Rapid, high-yield production in plants of individualized idiotype vaccines for non-Hodgkin's lymphoma.

BACKGROUND: Animal and clinical studies with plant-produced single-chain variable fragment lymphoma vaccines have demonstrated specific immunogenicity and safety. However, the expression levels of such fragments were highly variable and required complex engineering of the linkers. Moreover, the downstream processing could not be built around standard methods like protein A affinity capture. DESIGN: We report a novel vaccine manufacturing process, magnifection, devoid of the above-mentioned shortcomings and allowing consistent and efficient expression in plants of whole immunoglobulins (Igs). RESULTS: Full idiotype (Id)-containing IgG molecules of 20 lymphoma patients and 2 mouse lymphoma models were expressed at levels between 0.5 and 4.8 g/kg of leaf biomass. Protein A affinity capture purification yielded antigens of pharmaceutical purity. Several patient Igs produced in plants showed specific cross-reactivity with sera derived from the same patients immunized with hybridoma-produced Id vaccine. Mice vaccinated with plant- or hybridoma-produced Igs showed comparable protection levels in tumor challenge studies. CONCLUSIONS: This manufacturing process is reliable and robust, the manufacturing time from biopsy to vaccine is <12 weeks and the expression and purification of antigens require only 2 weeks. The process is also broadly applicable for manufacturing monoclonal antibodies in plants, providing 50- to 1000-fold higher yields than alternative plant expression methods.

Idiotype vaccines for human B-cell malignancies.

After twenty years of use in humans, customized idiotypic vaccination yet remains a non-approved, experimental therapeutic option for patients with lymphoma and myeloma. Potentially applicable to all B-cell malignancies whose cells express a clonal immunoglobulin or its epitopes on their surface, this treatment is designed to prevent disease recurrence or progression. Mostly used in follicular lymphoma patients so far, idiotype vaccines have clearly shown biological efficacy, clinical efficacy and clinical benefit in this setting, although no study aiming at regulatory approval of the procedure has been able to meet its main clinical endpoints. In mantle cell lymphoma, only biological efficacy has been proven for idiotypic vaccination, while in multiple myeloma a limited number of studies support the notion of biological and perhaps even clinical efficacy, although no credible evidence of clinical benefit has still emerged. Idiotype vaccines have been produced and administered in a number of substantially different manners. Therefore, the results of most clinical trials cannot be easily compared, and even less pooled together in meaningful meta-analyses. A more creative and yet scientifically sound way to design clinical trials of customized active immunotherapies will be key to the future development of idiotype vaccines, particularly considering that we currently lack any clinical or biological indicator to possibly predict which patients are more likely to respond to idiotypic vaccination from an immunologic point of view. This review aims at summarizing the multifaceted success achieved by idiotype vaccines, as well as at outlining the challenges awaiting them in the near future: how to improve feasibility, immunogenicity and efficacy, as well as how to confirm benefit and gain regulatory approval.

Vacuna idiotípica en el tratamiento del linfoma folicular: situación actual y perspectivas futuras / Idiotype vaccines in the treatment of follicular lymphoma: current status and future perspectives

El linfoma folicular (LF) está considerado como elsegundo tipo de linfoma no-Hodgkin más común, representandomás del 20% del total de los linfomas. Es unaenfermedad de progresión lenta y curso indolente enla que, a pesar de la buena respuesta al tratamiento,las recaídas son muy frecuentes y cada vez es más difícilconseguir respuestas completas. Por ello, se puedeconsiderar que hasta el momento, el LF es incurable.La búsqueda continua de nuevas estrategias terapéuticasen enfermedades neoplásicas, junto con un mejorconocimiento del sistema inmunitario, ha llevado ala aparición de una nueva disciplina, conocida con elnombre de inmunoterapia, que aprovecha la capacidaddel sistema inmunitario de atacar lo extraño sin dañarlo propio. El LF es un tumor muy apropiado para estetipo de tratamiento por presentar un antígeno específicode tumor: el idiotipo de la inmunoglobulina monoclonalexpresada en la membrana de todas las célulastumorales. Se han realizado diversos estudios en losque se ha probado la inmunoterapia como tratamientocomplementario al tratamiento convencional. Recientemente,nuestro grupo ha publicado un estudio en el quese observa claramente que los resultados que se obtienentras la vacunación idiotípica, cuando se consigue lainmunización adecuada del paciente, son mejores quelos obtenidos con quimioterapia sola. En este sentido,es necesario seguir investigando para aclarar si la vacunaciónidiotípica pudiera no sólo mantener remisionescompletas duraderas en los pacientes vacunados, sinoincluso conseguir la curación de los mismos. Por ello,resulta interesante abordar un mejor planteamiento delos ensayos clínicos, la mejora de la producción de lavacuna y el estudio de mecanismos de la célula tumoralcapaces de modificar la inmunoglobulina específica del tumor(AU)

