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.

[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.

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)

Cytokine gene transfer into dendritic cells for cancer treatment.

Bone marrow-derived dendritic cells have been used to treat established experimental tumors by unleashing a cellular immune response against tumor antigens. Such antigens are artificially loaded onto dendritic cells' antigen-presenting molecules by different techniques including incubation with synthetic antigenic determinants, tumor lysates or nucleic acids encoding for those relevant antigens. Ex vivo gene transfer with viral and non-viral vectors is frequently used to obtain expression of the tumor antigens and thereby to formulate the therapeutic vaccines. Efficacy of the approaches is greatly enhanced if dendritic cells are transfected with a number of genes which encode immunostimulating factors. In some cases, such as with IL-12, IL-7 and CD40L genes, injection inside experimental malignancies of thus transfected dendritic cells induces complete tumor regression in several models. In this case tumor antigens are captured by dendritic cells by still unclear mechanisms and transported to lymphoid organs where productive antigen presentation to T-cells takes place. Many clinical trials testing dendritic cell-based vaccines against cancer are in progress and partial clinical efficacy has been already proved. Transfection of genes further strengthening the immunogenicity of such strategies will join the clinical club soon.

Inducción de activación de NF-kB y maduración parcial en células dendríticas infectadas con adenovirus recombinantes / Dendritic cells infected with recombinant defective adenoviruses undergo NF-kB activation and partial maturation

Las células dendríticas se vienen usando como adyuvantes naturales para inducir respuestas inmunitarias con utilidad terapéutica. Para conseguir esto, los genes que codifican para antígenos relevantes son transfectados en células dendríticas mediante vectores virales y no virales. Los adenovirus recombinantes defectivos que codifican para antígenos o citoquinas se utilizan con gran eficiencia para transfectar ex vivo células dendríticas. Aquí hemos estudiado los efectos de infectar células dendríticas humanas y murinas con adenovirus que codifican para el gen reportero -galactosidasa (AdCMVLacZ). La infección con AdCMVLacZ induce la translocación nuclear de diferentes factores de transcripción de la familia de NF -B, a través la inducción de fosforilación de I -B según se demuestra mediante geles de retardo de movilidad e inmunoblots. La activación de NF- B se indujo también con capsides virales semipurificadas o adenovirus sin transgén, pero no mediante un adenovirus que codifica para un inhibidor dominante negativo de I -B (AdCMVI -B). A diferencia de AdCMVI B , AdCMVLacZ induce aumentos en la expresión de CD40, CD80 y CD86 con aumentos menos significativos de MHC clase II. También induce la expresión de IL-6 pero no de TNF ni IL-12. Estos cambios hacen que las células dendríticas sean más eficientes en inducir proliferación en MLR alogénicos. Nuestros resultados muestran que los adenovirus recombinantes inducen de forma independiente de transgén, cambios en el status madurativo de células dendríticas humanas y murinas que son relevantes para sus funciones. (AU)

Thrombopenic purpura induced by a monoclonal antibody directed to a 35-kilodalton surface protein (p35) expressed on murine platelets and endothelial cells.

OBJECTIVE: With the aim of obtaining monoclonal antibodies (mAbs) against mouse endothelial surface antigens, immunization of rats with a mouse-derived endothelial cell line (PY4.1) and subsequent hybridoma production were performed. MATERIALS AND METHODS: One of the mAbs produced by hybridoma EOL5F5 was selected for its surface binding to endothelial cell lines, and identification of the mAb-recognized antigen was performed by immunoprecipitation. Experiments were performed to analyze the effects of EOL5F5 on systemic administration to mice. RESULTS: EOL5F5-recognized antigen was a single band of 35 kDa under reducing and nonreducing conditions, features that do not match other known differentiation antigens with comparable tissue distribution. In vivo administration of purified EOL5F5 mAb to mice (n = 20) induced intense cutaneous purpura as well as severe but transient thrombocytopenia. Expression of EOL5F5-recognized antigen was detected on platelets from which it immunoprecipitated a moiety of identical electrophoretic pattern in SDS-PAGE, as the one recognized on endothelial cells. Immunohistochemically, EOL5F5-recognized antigen (p35) also was expressed on dermal capillaries, suggesting that, in addition to thrombocytopenia, damaging effects of the antibody on endothelial cells also might cause the observed purpura. CONCLUSIONS: Our results show induction of thrombocytopenic purpura in mice with an mAb against a single antigenic determinant expressed on both platelets and endothelium. EOL5F5 mAb injection sets the stage for useful experimental models that resemble immune thrombocytopenic purpura.

Genetic heterogeneity in the toxicity to systemic adenoviral gene transfer of interleukin-12.

Despite the efficacy of IL-12 in cancer experimental models, clinical trials with systemic recombinant IL-12 showed unacceptable toxicity related to endogenous IFNgamma production. We report that systemic administration of a recombinant adenovirus encoding IL-12 (AdCMVmIL-12) has a dramatically different survival outcome in a number of mouse pure strains over a wide range of doses. For instance at 2.5 x 10(9) p.f.u., systemic AdCMVmIL-12 killed all C57BL/6 mice but spared all BALB/c mice. Much higher IFNgamma concentrations in serum samples of C57BL/6 than in those from identically treated BALB/c were found. Causes for heterogeneous toxicity can be traced to differences among murine strains in the levels of gene transduction achieved in the liver, as assessed with adenovirus coding for reporter genes. In accordance, IL-12 serum concentrations are higher in susceptible mice. In addition, sera from C57BL/6 mice treated with AdCMVmIL-12 showed higher levels of IL-18, a well-known IFNgamma inducer. Interestingly, lethal toxicity in C57BL/6 mice was abolished by administration of blocking anti-IFNgamma mAbs and also by simultaneous depletion of T cells, NK cells, and macrophages. These observations together with the great dispersion of IFNgamma produced by human PBMCs upon in vitro stimulation with IL-12, or infection with recombinant adenovirus encoding IL-12, suggest that patients might also show heterogeneous degrees of toxicity in response to IL-12 gene transfer.

Infiltración prostática por linfomas no Hodgkin: a propósito de un caso

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Ignorancia inmunológica de antígenos tumorales e inyección intratumoral de células del sistema inmunitario / Immunological ignorance of tumor antigens and intratumor injection of immune system cells

La última década ha sido testigo de un debate sobre el status de la respuesta inmunitaria específica frente a antígenos asociados a células malignas en pacientes portadores de tumores. Algunos sostienen que existe una situación de tolerancia producto de la anergia o deleción de los clones linfocitarios relevantes, mientras que los modelos experimentales demuestran a menudo que existe un estado de ignorancia en el Sistema Inmunitario, en el que coexisten elementos re s p o n d e d o res y antígenos sin que ocurra tolerización ni respuesta efectora medible. Varios factores pueden explicar este estado, pero el que pare c e tener más importancia es la falta de acceso en condiciones apropiadas de las células del Sistema Inmunitario a las células malignas. En algunos casos la ignorancia inmunológica no puede ser distinguida de cierto grado de tolerancia periférica parcial. Proponemos que la inyección intratumoral de linfocitos T o NK y/o de células dendríticas con fines inmunoterapéuticos puede romper estos mecanismos de ignorancia o tolerancia parcial (AU)