Search

The CLL disease course is heterogeneous with many patients never requiring treatment and some having very aggressive rapid onset disease.Innate and adaptive immune compensatory mechanisms driven by malignant cells often lead to clonal proliferation, migration and resistance to treatment in CLL. Cell-to-cell interactions occurring within the tumor Micro-environment (TME) can impact greatly on the course of the disease as well as contribute to the variable spread of CLL cells, known as spatial heterogeneity. Following evidence showing the expression of BTK on many hematopoietic cells (an exception beting T lymphocytes) has given rise to the idea that inhibition of BTK with BTK inhibitors (BTKi) such as ibrutinib can help treat CLL.As BTK has a wide variation of expression among cells the use of BTKi has been shown to not only control CLL clones but also redistribute the balance of humoral immunity back toward those of healthy control. n this review article we look at role of BTK in the pathogenesis of CLL, the use of BTKi and their effect on humoral immunity. [ABSTRACT FROM AUTHOR]

Fludarabine (F) and cyclophosphamide (C) remain backbones of up-front chemotherapy regimens for chronic lymphocytic leukemia (CLL). We report long-term follow-up of a randomized F vs. FC trial in untreated CLL#. With median follow-up of 88 months, estimated median progression-free survival (PFS) was 19.3 vs. 48.1 months for F (n= 109) and FC (n= 118), respectively (p< 0.0001), and median overall survival (OS) was 88.0 vs. 79.1 months (p= 0.96). In multivariable analyses, variables associated with inferior PFS and OS respectively were age (p= 0.002,p< 0.001), Rai stage (p= 0.006,p= 0.02) and sex (p = 0.03, PFS only). Del(17)(p13.1) predicted shorter PFS and OS (p < 0.0001 for each), as did del(11q)(22.3) (p< 0.0001,p= 0.005, respectively), trisomy 12 with mutatedNotch1(p= 0.003,p= 0.03, respectively) and unmutatedIGHV(p= 0.009,p= 0.002, respectively), all relative to patients without these features. These data confirm results from shorter follow-up and further justify targeted therapies for CLL. [ABSTRACT FROM AUTHOR]

Abstract: Over the last decade, the active role of the microenvironment in the pathogenesis of B cell lymphomas has been recognized, delivering signals that favor clonal expansion and drug resistance. We are only beginning to understand the complex cross talk between neoplastic B cells and the tissue microenvironment, for example in secondary lymphoid organs, but some key cellular and molecular players have emerged. Mesenchymal stromal cells, nurselike cells (NLC) and lymphoma-associated macrophages (LAM), in concert with T cells, natural killer cells and extracellular matrix components participate in the dialog with the neoplastic B cells. B cell receptor signaling, activation via TNF family members (i.e. BAFF, APRIL), and tissue homing chemokine receptors and adhesion molecules are important in the interaction between malignant B cells and their microenvironment. Disrupting this cross talk is an attractive novel strategy for treating patients with B cell malignancies. Here, we summarize the cellular and molecular interactions between B cell lymphoma/leukemia cells and their microenvironment, and the therapeutic targets that are emerging, focusing on small molecule inhibitors that are targeting B cell receptor-associated kinases SYK, BTK, and PI3Ks, as well as on immunomodulatory agents and T cell mediated therapies. Clinically relevant aspects of new targeted therapeutics will be discussed, along with an outlook into future therapeutic strategies. [Copyright &y& Elsevier]

Preclinical animal models have largely ignored the immune-suppressive mechanisms that are important in human cancers. The identification and use of such models should allow better predictions of successful human responses to immunotherapy. As a model for changes induced in nonmalignant cells by cancer, we examined T-cell function in the chronic lymphocytic leukemia (CLI) Eμ-TCL1 transgenic mouse model. With development of leukemia. Eμ-TCL1 transgenic mice developed functional T-cell defects and alteration of gene and protein expression closely resembling changes seen in CLL human patients. Furthermore, infusion of CLL cells into young Eμ-TCL1 mice induced defects comparable to those seen in mice with developed leukemia, demonstrating a causal relationship between leukemia and the T-cell defects. Altered pathways involved genes regulating actin remodeling, and T cells exhibited dysfunctional immunological synapse formation and T-cell signaling, which was reversed by the immunomodulatory drug lenalidomide. These results further demonstrate the utility of this animal model of CLL and define a versatile model to investigate both the molecular mechanisms of cancer-induced immune sUppression and immunotherapeutic repair strategies. [ABSTRACT FROM AUTHOR]

