[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] ABSTRACT: A major challenge to transplant immunologists and physicians remains the separation of harmful graft-versus-host disease (GvHD) and beneficial graft-versus-tumour (GvT) effects after allogeneic haematopoietic stem cell transplantation. Recent advances in our understanding of the allogeneic immune response provide potential new opportunities to achieve this goal. Three potential new approaches that capitalize on this new knowledge are considered in depth; the manipulation of organ-specific cytokines and other pro-inflammatory signals, the selective manipulation of donor effector T cell migration, and the development of cell-mediated immunosuppressive strategies using donor-derived regulatory T cells. These new approaches could provide strategies for local control of allogeneic immune responses, a new paradigm to separate GvHD and GvT effects. Although these strategies are currently in their infancy and have challenges to successful translation to clinical practice, all have exciting potential for the future.
[Show abstract][Hide abstract] ABSTRACT: Cancer immune evasion is an emerging hallmark of disease progression. We have demonstrated previously that impaired actin polymerization at the T-cell immunologic synapse is a global immune dysfunction in chronic lymphocytic leukemia (CLL). Direct contact with tumor cells induces defective actin polarization at the synapse in previously healthy T cells, but the molecules mediating this dysfunction were not known. In the present study, we show via functional screening assays that CD200, CD270, CD274, and CD276 are coopted by CLL cells to induce impaired actin synapse formation in both allogeneic and autologous T cells. We also show that inhibitory ligand-induced impairment of T-cell actin dynamics is a common immunosuppressive strategy used by both hematologic (including lymphoma) and solid carcinoma cells. This immunosuppressive signaling targets T-cell Rho-GTPase activation. Of clinical relevance, the immunomodulatory drug lenalidomide prevented the induction of these defects by down-regulating tumor cell-inhibitory molecule expression. These results using human CLL as a model cancer establish a novel evasion mechanism whereby malignant cells exploit multiple inhibitory ligand signaling to down-regulate small GTPases and lytic synapse function in global T-cell populations. These findings should contribute to the design of immunotherapeutic strategies to reverse T-cell tolerance in cancer.
[Show abstract][Hide abstract] ABSTRACT: The relative merits of reduced-intensity allogeneic stem cell transplantation (RISCT) for high-risk indolent lymphoid malignancies are emerging, although the preferred conditioning regimen to manage the risks of graft-versus-host disease (GVHD) is not clearly defined. Here we report the outcome of 73 patients with lymphoid malignancies who received RISCT with a fludarabine/cyclophosphosphamide conditioning regimen and a median follow-up of 3 years. Median age was 54 years. Forty-eight per cent of patients had previously undergone autologous stem cell transplantation with a median of three prior therapies. Non-relapse mortality at 3 years was 19% but only 5% for patients with multiple myeloma (MM). Three-year overall survival and current progression-free survival was 67% and 63% respectively. Grade 2-4 acute GVHD occurred in 14% of patients while 49% had chronic GVHD requiring systemic immunosuppression. The preparatory regimen in this study has the advantage of reduced acute GVHD and low mortality, notably in patients with MM. In addition, this strategy provides long-term disease control in a significant proportion of patients with particular benefit in those with high-risk follicular lymphoma.
British Journal of Haematology 03/2012; 157(5):580-5.
[Show abstract][Hide abstract] ABSTRACT: While most myelodysplastic syndrome/acute myeloid leukemia cases are sporadic, rare familial cases occur and provide some insight into leukemogenesis. The most clearly defined familial cases result from inherited mutations in RUNX1 or CEBPA. Recently, novel germline mutations in GATA2 have been reported. We, therefore, investigated individuals from families with one or more first-degree relatives with myelodysplastic syndrome/acute myeloid leukemia with wild-type RUNX1 and CEBPA, for GATA2 mutations. Screening for other recurrent mutations was also performed. A GATA2 p.Thr354Met mutation was observed in a pedigree in which 2 first-degree cousins developed high-risk myelodys-plastic syndrome with monosomy 7. They were also observed to have acquired identical somatic ASXL1 mutations and both died despite stem cell transplantation. These findings confirm that germline GATA2 mutations predispose to familial myelodysplastic syndrome/acute myeloid leukemia, and that monosomy 7 and ASXL1 mutations may be recurrent secondary genetic abnormalities triggering overt malignancy in these families.
[Show abstract][Hide abstract] ABSTRACT: An intention-to-treat (ITT) analysis was performed in 103 unselected patients with relapsed/refractory classical Hodgkin lymphoma (CHL) comparing early relapse (<12 months) or failure of first-line therapy (ER/FTF) with late relapses (LR). Seventy one percentage proceeded to high-dose therapy/autologous stem cell rescue (HDT/ASCR) following salvage treatment. By ITT, 5-year overall survival (OS) was 50% for ER/FTF compared to 73% for LR patients (P = 0·012). However OS was equivalent for both groups if salvage treatment response was adequate to proceed to HDT/ASCR. ER/FTF patients remain a high-risk group largely due to a failure of salvage therapy: a point at which novel interventions could impact survival.
British Journal of Haematology 01/2012; 157(2):201-4.
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