Follicular lymphoma is the second most prevalentnon-Hodgkin lymphoma, representing 20% of all lymphomas.Follicular lymphoma is an indolent diseasewith a slow progression in which, although exhibitinga good response to treatment, relapse is very frequentand complete remission is not easy to maintain. Therefore,the disease is regarded as incurable. The searchfor new therapeutic strategies, together with a betterunderstanding of the immune system, has led to theemergence of a new treatment named immunotherapy.Follicular lymphoma is a malignancy suitable for thiskind of treatment given the fact that it is characterizedby presenting a unique tumour-specific antigen: theidiotype of the monoclonal immunoglobulin displayedon the membrane of tumour cells. Several studies havebeen conducted to test immunotherapy as complementaryto conventional treatment. In a previous study byour group, a clear benefit was evident is obtained afteridiotypic vaccination, when an adequate immunizationof the patient is obtained, in comparison to chemotherapyalone. In this sense, analysis is needed of whetheridiotypic vaccination can produce not only long-lastingand complete remission, but even cure. It would be ofgreat interest to consider an optimisation of the experimentaldesign of clinical trials, an improvementof vaccine production, and the study of the molecularmechanisms of the tumour cell which modify the targetimmunoglobulin(AU)

[Anemia in chronic lymphatic leukemia: is erythropoietin the solution?]. / La anemia en la leucemia linfática crónica: Es la eritropoyetina la solución del problema?

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 infiltration, 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.

Anti-idiotype antibodies in cancer treatment.

As a cancer immunotherapy tool, idiotypes (Ids) have been used in different ways over the last three decades, depending on the actual human tumor cell target. It all started with passive, monoclonal, anti-Id antibody treatment of B-cell lymphoma, a setting in which results were tantalizing, but logistics unsustainable. It then moved toward the development of anti-Id vaccines for the treatment of the same tumors, a setting in which we have recently provided the first formal proof of principle of clinical benefit associated with the use of a human cancer vaccine. Meanwhile, it also expanded in the direction of exploiting the antigenic mimicry of some Ids with Id-unrelated, tumor-associated antigens for the immunotherapy of a number of solid tumors, a setting in which clinical results are still far from being consolidated. All in all, over the years Id-based immunotherapy has paved the way for a number of seminal therapeutic improvements for cancer patients, including the development of most if not all Id-unrelated monoclonal antibodies that have recently revolutionized the field.

La anemia en la leucemia linfática crónica: ¿es la eritropoyetina la solución del problema? / No disponible

La anemia es una complicación frecuente de la leucemia linfática crónica, que con frecuencia condiciona el pronóstico y la calidad de vida de estos pacientes. Distintos mecanismos fi siopatológicos conducen a este estado, entre ellos la infi ltración medular, el hiperesplenismo, la hemólisis inmune o la toxicidad de los tratamientos. El tratamiento con eritropoyetina humana recombinante se ha mostrado efi caz para el tratamiento de la anemia asociada a distintos síndromes linfoproliferativos. En este trabajo se analizan las evidencias disponibles sobre el tratamiento con eritropoyetina en la leucemia linfática crónica. Se revisan las distintas opciones posológicas, los posibles factores predictores de respuesta como los niveles de eritropoyetina endógena y el papel de la darbopoietina alfa

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

The results of consolidation with autologous stem-cell transplantation in patients with peripheral T-cell lymphoma (PTCL) in first complete remission: the Spanish Lymphoma and Autologous Transplantation Group experience.

