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En la actualidad las vacunas contra el cáncer se conciben como armas terapéuticas, en contraste con las preventivas que se administran frente a enfermedades infecciosas. Entre las más potentes vacunas terapéuticas se encuentra la vacunación anti-idiotipo, que emplea como diana la inmunoglobulina tumor-específica, el único antígeno completo tumor-específico conocido que se expone en la membrana de ciertas enfermedades hematológicas de extirpe B. La vacunación idiotípica ha demostrado ya beneficios clínicos y en la actualidad existen dos ensayos clínicos fase III que abordan esta opción terapéutica. Asímismo se van desarrollando otras estrategias que incluyen el empleo de células dendríticas o la producción de vacunas idiotípicas por mecanismos moleculares, que sin duda aportarán en los próximos años conclusiones beneficiosas para el tratamiento de los pacientes con cáncer.

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.

BACKGROUND AND OBJECTIVE: To examine the long-term clinical course and prognostic factors of patients with advanced aggressive non-Hodgkin's lymphoma (NHL) treated with third-generation regimens as front-line chemotherapy. DESIGN AND METHODS: A total of 348 patients aged

T regulatory cells type 1 (Tr1 cells) are excellent candidates for cell therapy in multiple sclerosis (MS). The aim of our study was to assess the functional state of Tr1 cells and IL-10R signaling in patients with MS. Tr1 cells were induced in vitro by activation with anti-CD46 antibodies in controls and patients with MS. Cells were phenotyped by cytometry and suppression assays, and the expression of cytokines and transcription factors was evaluated by real-time PCR, ELISA, cytometry and Western blotting. We found that the activity of Tr1 cells and IL-10R signaling is impaired in MS patients since Tr1 cells isolated from MS patients produced less IL-10 than those obtained from controls. Indeed, the supernatants from Tr1 cells from controls did not suppress the proliferation of stimulated CD4(+) cells from patients with MS. Furthermore, the IL-10R signaling pathway was not fully active in CD4(+) cells from MS patients and these cells had higher baseline levels of SOCS3 transcripts than controls. Indeed, after in vitro IL-10 stimulation, the expression levels of the STAT1, STAT3 and IL-10RA genes were higher in MS patients than in controls. Moreover, Stat-3 phosphorylation was lower in controls than in patients after IL-10 stimulation. These results indicate that IL-10 regulatory function is impaired in patients with MS.

Anemia is a common complication in the clinical course of chronic lymphocytic leukemia. Low hemoglobin levels both correlate with an adverse prognosis and adversely affect the quality of life of chronic lymphocytic leukemia patients. Different physiopathological phenomena may lead to anemia: marrow infi ltration, hypersplenism, immune hemolysis or toxicity of chemotherapy. Treatment with human recombinant erythropoietic agents has been shown to be effective for anemia associated with different lymphoproliferative syndromes. This paper analyses the available evidence on erythropoietic agent treatment for chronic lymphocytic leukemia associated anemia. The comparative effect of different dosage schemes, the role of possible response-prediction factors such as the endogenous erythropoietin level and the results achieved using darbopoietin alpha are reviewed.

OBJECTIVES: Angioimmunoblastic T-cell lymphoma (AIL) is a rare lymphoma with a poor prognosis and no standard treatment. Here, we report our experiences with 19 patients treated with high-dose chemotherapy and autologous stem cell transplantation (HDC/ASCT) within the GELTAMO co-operative group between 1992 and 2004. METHODS: The median age at transplantation was 46 yr. Fifteen patients underwent the procedure as front-line therapy and four patients as salvage therapy. Most patients received peripheral stem cells (90%) coupled with BEAM or BEAC as conditioning regimen (79%). RESULTS: A 79% of patients achieved complete response, 5% partial response and 16% failed the procedure. After a median follow-up of 25 months, eight patients died (seven of progressive disease and secondary neoplasia), while actuarial overall survival and progression-free survival at 3 yr was 60% and 55%. Prognostic factors associated with a poor outcome included bone marrow involvement, transplantation in refractory disease state, attributing more than one factor of the age-adjusted-International Prognostic Index, Pretransplant peripheral T-cell lymphoma (PTCL) Score or Prognostic Index for PTCL. CONCLUSIONS: More than half of the patients with AIL that display unfavourable prognostic factors at diagnosis or relapse would be expected to be alive and disease-free after 3 yr when treated with HDC/ASCT. Patients who are transplanted in a refractory disease state do not benefit from this procedure.

