RESUMEN
Idiotype protein, among the first identified tumor-specific antigens, has been found to stimulate both humoral and cellular responses in lymphoma and myeloma patients. With the increasing use of B cell depletion treatments such as rituximab in clinic, the cellular response mediated by idiotype-specific T cells has become increasingly important as an adjunct therapy for lymphoma and myeloma. Here, we review the idiotype protein as a tumor antigen and the characteristics of the T cell response elicited idiotype vaccination. We also analyze the T cell epitopes that have been identified in idiotype protein and introduce our new findings of additional T cell epitopes derived from the Ig light chain. Finally, we propose new directions in the generation of idiotype-specific T cells for tumor therapy.
Asunto(s)
Idiotipos de Inmunoglobulinas/inmunología , Linfoma/inmunología , Mieloma Múltiple/inmunología , Linfocitos T/inmunología , Animales , Antígenos de Neoplasias/inmunología , Epítopos de Linfocito T , Humanos , Cadenas Ligeras de Inmunoglobulina/inmunología , Inmunoterapia , Ratones , VacunaciónRESUMEN
The clonal immunoglobulin molecule, idiotype (ID), expressed on the surface of B-cell malignancies can function as a tumor-specific antigen. BiovaxID is a patient-specific therapeutic cancer vaccine composed of the tumor idiotype conjugated to a carrier protein, keyhole limpet hemocyanin (KLH). In a Phase II clinical trial, administration of ID-KLH vaccine together with granulocyte-macrophage colony-stimulating factor to follicular lymphoma patients in complete remission induced tumor-specific cellular and humoral immunity and molecular remissions, and was associated with prolonged disease-free survival. A randomized, double-blind, Phase III clinical trial is ongoing to definitively determine the clinical benefit of BiovaxID plus granulocyte-macrophage colony-stimulating factor vaccination in patients with follicular lymphoma.
Asunto(s)
Vacunas contra el Cáncer/uso terapéutico , Drogas en Investigación/uso terapéutico , Idiotipos de Inmunoglobulinas/uso terapéutico , Linfoma no Hodgkin/prevención & control , Animales , Vacunas contra el Cáncer/inmunología , Células Clonales , Humanos , Linfoma no Hodgkin/inmunologíaRESUMEN
The unique antigenic determinants, termed idiotype, of the immunoglobulin expressed on a given B-cell malignancy can serve as a tumor-specific antigen for active immunotherapy. Administration of autologous tumor-derived idiotype protein conjugated to a carrier protein, keyhole limpet hemocyanin, together with granulocyte-macrophage colony-stimulating factor to follicular lymphoma patients in complete clinical remission was associated with induction of tumor-specific cellular and humoral immunity, molecular remissions, and prolonged disease-free survival. Idiotype vaccination in patients with mantle cell lymphoma following rituximab-containing chemotherapy induced tumor-specific T-cell immunity in the absence of B cells, suggesting that vaccines may be used in combination with rituximab. Three double-blind, randomized, Phase III idiotype vaccine trials are currently ongoing to definitively determine the clinical benefit of idiotype-keyhole limpet hemocyanin plus granulocyte-macrophage colony-stimulating factor vaccination in patients with lymphoma. Results from early clinical trials with idiotype vaccines suggested that both humoral and cellular immune responses may be independently associated with tumor regression and improved progression-free survival. With the increased use of rituximab for the treatment of follicular lymphoma and other B-cell non-Hodgkin's lymphomas, further improvement in the potency of the vaccines would require strategies to enhance T-cell responses, as rituximab depletes normal B cells and impairs the generation of antibody responses.