BACKGROUND: Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of aggressive lymphomas associated with poor prognosis with standard chemotherapy. Consolidation with autologous stem-cell transplantation (ASCT) may improve survival. We present 74 patients transplanted in first complete response (CR) from the Spanish Lymphoma and Autologous Transplantation Group cooperative group. PATIENTS AND METHODS: Median age was 46 years. Eighty-eight percent presented advanced (III-IV) Ann Arbor stage; 53% had B symptoms; 52% had high lactate dehydrogenase; 65% had two or three risk factors of the adjusted-International Prognostic Index; 58% presented a high Tumor score and in 14% more than two adverse factors of the Prognostic Index for peripheral T-cell lymphoma (PIT) were observed. RESULTS: With a median follow-up of 67 months from diagnosis, the 5-year overall survival (OS) was 68% and progression-free survival (PFS) reached 63%. The multivariate analysis showed that the only factor associated with a shorter OS and PFS was the presence of more than two risk factors from the PIT risk system. CONCLUSIONS: In a retrospective study with a prolonged follow-up, consolidation with ASCT in CR patients who had presented unfavorable prognostic factors at diagnosis substantially increased the OS and PFS when compared with conventional chemotherapy. The PIT risk system identified 14% of patients without benefit from ASCT consolidation. Thus, other innovative therapies are still necessary in certain cases.

[The immunotherapy potential of agonistic anti-CD137 (4-1BB) monoclonal antibodies for malignancies and chronic viral diseases]. / El potencial de la inmunomodulación con anticuerpos monoclonales anti-CD137 (4-1BB) para terapia de enfermedades malignas e infecciones virales crónicas.

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.

El potencial de la inmunomodulación con anticuerpos monoclonales anti-CD137 (4-1BB) para terapia de enfermedades malignas e infecciones virales crónicas / The immunotherapy potential of agonistic anti-CD137 (4-1BB) monoclonal antibodies for malignancies and chronic viral diseases

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

Critical appraisal of the current status of dendritic cell based therapy

Una serie de circunstancias históricas han otorgado a las células dendríticas un lugar importante en la inmunoterapia antitumoral. El descubrimiento de su papel fundamental en la presentación antigénica ha propiciado su uso como adyuvantes en protocolos de vacunación en modelos tumorales de ratón. En estos modelos se llegaron a obtener remisiones tumorales. A finales de los años 90 la coincidencia de (i) estos prometedores resultados preclínicos, (ii) la disponibilidad en hospitales de áreas de terapiacelular (desarrolladas sobre todo para transplantes de médula ósea y (iii) protocolos de cultivo sencillos para diferenciar células dendríticas a partir de monocitos o precursores mieloides han impulsado la realización de múltiples ensayos clínicos. Los primeros datos clínicos no cumplieron las expectativas, pero se están extrayendo conclusiones sobre la actividad biológica e incluso se han obtenido algunos casos de respuestas clínicas en pacientes con cánceres avanzados. En cualquier caso, algunos de los ensayos que mejores resultados estaban obteniendo se encuentran bajo sospecha de fraude científico y otros buenos resultados obtenidos en los grupos piloto no se han reproducido cuando se han utilizado los mismos protocolos en grupos más amplios de pacientes.La situación actual del campo puede ser vista como una botella medio llena o medio vacía. En cualquier caso, se necesita mejorarla potencia terapéutica a nivel preclínico incluso con el riesgo de efectos adversos (AU)

