Dendritic cell vaccine strategies for renal cell carcinoma.

Dendritic cell (DC) vaccines are an important experimental immunotherapy for renal cell carcinomas. DC vaccines have proven safe, but only minimal clinical efficacy has been observed to date. DC vaccine strategies reflect the continually evolving understanding of DC biology. The use of mature DCs is particularly important to avoid the induction of regulatory T cells. Better defined sources of immunizing antigens and more efficient antigen-loading will contribute to DC vaccines of better quality. Improved clinical efficacy may also be achieved using DCs that secrete biologically active IL-12, which fosters innate immunity and polarizes T helper type 1 responses that contribute to optimal antitumor immunity. Furthermore, combination therapies that treat systemic immune suppression will be crucial for obtaining improved clinical responses to DC vaccines in patients with advanced disease

Third generation dendritic cell vaccines for tumor immunotherapy.

This review summarizes our studies of the past several years on the development of third generation dendritic cell (DC) vaccines. These developments have implemented two major innovations in DC preparation: first, young DCs are prepared within 3days and, second, the DCs are matured with the help of Toll-like receptor agonists, imbuing them with the capacity to produce bioactive IL-12 (p70). Based on phenotype, chemokine-directed migration, facility to process and present antigens, and stimulatory capacity to polarize Th1 responses in CD4(+) T cells, induce antigen-specific CD8(+) CTL and activate natural killer cells, these young mDCs display all the important properties needed for initiating good antitumor responses in a vaccine setting

Limitations for TCR gene therapy by MHC-restricted fratricide and TCR-mediated hematopoietic stem cell toxicity.

The clinical use of lymphocytes engineered to express high affinity T-cell receptors (TCRs) specific for two broadly expressed tumor-associated antigens is strongly limited by MHC-restricted fratricide of lymphocytes and TCR-mediated killing of hematopoietic stem cells. Specific clinical applications must therefore be conceived to bypass these limitations

High-quality and high-avidity T cell clones specific for tumor-associated antigens and how to find them.

The adoptive transfer of lymphocytes expressing high-avidity T-cell receptors with antitumor specificity provides a promising therapy for cancer patients. Recently, we compared 12 HLA-A2-restricted, tyrosinase peptide-specific CD8+ cytotoxic T-lymphocyte (CTL) clones and demonstrated that polyfunctional type 1 helper (Th1)-cytokine secretion serves to rapidly select high-quality, high-avidity CTLs

Immune suppression in renal cell carcinoma.

The clear evidence that tumor-infiltrating lymphocytes with anti-tumor activity exist in situ raises the question why renal cell carcinomas (RCCs) progress in vivo. A complex array of factors and pathways has been identified that impinges on innate and adaptive effector cells thereby inhibiting their activity against RCCs. The current picture of suppressive mechanisms that contribute to the failure of the immune system to control RCCs is reviewed here. Understanding these complex host-tumor interactions has broad implications for successful application of cytokine therapy and other forms of immunotherapy for RCC