (CLL). We investigated the phenotype and function of T cells from CLL patients and age-matched controls. CD8(+) and CD4(+) T cells from CLL patients had increased expression of exhaustion markers CD244, CD160, and PD1, with expansion of a PD1(+)BLIMP1(HI) subset. These molecules were most highly expressed in the expanded population of effector T cells in CLL. CLL CD8(+) T cells showed functional defects in proliferation and cytotoxicity, with the cytolytic defect caused by impaired granzyme packaging into vesicles and non-polarized degranulation. In contrast to virally-induced exhaustion, CLL T cells showed increased production of interferon-γ and TNFα and increased expression of TBET, and normal IL2 production. These defects were not restricted to expanded populations of CMV specific cells, as while CMV seropositivity modulated the distribution of lymphocyte subsets, the functional defects were present irrespective of CMV serostatus. Therefore, while CLL CD8(+) T cells exhibit features of T-cell exhaustion, they retain the ability to produce cytokines. These findings also exclude CMV as the sole cause of T cell defects in CLL.
    Full-text · Article · Dec 2012 · Blood
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