A set of historical circumstances has centred the field of cancer immunotherapy on dendritic cells (DC). The discovery of their central role in antigen presentation for immunization gave rise to their use as adjuvants for cancer vaccination in transplantable tumour models in mice. Tumour rejections of experimental transplantable tumour models were achieved. During the late 90s concurrence of (i) this encouraging preclinical data, (ii) the availability of hospital cell therapy facilities that have been mainly set up for bone marrow transplantation and (iii) simple culture means to differentiate DC from monocytes or myeloid precursors spurred many clinical trials worldwide. Early clinical experience has not met the great expectations raised, but many lessons are being learned in terms of biological activity and cases of clinical response in advanced cases are routinely reported. However, some of the trials that reported the most encouraging clinical responses have confronted controversy due to scientific misconduct orto accumulation of successful cases in the pilot groups of patients that were not so reproducible when more patients were studied under the same protocols. The current status of the field could be seen as a half empty or a half full bottle. In either case, improvements are needed from the lab bench to increase therapeutic potency, even at the risk of side effects (AU)

Critical appraisal of the current status of dendritic cell based therapy

Una serie de circunstancias históricas han otorgado a las célulasdendríticas un lugar importante en la inmunoterapia antitumoral.El descubrimiento de su papel fundamental en la presentaciónantigénica ha propiciado su uso como adyuvantes en protocolosde vacunación en modelos tumorales de ratón. En estosmodelos se llegaron a obtener remisiones tumorales. A finales delos años 90 la coincidencia de (i) estos prometedores resultadospreclínicos, (ii) la disponibilidad en hospitales de áreas de terapiacelular (desarrolladas sobre todo para transplantes de médulaósea y (iii) protocolos de cultivo sencillos para diferenciar célulasdendríticas a partir de monocitos o precursores mieloides hanimpulsado la realización de múltiples ensayos clínicos. Los primerosdatos clínicos no cumplieron las expectativas, pero se estánextrayendo conclusiones sobre la actividad biológica e incluso sehan obtenido algunos casos de respuestas clínicas en pacientescon cánceres avanzados. En cualquier caso, algunos de los ensayosque mejores resultados estaban obteniendo se encuentran bajosospecha de fraude científico y otros buenos resultados obtenidosen los grupos piloto no se han reproducido cuando se hanutilizado los mismos protocolos en grupos más amplios de pacientes.La situación actual del campo puede ser vista como una botellamedio llena o medio vacía. En cualquier caso, se necesita mejorarla potencia terapéutica a nivel preclínico incluso con el riesgode efectos adversos

A set of historical circumstances has centred the field of cancerimmunotherapy on dendritic cells (DC). The discovery of theircentral role in antigen presentation for immunization gave rise totheir use as adjuvants for cancer vaccination in transplantabletumour models in mice. Tumour rejections of experimental transplantabletumour models were achieved. During the late 90s concurrenceof (i) this encouraging preclinical data, (ii) the availabilityof hospital cell therapy facilities that have been mainly set upfor bone marrow transplantation and (iii) simple culture meansto differentiate DC from monocytes or myeloid precursors spurredmany clinical trials worldwide. Early clinical experience hasnot met the great expectations raised, but many lessons are beinglearned in terms of biological activity and cases of clinical responsein advanced cases are routinely reported. However, someof the trials that reported the most encouraging clinical responseshave confronted controversy due to scientific misconduct orto accumulation of successful cases in the pilot groups of patientsthat were not so reproducible when more patients were studiedunder the same protocols. The current status of the field could beseen as a half empty or a half full bottle. In either case, improvementsare needed from the lab bench to increase therapeuticpotency, even at the risk of side effects

[Past, present and future of anti-idiotype vaccination]. / Pasado, presente y futuro de la vacunación anti-idiotipo.

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.

[Active immunotherapy in the treatment of haematological neoplasias]. / Inmunoterapia activa en el tratamiento de neoplasias hematológicas.

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 standard-dose 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 (i.v.) and 100 mg intracarotid cisplatin for cytoreduction (not for mobilization). At 1 month after this CT, they were mobilized with 12 microg/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 CD34+ cells was significantly lower in the CT-treated patients, both on the fourth day of filgrastim (15 vs 36 cells x 10(6)/l; P=0.01) and on the fifth (25 vs 58 cells x 10(6)/l; P=0.003), as it was the number of CD34+ cells collected per apheresis (1.3 vs 3.5 x 10(6)/l; P<0.0005). The toxic effect of a single course of BCNU-cisplatin CT led to significant impairment of the filgrastim-induced mobilization response.