B-cell chronic lymphocytic leukaemia (CLL) should be an ideal target for immune-mediated responses. CLL arises from B cells that can act as antigen-presenting cells (APCs), expresses unique tumour antigens, and has been shown to be a target of the allogeneic T cells which mediate a graft-versus-leukaemia effect. Despite these potential benefits, immune responses against CLL cells have been difficult to elicit. CLL induces immune defects in the host, the tumour cells are inefficient APCs, and therapies given to patients with CLL are themselves immunosuppressive. Successful vaccination approaches in this disease will require steps to overcome these difficulties, including identification of the targets of immune responses in this disease to enable monitoring of the immune response after vaccination, improved presentation of antigens, and steps to improve the immune defects that accompany this disease. [Copyright &y& Elsevier]

Despite the presence of tumor antigens, the paucity of clinically significant T-cell mediated immune responses against human tumors is striking. This may, in part, be because of the inability of cancer cells to function as efficient antigen-presenting cells. For full activation, T cells must receive two signals delivered by antigen-presenting cells. The first is antigen-specific and is delivered by presentation of antigenic peptide by the major histocompatibility complex molecules to the T-cell receptor. This signal, although necessary, is in itself insufficient to mediate T-cell activation, cytokine release, and subsequent T-cell proliferation and function. For full T-cell activation, T cells require delivery of a secondary, costimulatory signal, such as that delivered by members of the B7 family to their receptor on the T-cell, CD28. Delivery of an antigen signal in the absence of costimulation does not result in productive immunity, but rather in anergy, a state of antigen-specific T-cell nonresponsiveness. To induce T-cell proliferation against B-cell malignancies, the tumor cell must first be induced to express B7 or the tumor antigen must be presented by an efficient antigen-presenting cell. Simple expression of B7 on the tumor cell alone, however, cannot reverse anergy. Reversal of anergy is a complex process involving stepwise repair of the T-cell defect and can be accomplished by prolonged exposure to interleukin-2, signaling through the CD2 pathway, followed by antigen presentation with B7-mediated costimulation. Successful immunotherapeutic strategies in the B-cell malignancies will likely require steps to reverse established anergy in the tumor-bearing host as well as effective tumor-antigen presentation. [ABSTRACT FROM AUTHOR]

In this article, the authors opines on the research "Mitochondrial metabolism contributes to oxidative stress and reveals therapeutic targets in chronic lymphocytic leukemia" by R. Jitschin and colleagues, present within the issue. It discusses the increased mitochondrial oxidative phosphorylation and production of reactive oxygen species (ROS), which leads to reduced T-cell immune function.

The authors discuss the study by G. D. Raa and colleagues on the preservation of cytomegalovirus (CMV)-specific CD8+ T-cell function in chronic lymphocytic leukemia (CCL). They mention that the findings counter the chronic viral stimulation hypothesis through CMV is a major contributor to the depleted T-cell phenotype found in CLL. They say that the observations also challenge the paradigm that there is T-cell function global inhibition in CLL.

The toxicity burden and long-term anti-leukaemic effect of non-myeloablative ( NMA) allogeneic haematopoietic stem-cell transplantation ( AHSCT) for acute myeloid leukaemia ( AML) and myelodysplasia ( MDS) remains undefined. We report the outcome of 56 patients with AML/ MDS transplanted from human leucocyte antigen-matched donors using NMA conditioning without T-cell depletion. With a median follow-up of 5 years, treatment-related mortality was 9% and current disease-free survival ( CDFS) was 45% (overall) and 55% (patients transplanted in remission). Development of graft-versus-host disease upon withdrawal of post-transplant immunosuppression was associated with less relapse and better CDFS. These data confirm that NMA AHSCT without T-cell depletion is safe and can result in sustained remissions of AML/ MDS. [ABSTRACT FROM AUTHOR]

The authors discuss aspects of cost and efficacy of chimeric antigen receptor (CAR) T cells in the treatment of chronic lymphocytic leukemia (CLL). They have demonstrated an electroporate human natural killer cells with a receptor encoding anti-CD19 for the treatment of B-cell malignancies like follicular lymphoma. However, the authors believe that further studies are required to evaluate the clinical scenarios for the infusion of these cells.