BACKGROUND AND OBJECTIVES: Preliminary data on the use of autologous stem cell transplantation (ASCT) as a salvage therapy for peripheral T-cell lymphoma (PTCL) indicate that the results are similar to those obtained in aggressive B-cell lymphomas. The aim of our study was to analyze outcomes of a large series of patients with PTCL with a prolonged follow-up who received ASCT as salvage therapy. DESIGN AND METHODS: Between 1990 and 2004, 123 patients in this situation were registered in the GELTAMO database. The median age at transplantation was 43.5 years; in 91% of patients the disease was chemosensitive. RESULTS: Seventy-three percent of the patients achieved complete remission, 11% partial remission and the procedure failed in 16%. At a median follow-up of 61 months, the 5-year overall and progression-free survival rates were 45% and 34%, respectively. The presence of more than one factor of the adjusted International Prognostic Index (a-IPI) and a high beta2-microglobulin at transplantation were identified as adverse prognostic factors for both overall and progression-free survival and allowed the population to be stratified into three distinct risk groups. INTERPRETATION AND CONCLUSIONS: Our data show that approximately one third of patients with PTCL in the salvage setting may enjoy prolonged survival following ASCT, provided they are transplanted in a chemosensitive disease state. The a-IPI and beta2-microglobulin level predict the outcome after ASCT in relapsing/refractory PTCL.

La manipulación farmacológica del sistema inmunitario para conseguir respuestas linfocitarias de mayor intensidad tiene aplicación potencial en inmunoterapia tumoral y en el tratamiento de enfermedades virales crónicas. Los anticuerpos monoclonales inmunoestimuladores se definen como una familia de fármacos que aumentan la respuesta inmunitaria al interaccionar como ligandos artificiales con proteínas funcionales del sistema inmunitario, activando o inhibiendo su función. Hay anticuerpos monoclonales humanizados dirigidos frente al receptor inhibidor linfocitario CD152 (CTLA-4) que se están probando en ensayos clínicos con evidencia de actividad antitumoral, aunque con la contrapartida de producir reacciones autoinmunitarias severas. Los anticuerpos anti-CD137 tienen la capacidad de inducir potentes respuestas inmunitarias, mediadas principalmente por linfocitos T citotóxicos, con el resultado de erradicar tumores transplantables de ratón de forma comparativamente superior a los anticuerpos frente a CD152. CD137 (4-1BB) es un antígeno de diferenciación expresado selectivamente en la superficie de linfocitos T y NK activados y sobre células dendríticas. Los anticuerpos monoclonales que actúan como ligandos artificiales estimuladores de este receptor (anticuerpos monoclonales agonistas anti-CD137) potencian la inmunidad celular antitumoral y antiviral en modelos experimentales murinos. Paradójicamente, estos mismos anticuerpos previenen o mejoran el curso de enfermedades autoinmunitarias establecidas en ratones como modelo. A la luz de estos datos experimentales, varios grupos de investigación han procedido a la humanización de anticuerpos dirigidos frente a CD137 humano y se plantea la inminente realización de los primeros ensayos clínicos.