Inmunoterapia activa en el tratamiento de neoplasias hematológicas / Active immunotherapy in the treatment of haematological neoplasias

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 (AU)

Indolent lymphoma: the pathologist's viewpoint.

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.

Inmunoterapia del cáncer 2002 / No disponible

No dispoinble

Efficacy of vinorelbine, epirubicin and prednisone combination regimen in pretreated elderly patients with aggressive non-Hodgkin's lymphoma.

BACKGROUND AND OBJECTIVES: To assess the efficacy and toxic profile of the NAEPP protocol, a regimen including vinorelbine, epirubicin and prednisone, in a particularly troublesome subset of patients: pretreated elderly patients with aggressive non-Hodgkin's lymphoma (NHL). DESIGN AND METHODS: From November 1998 to January 2000, 20 pretreated patients who had all relapsed after first-line VNCOP-B chemotherapy were enrolled in a phase II trial and treated with the NAEPP regimen: vinorelbine (25 mg/m(2) i.v. on days 1 and 8), epirubicin (40 mg/m(2) i.v. on days 1 and 8), and prednisone (40 mg/m(2) on days 1 and 8) with granulocyte colony-stimulating factor administered at 5 mg/kg/day on days 2-5 and days 9-12. Chemotherapy was repeated every 4 weeks for a total of 6 cycles. RESULTS: Six (30%) patients achieved complete remission (CR) and 7 (35%) had partial responses (PR), giving an overall response rate of 65%. The response rate was not affected either by type of relapse presentation (nodal versus nodal plus extranodal), presence of bulky disease, or time of relapse. No major toxic effects were recorded. INTERPRETATION AND CONCLUSIONS: These preliminary data suggest that the NAEPP regimen is an effective combination with a low toxicity profile in elderly pretreated patients with aggressive NHL. Further trials using NAEPP as a consolidation phase following first-line treatment are needed to establish the advantage in terms of CR rate and relapse-free survival in these patients.

Expression of the c-met proto-oncogene and its ligand, hepatocyte growth factor, in Hodgkin disease.

The receptor for hepatocyte growth factor (HGF) is a transmembrane tyrosine kinase that is encoded by the proto-oncogene c-met. Recently, c-MET was detected in Reed-Sternberg (RS) cells from Epstein-Barr virus-positive (EBV(+)) Hodgkin disease (HD). The c-MET, EBER-1, and LMP-1 expression in 45 lymph node biopsies and 12 bone marrow biopsies obtained from patients with HD was analyzed. In addition, HGF levels in serum samples from 80 healthy individuals and 135 HD patients in different phases of disease. In all 45 lymph node and 12 bone marrow samples examined, RS cells expressed c-MET but not HGF(+). These results were independent of the EBV infection. Interestingly, several HGF(+) dendritic-reticulum cells were found scattered around c-MET(+) RS cells. The mean +/- SEM serum HGF levels in HD patients at diagnosis and at the time of relapse were 1403 +/- 91 (95% confidence interval [CI], 1221-1585) and 1497 +/- 242 pg/mL (95% CI, 977-2017), respectively. HGF values were significantly higher than those of healthy individuals (665 +/- 28 pg/mL; 95% CI, 600-721; and P <.001 for both groups of patients) and of HD patients in remission (616 +/- 49 pg/mL; 95% CI, 517-714; and P <.001 for both groups of patients). A significant correlation was found between serum HGF levels and B symptoms at diagnosis (P =.014). In conclusion, this study indicates that HGF and c-MET constitute an additional signaling pathway between RS cells and the reactive cellular background, thereby affecting adhesion, proliferation, and survival of RS cells. Furthermore, the serum concentration of HGF in HD patients may be a useful tool in monitoring the status of disease.