Abstract: According to the immune-surveillance hypothesis, cancer cells evolve strategies to evade or suppress the immune system as part of the development of this disease. The malignant B-cells of chronic lymphocytic leukaemia are prime examples of this premise, having been shown to generate a variety of ways of suppressing T-cell anti-tumour immune responses and these are summarized here. These mechanisms range from impairment of antigen presentation by the tumour cells themselves, to suppression of the immune microenvironment by contact dependent pathways and alterations in the cytokine milieu. By understanding these defects, novel targeted therapies can be developed with the aim of restoring T-cell function. Indeed, some of the recent advances in the treatment of chronic lymphocytic leukaemia have been demonstrated to have profound immunomodulatory effects, repairing these defects in T-cell function. [ABSTRACT FROM AUTHOR]

Donor T-cell immune responses can eradicate lymphomas after allogeneic hematopoietic stem-cell transplantation, but can also damage healthy tissues resulting in harmful Graft-versus-Host Disease (GvHD). Next-generation sequencing has recently identified many new genetic lesions in follicular lymphoma. One such gene, TNFRSF14, abnormal in 40% of follicular lymphoma patients, encodes the herpes-virus-entry mediator (HVEM) which limits T-cell activation via ligation of B- and T-lymphocyte attenuator. As lymphoma B-cells can act as antigen-presenting cells, we hypothesized that TNFRSF14 aberrations that reduce HVEM expression could alter the capacity of follicular lymphoma B-cells to stimulate allogeneic T-cell responses and impact the outcome of allogeneic hematopoietic stem-cell transplantation. In an in vitro model of alloreactivity, human lymphoma B-cells with TNFRSF14 aberrations had reduced HVEM expression and greater alloantigen-presenting capacity than wild-type lymphoma B-cells. The increased immune stimulatory capacity of lymphoma B-cells with TNFRSF14 aberrations had clinical relevance, associating with higher incidence of acute GvHD and in patients undergoing allogeneic hematopoietic stem-cell transplantation. Follicular lymphoma patients with TNFRSF14 aberrations may benefit from more aggressive immunosuppression to reduce harmful GvHD after transplantation. Importantly, this study is the first to demonstrate the impact of an acquired genetic lesion on the capacity of tumor cells to stimulate allogeneic T-cell immune responses which may have wider consequences for adoptive immunotherapy strategies. [ABSTRACT FROM AUTHOR]

T-cell defects, immune suppression and poor antitumor immune responses are hallmarks of Chronic Lymphocytic Leukemia (CLL), and PD-1/PD-L1 inhibitory signaling has emerged as a major immunosuppressive mechanism. However, the effect of different microenvironments and the confounding influence of aging are poorly understood. The current study uses the Eμ-TCL1 mouse model, which replicates human T-cell defects, as a preclinical platform to longitudinally examine patterns of T-cell dysfunction alongside developing CLL and in different microenvironments, with a focus on PD-1/PD-L1 interactions. The development of CLL was significantly associated with changes in T-cell phenotype across all organs and function. Although partly mirrored in aging wild-type mice, CLL-specific T-cell changes were identified. Murine CLL cells highly expressed PD-L1 and PD-L2 in all organs, with high PD-L1 expression in spleen. CD3+CD8+ T-cells from leukemic and aging healthy mice highly expressed PD-1, identifying aging as a confounder, but adoptive transfer experiments demonstrated CLL-specific PD-1 induction. Direct comparisons of PD-1 expression and function between aging CLL mice and controls identified PD-1+ T cells in CLL as a heterogeneous population with variable effector function. This is highly relevant for therapeutic targeting of CD8+ T-cells, showing the potential of reprogramming and selective subset expansion to restore anti-tumor immunity. [ABSTRACT FROM AUTHOR]

