ADMIN OF AUTOLOGOUS DENDRITIC CELLS ACTIVATED BY GM-CSF & IL-4 AS TUMOR VACCINE

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Bladder cancer will kill 12,000 people this year. Nearly 30-35% of patients present with muscle invasive disease. The standard therapy is radical cystectomy, however, 40-50% of patients will recur. Neoadjuvant chemotherapy offers no clear survival benefit in this setting, so novel treatment strategies are necessary. Dendritic cells (DC) are highly potent antigen presenting cells that stimulate primary and secondary immune responses. Preclinical in vitro and animal data have shown that enriched DC can be harvested from peripheral blood and cultured in the presence of cytokines to enhance DC function. Using tumor lysates or antigen peptide culture, tumor-specific presentation can result in a heightened T-cell response and an antitumor effect in animals and in humans. Data from ongoing Phase I trials in a variety of advanced adult and pediatric tumors has also demonstrated a minimal observable toxicity with the administration of intradermal dendritic cell vaccination. The hypothesis of this proposal is that DC can be utilized to present bladder tumor specific antigens to the immune system through exposure to tumor antigens using intratumoral injection. This Phase I trial will outline the safety profile of intratumoral injection of activated and KLH-pulsed autologous dendritic cells. In this regard, a dose escalation of dendritic cell administration will be employed. We will study the feasibility of intravesical intratumoral cell injection using flexible cystoscopy for visually directed administration in the outpatient setting. Further, immunologic and antitumor responses related to DC vaccination will be explored through immunologic and immunohistochemical analyses. The specific aims of this study include the following: 1. To determine the safety of weekly intratumoral administration of autologous, activated, KLH-pulsed dendritic cell vaccines in locally advanced bladder cancer patients. 2. To outline the feasibility of serial intratumoral DC injections. 3. To evaluate the immunologic response to activated KLH-pulsed DC therapy.