La manipulación farmacológica del sistema inmunitario para conseguir respuestas linfocitarias de mayor intensidad tiene aplicación potencial en inmunoterapia tumoral y en el tratamiento de enfermedades virales crónicas. Los anticuerpos monoclonales inmunoestimuladores se definen como una familia de fármacos que aumentan la respuesta inmunitaria al interaccionar como ligandos artificiales con proteínas funcionales del sistema inmunitario, activando o inhibiendo su función. Hay anticuerpos monoclonales humanizados dirigidos frente al receptor inhibidor linfocitario CD152 (CTLA-4) que se están probando en ensayos clínicos con evidencia de actividad antitumoral, aunque con la contrapartida de producir reacciones autoinmunitarias severas. Los anticuerpos anti-CD137 tienen la capacidad de inducir potentes respuestas inmunitarias, mediadas principalmente por linfocitos T citotóxicos, con el resultado de erradicar tumores transplantables de ratón de forma comparativamente superior a los anticuerpos frente a CD152. CD137 (4-1BB) es un antígeno de diferenciación expresado selectivamente en la superficie de linfocitos T y NK activados y sobre células dendríticas. Los anticuerpos monoclonales que actúan como ligandos artificiales estimuladores de este receptor (anticuerpos monoclonales agonistas anti-CD137) potencian la inmunidad celular antitumoral y antiviral en modelos experimentales murinos. Paradójicamente, estos mismos anticuerpos previenen o mejoran el curso de enfermedades autoinmunitarias establecidas en ratones como modelo. A la luz de estos datos experimentales, varios grupos de investigación han procedido a la humanización de anticuerpos dirigidos frente a CD137 humano y se plantea la inminente realización de los primeros ensayos clínicos. Pharmacological intervention on the immune system to achieve more intense lymphocyte responses has potential application in tumour immunology and in the treatment of chronic viral diseases. Immunostimulating monoclonal antibodies are defined as a new family of drugs that augment cellular immune responses. They interact as artificial ligands with functional proteins of the immune system, either activating or inhibiting their functions. There are humanized monoclonal antibodies directed to the inhibitory receptor CD152 (CTLA-4) that are being tested in clinical trials with evidence of antitumoural activity. As a drawback, anti-CTLA-4 monoclonal antibodies induce severe autoimmunity reactions in a fraction of the patients. Anti-CD137 monoclonal antibodies have the ability to induce potent immune responses mainly mediated by cytotoxic lymphocytes with the result of frequent complete tumour eradications in mice. Comparative studies in experimental models indicate that the antitumour activity of anti-CD137 monoclonal antibodies is superior to that of anti-CD152. CD137 (4-1BB) is a leukocyte differentiation antigen selectively expressed on the surface of activated T and NK lymphocytes, as well as on dendritic cells. Monoclonal antibodies acting as artificial stimulatory ligands of this receptor (anti-CD137 agonist antibodies) enhance cellular antitumoural and antiviral immunity in a variety of mouse models. Paradoxically, anti-CD137 monoclonal antibodies are therapeutic or preventive in the course of model autoimmune diseases in mice. In light of these experimental results, a number of research groups have humanized antibodies against human CD137 and early clinical trials are about to start.

BACKGROUND: Fludarabine monophosphate (FLU) is an adenine nucleoside analogue with promising therapeutic activity in lymphoproliferative disorders. In addition, the effectiveness of alpha-interferon (alpha-IFN) in low-grade non-Hodgkin's lymphoma (LG-NHL) and B-cell chronic lymphocytic leukemia (B-CLL) has been demonstrated in several clinical trials. METHODS: In a phase II study of 45 patients with B-CLL and 28 with LG-NHL, we used FLU as second and third-line chemotherapy. Dosages of 25 mg/m2 were given in 30-minute infusions for 5 consecutive days. Treatment was repeated every 28 days depending on patients' clinical status for a maximum of 6 cycles. Entrance in the human lymphoblastoid alpha-IFN maintenance portion of the study depended on response to initial FLU. Following randomization we administered alpha-IFN, or no therapy at all, to patients who obtained a complete or a partial response after FLU therapy. The alpha-IFN dose was 3 x 10(6) U three times per week until disease progression. RESULTS: Twenty-one B-CLL patients achieved major responses, as did 17 of those with LG-NHL. Twenty-four of the former group and 11 of the latter failed to respond or obtained only a minor response. The 38 patients who responded well and entered the second part of the trial showed significant prolongation of remission duration with maintenance alpha-IFN. CONCLUSIONS: In consideration of its significant activity, the role of FLU in the management of lymphoproliferative disorders needs to be evaluated further; at the same time, this preliminary analysis seems to indicate that maintenance alpha-IFN may extend remission duration in B-CLL and LG-NHL.

