The potency of dendritic cells in activating T-cell responses provides the rationale for yet another antitumor vaccination strategy. The use of antigen-loaded dendritic cells to stimulate therapeutically useful cytotoxic T-cell responses to tumors has now undergone clinical trials in humans with cancer. One such vaccine, sipuleucel-T (Provenge), was recently approved for treatment of metastatic prostate cancer. In this therapy, a patient’s monocytes are extracted from peripheral blood and cultured with a fusion protein containing the antigen prostatic acid phosphatase (PAP), which is expressed by most prostate cancers, and the cytokine granulocyte–macrophage colony-stimulating factor (GM-CSF), which induces monocytes to undergo maturation to monocyte-derived dendritic cells. The resulting cells are reinfused into the patient to induce an immune response specific to the PAP antigen. This treatment reduced the risk of death by 22% and improved survival by about 4 months relative to a placebo group. Other methods in clinical trials include loading dendritic cells ex vivo with DNA encoding the tumor antigen or with mRNA derived from tumor cells, and the use of apoptotic or necrotic tumor cells as sources of antigens.
16-19 Checkpoint blockade can augment immune responses to existing tumors.
Other approaches to tumor immunotherapy attempt to strengthen the natural immune responses against a tumor by one of two approaches: by making the tumor itself more immunogenic, or by relieving the normal inhibitory mechanisms that regulate these responses. The first kind of approach has been explored by inducing the expression of co-stimulatory molecules, such as B7 molecules, on tumor cells and then using these cells to activate tumor-specific naive T cells. Similarly, tumor cells may be transfected with the gene encoding granulocyte–macrophage colony-stimulating factor (GM-CSF) in order to induce the maturation of tumor-proximal monocytes into monocytederived dendritic cells. Once these cells have differentiated and capture antigens from the tumor, they may migrate to the local lymph nodes and activate tumor-specific T cells. No approved therapies have yet emerged from these approaches. In mice, B7-transfected cells seem less potent than the monoctye-derived dendritic cells differentiated by GM-CSF in inducing antitumor responses. This may be because molecules in addition to B7 act in priming naive T cells and these molecules may be expressed only by specific types of cross-presenting dendritic cells.
Another approach to cancer immunotherapy is called checkpoint blockade, which attempts to interfere with the normal inhibitory signals that regulate lymphocytes. Immune responses are controlled by several positive and negative immunological checkpoints. A positive checkpoint for T cells is controlled by the B7 co-stimulatory receptors expressed by professional antigen-presenting cells such as dendritic cells, as discussed earlier. Negative immunological checkpoints are provided by inhibitory receptors such as CTLA-4 and PD-1.
CTLA-4 imposes a critical checkpoint for potentially autoreactive T cells by binding to B7 molecules on dendritic cells and delivering a negative signal that must be overcome by other signals before T cells can become activated. Blocking CTLA-4 with antibodies may therefore lower the threshold for T-cell activation. Some evidence also indicates that anti-CTLA-4 antibodies may augment immune responses by eliminating regulatory T cells, which express CTLA-4 on their surface. Whatever the mechanism, the absence of this checkpoint causes self-reactive T cells that are normally held in check to become activated instead and produce a multi-tissue autoimmune reaction, as seen in CTLA-4-deficient mice.