Vaccines are biologic substances that are designed to stimulate the host immune system to elicit a neutralizing response against clinically relevant targets, including pathogens and tumors*. Active immunotherapy with vaccines has been extremely effective as prevention against infectious pathogens. However, effective vaccine therapy of chronic infectious diseases or cancer, in the therapeutic setting, remains a promising but largely unrealized goal. Hematologic malignancies are an excellent model system for vaccine therapies, in part because of accessibility to the hematopoietic and lymphatic space and susceptibility to immune effector mechanisms and availability of tumor cells for mechanistic studies.
Acronyms and Abbreviations
cDNA, complementary DNA; CTLA-4, cytotoxic T-lymphocyte antigen-4; GM-CSF, granulocyte-monocyte colony-stimulating factor; HLA, human leukocyte antigen; IL, interleukin; KLH, keyhole limpet hemocyanin; PD-1, programmed cell death protein-1; PD-L, programmed death ligand.
ADVANTAGES OF CANCER VACCINE THERAPY
Immunity elicited by therapeutic cancer vaccines offers several advantages over passive immunotherapy using monoclonal antibodies. In active immune therapy, all components of the effector immune response are host derived without murine or xenogeneic components that could cause indirect toxicity. The lack of foreign components also allows the host response to be sustained. Also, if the vaccine contains more than a single determinant of the target antigen, the immune response could be broad in scope, recognizing more than a single epitope in the antigen (polyclonal). This feature might be of particular importance for cancer immunotherapy, as mutation of individual peptide epitopes is a possible mechanism of immune evasion by tumors. In addition to inducing antibodies, which can recognize intact proteins on the surface of tumor cells, vaccines activate T cells that can recognize peptide fragments derived from proteins that may be endogenously processed and presented on the surface of tumor cells. Such T cells have various effector mechanisms capable of neutralizing tumor cells, including lysis of the tumor cell by cell-to-cell contact and the local production of cytokines that might directly neutralize tumor cells (e.g., interferon-γ).
COMPONENTS OF THERAPEUTIC CANCER VACCINES
Most therapeutic cancer vaccines that are being tested in clinical trials have at least three components: antigenic material derived from the tumor, a carrier, and an adjuvant. The antigenic material is usually a protein or peptide derived from the tumor that is either uniquely expressed or is overexpressed in the tumor, compared with normal tissues. A unique tumor antigen or the overexpression of the antigen to prevent the tumor is necessary to prevent the induction of an unwanted autoimmune response against normal tissues following vaccination. The carrier is necessary for delivery of the tumor antigen to antigen-presenting cells, such as dendritic cells, so as to induce the immune response against the tumor antigen. The third component of ...