Cancer vaccines are conceived as therapeutic tools, in contrast to the prophylactic vaccines used to fight against infectious diseases. Among the most potent therapeutic vaccines, anti-idiotype vaccination is directed against the tumor idiotype, the only well-characterized tumor antigen displayed in neoplastic B-cells. Anti-idiotype vaccines have demonstrated clinical benefit against follicular lymphoma and are currently being evaluated in two different phase III clinical trials. Additional emerging strategies, which include the use of dendritic cells and the production of vaccines via molecular means will surely allow us to draw important conclusions concerning the treatment of cancer patients.

Background and Objectives. Among B-cell malignancies, follicular lymphomas (FL) more frequently show acquired, potential N-glycosylation sites (AGS) within tumor-specific immunoglobulin. The aim of this study was to extend this observation and to evaluate the pattern of presentation of AGS within five different forms of B-cell lymphoma. Design and Methods. We sequenced the tumor-specific immunoglobulin heavy chain variable region fragment, including complementarity-determining regions 2 and 3, of forty-seven consecutive patients with a B-cell malignancy enrolled in idiotype vaccine clinical trials. This sequencing approach is known to allow the identification of most AGS. We then statistically analyzed differences in presentation pattern, in terms of tumor histology, immunoglobulin isotype, AGS location and amino acid composition. Results. All twenty-four FL cases presented with at least one AGS, whereas the vast majority of four B-cell lymphoma types other than FL did not. The non- FL group of tumors included four cases of Burkitt’s lymphoma, six of diffuse large cell lymphoma, seven mantle cell lymphomas and six small lymphocytic lymphomas. Most IgM-bearing follicular lymphoma cases featured their AGS within complementarity-determining region 2, as opposed to those bearing an IgG, which mostly displayed the AGS within complementarity- determining region 3. The vast majority of AGS located within either complementarity- determining region ended with a serine residue, whereas those located within framework regions mostly featured threonine as the last amino acid residue. Interpretation and Conclusions. In our series, all cases of FL had AGS within their tumor-specific immunoglobulin heavy chain variable regions. In contrast, most B-cell malignancies other than FL did not. Further studies are warranted in order to establish the possible meaning of these findings in terms of disease pathogenesis, their diagnostic value in doubtful cases and their potential implications for immunotherapy.

La continua búsqueda de abordajes terapéuticos que mejoren los tratamientos convencionales de las enfermedades neoplásicas junto con el mejor conocimiento del sistema inmunitario ha llevado en los últimos años al desarrollo de la inmunoterapia. Básicamente se pueden distinguir dos formas de inmunoterapia: la inmunoterapia pasiva, que consiste en la transferencia de anticuerpos o células previamente generados in vitro que se dirigen contra el tumor, y la inmunoterapia activa, que pretende activar in vivo el sistema inmunitario e inducirlo a elaborar una respuesta específica contra los antígenos tumorales. Las neoplasias hematológicas, concretamente algunos linfomas B, expresan en su membrana una inmunoglobulina que se considera un verdadero antígeno específico de tumor; por eso estas enfermedades se han convertido en la diana ideal de los tratamientos de inmunoterapia. Las alternativas son muchas, desde las vacunas proteicas que ya han demostrado beneficios clínicos, hasta las de segunda generación, que aprovechan las nuevas técnicas de biología molecular para aumentar la eficacia de las vacunas y conseguir su producción de forma más rápida y menos costosa, pero con las que todavía no hay resultados clínicos definitivos. 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.

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.

