? The goal of this project is to develop a new method of treatment for Human B cell lymphoma. The immunoglobulin made by each malignant B cell tumor (idiotype) is unique and has been proven to be an effective target for specific immune attack. We will conduct Human Clinical Trials in which patients in their first and best remission after standard chemotherapy will be immunized with a vaccine made from the immunoglobulin protein derived from their own tumor. Separate trials are being conducted for idiotype proteins made by rescue hybridomas, by transfected mammalian cells and by tobacco plants. The patients will be observed for immune response and for clinical outcome. In addition a clinical trial is being performed for patients who have y et not had chemotherapy during their ?watch and wait? period. Also, clinical trials will be performed in which the vaccine will be a naked DNA molecule coding for the idiotypic protein. Animal models of B cell lymphoma will be used to develop more powerful methods of vaccination against the idiotype and to study the mechanisms of tumor immunity. Specifically, we will study the additive effects of immuno stimulatory molecules fused on the DNA or protein vaccines. Viral vectors will be developed for the introduction of immunoglobulin genes into dendritic cells, which in turn will be tested for vaccine potency. Finally, vaccine methods will be optimized for th induction of cytotoxic T cell responses against the tumor cells.? ? ? ABSTRACT FOR EXTENSION? CLINICAL TRIALS? 1. Complete immune analyses and clinical follow up of patients enrolled in all current trials.? A total of 104 patients are currently being actively followed for clinical outcome and immune response to the various trials. Some trials are actively accruing patients and or vaccinating patients. At least an equal number of patients are also still being actively followed from previous trials supported by this grant. Most of these patients are alive and are still free of lymphoma. The most important data about disease recurrence, overall survival and the relationship of these events to vaccine maneuvers and immune responses is yet to be acquired. At least five years of continued follow up and immune response testing will be necessary to harvest the data from our trials. In addition, whenever tumors recur during follow up after vaccination biopsies be will obtained of the tumor and an extensive analysis will be done to compare the phenotype of the recurring tumor, including the idiotype gene sequence, to that of the original tumor. This analysis will tell us the tumor relapsed because of an ineffective immune response or because of genetic variation within the tumor cell population which evaded the immune response.? 2. Test the clinical activity of Rituximab in patients progressing after vaccination.? When patients who have been vaccinated have recurrence of their lymphoma and eventually need further therapy, we have instituted a formal plan to test the effect Rituximab treatment. This is a very unique and special population of patients. One of the theories about the therapeutic effect Rituximab is that it leads to an immune? response against the tumor. Our patients, who have been vaccinated against idiotype, may therefore have an enhanced sensitivity to Rituximab, whether or not we had been able to find evidence of an immune response to the idiotype. Moreover, we will be able to test the effect, positive or negative, of Rituximab on any residual? immune response induced by their prior vaccination.? 3. Design and initiate new phase 11 trial for DNA vaccine.? The results from our first DNA vaccine trial is sufficiently encouraging to warrant a new trial with either an increased dose of DNA or an alternative DNA construct containing immuno stimulatory sequences.? 4. Design and initiate new phase1 trial for tobacco plant vaccine? It is already clear that immune responses are occurring for our patients on the current Phase I /II trial and that the material produced in tobacco plants is safe. We will pick the most promising dose and regimen and beginning a Phase I trial at the end of 2002.? ? ANIMAL MODELS AND PRECLINICAL STUDIES? 1. Cell free protein vaccine production system? We will optimize an already powerful cell free protein production system and test a series of idiotype constructs for the induction of protective immunity syngeneic animals. Anticipating the effectiveness of idiotype vaccination, the goal of this work will be to design a system for the rapid and cost effective production of idiotype? vaccines for large number of patients.? 2. Costimulatory molecules as vaccine enhancers? We will explore the effectiveness of tumor cells transduced with the three costimulatory molecules B 7-1.? 1, LFA-3 (TRICOM Vector) to act as whole cell vaccine in several lymphoma tumor models. The therapeutic power of cells transduced with these three genes will be compared to that of cells transduced with CD4l ligand.? Our goal will be to understand the mechanism of tumor protection and to develop new clinical trials based on vaccination with whole tumor cells transduced with the most effective costimulatory molecules.? The possibility exists that the effect of the TRICOM vector is on the antigen presenting cell rather than on the tumor cell itself. This concept will be tested by experiments co-injecting virus ,by co-injecting virus transduced tumor cells. Also experiments will be performed in chimeric mice whose antigen presenting cells and? tumor cells are of different genetic backgrounds.? 3. Antigen loaded dendritic cells as vaccines? Dendritic cells loaded with idiotype have so far proven to be the most potent means of inducing a therapeutic immune response, both in animal models and in humans. We will extend our work on dendritic cells and explore new methods of loading DCs with idiotype as well as with whole tumor cell extracts. Again, our eventual intention? will be to design new clinical trials based on the enhanced potency of the vaccine maneuver provided DCs.?
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