Tumor cell-based vaccination in renal cell carcinoma: rationale. approaches, and recent clinical development.
Since there is some evidence for spontaneous immunity against renal cell carcinoma, vaccination strategies are often used in patients with this tumor type, both in the adjuvant and the metastatic setting. Therefore, therapeutic strategies aim at augmenting anti-tumor immunity, but tumor-specific antigens suitable for vaccination purposes in renal cell carcinoma still remain to be identified. Early approaches used whole tumor cells or cell lysates with or without non-specific adjuvants like BCG. Studies investigating tumor cell vaccines have demonstrated immunological responses following vaccination, like positive cutaneous delayed hypersensitivity reactions indicating biological acitivity of tumor cell vaccines, and clinical responses have been observed as well. However, no clinical benefit has been demonstrated in randomized phase III trials. In recent years, efforts to develop more potent vaccines resulted in more sophisticated methods of tumor vaccination: The insertion of "neo-antigens" to enhance immunogenicity, the insertion of T-cell co-stimulatory molecules to enhance anti-tumor T-cell activation and the local production of cytokines to enhance T-cell function or the migration of antigen-presenting cells. Tumor cells have been genetically modified to express and produce cytokines, which in turn enhance the immunogenicity of the vaccine. The important role of dendritic cells has been recognized and tumor antigen-pulsed dendritic cells have been proposed. Hybrid cell vaccines are another promising approach. Safety and some effectiveness of these vaccines were demonstrated in phase I and II trials. However, randomized phase III trials are mandatory to confirm the usefulness of vaccination strategies. This review will describe the principals of tumor vaccination and, in a second part, focus on clinical studies of tumor vaccination in patients with renal cell carcinoma.