Indolent lymphoma: the pathologist's viewpoint

Abstract Indolent lymphomas have recently been the object of numerous studies, which have focused on new aspects relevant both for the better comprehension of their histogenesis and the identification of new therapeutic strategies. As marginal-zone lymphoma (MZL) represents the category of indolent lymphomas that has obtained more benefit from such an approach, the authors focused on the most recent achievements and not yet solved controversies in this area. In spite of their postulated common derivation, the three categories of MZL of the WHO Classification appear dissimilar. In fact, they show significant molecular differences among them as well as a certain heterogeneity within each group. By no means, there is a cogent need of more refined tools to revise these neoplasms and to produce a more rational grouping. The recent identification of the IRTA gene family corresponding to IG-like receptors differentially expressed in B-cells might contribute to their better understanding

Variations in “rescuability” of immunoglobulin molecules from different forms of human lymphoma: implications for anti-idiotype vaccine development

Idiotypic (Id) vaccination has shown promising results in patients with follicular lymphoma (FL). However, it still remains unclear whether the same approach might be suitable for the treatment of other B-cell malignancies. For this reason, we recently performed an interim analysis of patients proposed to receive this treatment at our center. The feasibility of employing idiotype vaccines was evaluated for five different B-cell malignancies in their first relapse, both in terms of induction and fusion, as well as overall treatment. Our data suggest that, unlike follicular lymphoma (87%), this approach is not feasible to treat other B-cell malignancies (0–20%) such as mantle cell, small lymphocytic, diffuse large cell and Burkitt’s lymphoma (P < 0.01). The main difficulties encountered were technical problems related to the survival of idiotype-producing hybridomas (83%) and the early loss of idiotype production by growing hybridomas (17%). However, it remains possible that an idiotype vaccine might still be produced through molecular means for most, if not all cases of relapsing B-cell malignancies

Active immunotherapy in the treatment of haematological neoplasias

Abstract The continuous search for therapeutic approaches that improve the conventional treatments of neoplasms, together with an improved understanding of the immune system, has led in recent years to the development of Immunotherapy. Basically, a distinction can be made between two forms of immunotherapy: passive immunotherapy, which consists in the transfer of antibodies or cells previously generated in vitro that are directed against the tumour, and active immunotherapy, which attempts to activate in vivo the immune system and induce it to elaborate a specific response against the tumor antibodies. Hematological neoplasms, specifically some B lymphomas, express in their membrane an immunoglobulin that is considered a specific antigen of the tumour, which is why these diseases have become the ideal target for immunotherapy treatments. There are many alternatives, ranging from protein vaccines, which have already shown clinical benefits, to those of the second generation, which make use of the new techniques of molecular biology to increase the efficacy of the vaccines and obtain their production in a quicker and less costly way, but with which there are not yet definitive clinical results

A single prior course of BCNU-cisplatin chemotherapy has a significant deleterious effect on mobilization kinetics of otherwise untreated patients

Extensive prior treatment with cytotoxic agents is associated with impaired mobilization of hematopoietic cells. To assess the effect of a single course of standarddose chemotherapy (CT), we compared the results of filgrastim-induced mobilization among two sequential groups of grade III–IV malignant glioma patients included in a hematopoietic transplantation program. The first group (21 patients) had never been treated with CT until 2 days after surgery, when they received a course of 100 mg/m2 BCNU (IV) and 100 mg intracarotid cisplatin for cytoreduction (not for mobilization). At 1 month after this CT, they were mobilized with 12 lg/kg filgrastim. The second group (22 patients) was mobilized with the same dose of filgrastim directly after the surgery, without having ever received any prior CT. The blood level of CD34þ cells was significantly lower in the CT-treated patients, both on the fourth day of filgrastim (15 vs 36 cells 106/l; P¼0.01) and on the fifth (25 vs 58 cells 106/l; P¼0.003), as it was the number of CD34þ cells collected per apheresis (1.3 vs 3.5 106/l; Po0.0005). The toxic effect of a single course of BCNUcisplatin CT led to significant impairment of the filgrastim-induced mobilization response. Bone Marrow Transplantation advance onlin

Clinical implications of antigen transfer mechanisms from malignant to dendritic cells: Exploiting cross-priming

Expansion and activation of cytolytic T lymphocytes bearing high-affinity T-cell receptors specific for tumor antigens is a major goal of active cancer immunotherapy. Physiologically, T cells receive promitotic and activating signals from endogenous professional antigen-presenting cells (APC) rather than directly from malignant cells. This phenomenon fits with the broader concept of cross-presentation that earlier was demonstrated for minor histocompatibility and viral antigens. Many mechanisms have been found to be capable of transferring antigenic material from malignant cells to APC so that it can be processed and subsequently presented by MHC class I molecules expressed on APC. Dendritic cells (DC) are believed to be the most relevant APC mediating cross-presentation because they can take up antigens from apoptotic, necrotic, and even intact tumor cells. There exist specific molecular mechanisms that ensure this transfer of antigenic material: 1) opsonization of apoptotic bodies; 2) receptors for released heat shock proteins carrying peptides processed intracellularly; 3) Fc receptors that uptake immunocomplexes and immunoglobulins; and 4) pinocytosis. DC have the peculiar capability of reentering the exogenously captured material into the MHC class I pathway. Exploitation of these pieces of knowledge is achieved by providing DC with complex mixtures of tumor antigens ex vivo and by agents and procedures that promote infiltration of malignant tissue by DC. The final outcome of DC cross-presentation could be T-cell activation (cross-priming) but also, and importantly, T-cell tolerance contingent upon the activation/maturation status of DC. Artificial enhancement of tumor antigen cross-presentation and control of the immune-promoting status of the antigen-presenting DC will have important therapeutic implications in the near future

Potentiation of therapeutic immune responses against malignancies with monoclonal antibodies

Immunotherapeutic monoclonal antibodies (mAbs) can be defined as those that exert their functions by tampering with immune system cell molecules, causing an enhancement of antitumor immune responses. Some of these antibodies are agonistic ligands for surface receptors involved in the activation of lymphocytes and/or antigen-presenting cells, whereas others are antagonists of mechanisms that normally limit the intensity of immune reactions. Several mAbs of this category have been described to display in vivo antitumor activity in mouse models. Only anti–CTLA-4 (CD152) mAb has entered clinical trials, but the preclinical effects described for anti- CD40, anti-CD137 (4-1BB), anti-CD102 (intercellular adhesion molecule-2), and regulatory T cell-depleting mAbs should lead to their prompt clinical development. Their use in combination with immunizations against tumor antigens has been reported to be endowed with synergistic properties. This new group of antitumor agents holds promise for at least additive effects with conventional therapies of cancer and deserves intensive translational research