T-cell exhaustion, originally described In chronic viral Infections, was recently 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. CDB+ and CD4+ T cells from CLL patients had Increased expression of exhaustion markers CD244, CD160, and PD1, with expansion of a PD1+BLIMP1HI 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 nonpolarized degranulation. In contrast to virally induced exhaustion, CLL T cells showed increased production of interferon-γ and TNFa and increased expression of TBET, and normal IL2 production. These defects were not restricted to expanded populations of cytomegalovirus (CMV)-specific cells, although CMV seropositivity modulated the distribution of lymphocyte subsets, the functional defects were present irrespective of CMV serostatus. Therefore, although 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract: To date, studies on T cells in acute myeloid leukemia (AML) have been limited to flow cytometric analysis of whole peripheral blood mononuclear cell (PBMC) specimens or functional work looking at the impact of AML myeloblasts on normal or remission T cells. This lack of information on T cells at the time of presentation with disease is due in part to the difficulty in isolating sufficiently pure T cells from these specimens for further study. Negative immunomagnetic selection has been the method of choice for isolating immune cells for functional studies due to concerns that binding antibodies to the cell surface may induce cellular activation, block ligand–receptor interactions or result in immune clearance. In order specifically to study T cells in presentation AML specimens, we set out to develop a method of isolating highly pure CD4 and CD8 T cells by negative selection from the peripheral blood (PB) of newly diagnosed AML patients. This technique, unlike T cell selection from PB from normal individuals or from patients with chronic lymphocytic leukaemia, was extremely problematic due to properties of the leukaemic myeloblasts. A successful method was eventually optimized requiring the use of a custom antibody cocktail consisting of CD33, CD34, CD123, CD11c and CD36, to deplete myeloblasts. [Copyright &y& Elsevier]

To examine the impact of tumors on the immune system, we compared global gene expression profiles of peripheral blood T cells from previously untreated patients with B cell chronic lymphocytic leukemia (CLL) with those from age-matched healthy donors. Although the cells analyzed were not part of the malignant clone, analysis revealed differentially expressed genes, mainly involved in cell differentiation in CD4 cells and defects in cytoskeleton formation, vesicle trafficking, and cytotoxicity in CD8 cells of the CLL patients. In coculture experiments using CLL cells and T cells from healthy allogeneic donors, similar defects developed in both CD4 and CD8 cells. These changes were induced only with direct contact and were not cytokine mediated. Identification of the specific pathways perturbed in the T cells of cancer-bearing patients will allow us to assess steps to repair these defects, which will likely be required to enhance antitumor immunity. [ABSTRACT FROM AUTHOR]

Studies the prevention of T cell anergy through signalling the common gamma chain of the interleukin-2 receptor. Stimulation of human T cell clones; Examination of Jak3 kinase phosphorylation; Proliferation of anergized cells.

Background: Successful allogeneic bone marrow transplantation relies on global immunosuppression or elimination of T cells. In contrast, the induction of anergy can inactivate specific sets of alloreactive T cells in the donor marrow. Previous work has shown that anergy can be induced by blocking the interaction of the B7 molecule on the surface of antigen-presenting cells with the CD28 molecule on the surface of T cells, thus preventing key signaling events essential for the activation of T cells. To investigate the feasibility of this approach with respect to transplantation of histoincompatible bone marrow, we undertook a clinical trial of ex vivo induction of anergy in T cells present in donor marrow to recipient alloantigens. Methods: Outcomes in 12 transplant recipients were evaluated. The recipients' peripheral-blood lymphocytes were collected before myeloablation and served as alloantigen-presenting cells. To induce alloantigen-specific anergy, bone marrow from a donor mismatched with the recipient for one HLA haplotype was cocultured with irradiated cells from the recipient for 36 hours in the presence of CTLA-4–Ig, an agent that inhibits B7:CD28-mediated costimulation. After conventional myeloablation and immunoprophylaxis, the treated donor cells were transfused into the recipient. Results: After the induction of anergy, the frequency of T cells capable of recognizing alloantigens of the recipient in donor marrow was sharply reduced (P<0.001), whereas the responsiveness to alloantigens from persons unrelated to the recipient or the donor was unaffected (P=0.51). In the 11 patients who could be evaluated, the haploidentical bone marrow cells engrafted. Of these 11 patients, 3 had acute graft-versus-host disease (GVHD) confined to the gastrointestinal tract. No deaths were attributable to GVHD. Five of the 12 patients were alive and in remission 4.5 to 29 months after transplantation. Conclusions: Donor bone marrow treated ex vivo to induce anergy to alloantigens from the recipient can reconstitute hematopoiesis in vivo with a relatively low risk of GVHD. (N Engl J Med 1999;340:1704-14.) [ABSTRACT FROM AUTHOR]