Acute promyelocytic leukemia (APL) represents a biologic and clinically well-defined subtype of acute nonlymphocytic leukemia with specific morphologic and karyotypic characteristics. Although secondary leukemia and myelodysplastic syndromes (MDS) are the most frequent secondary neoplasms following chemotherapy for acute leukemia, their development after complete remission in patients with APL is uncommon. We describe the clinical and genetic features of two APL patients who achieved CR after chemotherapy and all-trans retinoid acid treatment and subsequently developed a MDS. Therapy-related MDS karyotype changes such as abnormalities of chromosomes 5 and 7 were found in the cytogenetic analysis. Since TP53 alteration was detected in one case, possible implications of these findings in the onset of MDS are discussed.

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.

With the development and refinement of new guidance methods for percutaneous biopsies, many investigators have reported studies supporting a role for radiologically guided core-needle biopsy in the diagnosis of malignant lymphoma under certain clinical circumstances. The aims of this report are to evaluate the efficacy of findings at ultrasound (US)-guided core-needle biopsy of abdominal lymphoma on patient care and define the key determinants of clinical success.US-guided core needle biopsies were performed in 55 patients with abdominal lymphoma: 44 non-Hodgkin's lymphoma (NHL) and 11 Hodgkin's disease (HD); 41 had had no prior lymphoma and 14 had previously diagnosed lymphoma. All the biopsies were performed under US control using a 21-gauge modified Menghini needle. Overall, 53/55 (96%) patients were treated on the basis of biopsy findings only, including 14/14 (100%) patients with a history of lymphoma and 39/41 (93%) patients with no such history.In 46/53 (87%) patients it was possible to assess the specific histotype. No differences between the diagnostic rates of HD and high grade-NHL were recorded. There were no complications related to the biopsies.Our data indicate that abdominal US-guided core-needle biopsy should be considered as an effective and safe procedure in the diagnosis of patients with lymphoma offering the possibility of determining the tumor subtype and the subsequent specific treatment.

Fludarabine (FLU) is a new antimetabolite chemotherapeutic agent with promising activity in lymphoproliferative disorders and, in particular, in low-grade non-Hodgkin's lymphoma (LG-NHL). Recently, a few reports have described interesting results using FLU in polychemotherapy regimens. In order to evaluate FLU in combination with other antineoplastic agents, we used a combination of FLU and idarubicin, called the FLU-ID regimen, to treat 10 patients with recurrent LG-NHL. The FLU-ID regimen was as follows: FLU 25 mg/sqm i.v. on days 1 to 3 and idarubicin 12 mg/sqm i.v. on day 1. Of the 10 patients, 2 (20%) achieved complete response (CR), 5 (50%) partial response, and the remaining 3 showed no benefit from the treatment. The 2 CR patients are still in remission after 6 and 8 months, respectively. The median duration of overall survival of all patients was 8 months. The major toxic effects observed were neutropenia (40%) and infections and/or febrile episodes (15%); no fatalities due to drug side effects occurred. These results indicate the efficacy of the FLU-ID regimen in inducing a good remission rate with moderate side effects in recurrent LG-NHL.

Age is an important factor, especially in patients with advanced lymphoma who require more intensive and extensive therapy for any possible chance of cure. In fact, attenuation of treatment to diminish treatment-related toxicity decreases the capacity of the therapy to effect a cure.Between December, 1991 and February 1993, 29 previously untreated patients 60 years and older with high-grade non-Hodgkin's lymphoma (HG-NHL), according to the Kiel classification, were treated with a combination therapy including cyclophosphamide, mitoxantrone, vincristine, etoposide, bleomycin, and prednisone (VNCOP-B).Twenty-two patients achieved a complete pathologic remission and 5 had a partial response, with a reduction of more than 50% of tumor-related manifestations. Only two cases were resistant to VNCOP-B. Overall survival was 75%, with a median follow-up of 13 months from diagnosis; four of the patients who achieved complete response relapsed after a median follow-up of 11 months from the completion of treatment. Clinical and hematologic toxicity was irrelevant: in 12 patients, neutropenia was responsible for a temporary interruption of therapy for 1-2 weeks.This regimen was effective in inducing a good remission rate with moderate toxic effects in elderly patients with HG-NHL, but a longer follow-up is warranted before definitive conclusions can be drawn.