Cancer vaccines for established cancer: how to make them better?

If one envisions dendritic cells (DCs) as nature's adjuvant, then it is easy to predict that they would be advantageous for cancer immunotherapy. Advances in culture processes that generate large numbers of purified and functionally mature DCs raised the possibility that DCs might be promising clinical agents to generate effective immune responses against cancer. The use of mature DCs as cellular vaccines was proposed to be superior to conventional strategies aimed at treating cancer, yet a phase III clinical trial in patients with melanoma demonstrated no increased benefit of DCs over standard therapy. Despite this and other apparent failures, we propose that DC-based therapy should not be discarded but rather reassessed. The heterogeneity of DCs and their interaction with other innate cells and regulatory and effector pathways must be clearly understood before the full therapeutic benefit of DCs are recognized. Several aspects of DC vaccination require optimization including the following: effective delivery of vaccines to DCs in lymphoid tissues; incorporation of components that induce appropriate DC activation; and facilitation of innate and adaptive interactions and reduction of regulatory T-cell networks or suppressive microenvironments that hinder the function of immune effectors. Application of this knowledge is resulting in encouraging new data in pre-clinical settings, where multiple arms of the immune system are targeted for cancer therapy.