Oxford American handbook of oncology. Second Edition. Oxford University Press (2015)
Growing evidence suggests that loss of tumor immunosurveillance plays a major role in the progression of malignancy. The discovery of viruses involved in tumorigenesis (such as HPV in cervical cancer) and tumor-associated antigens (ta a) has led researchers to target malignancies through immunotherapeutic approaches. These may take the form of nonspecific or specific immunotherapy strategies.
The aim of nonspecific therapy is to boost immunity against malignancies through enhancement of the systemic immune response. Examples include interferon-1 (IFN-1) injection or use of high-dose interleukin-2 (IL-2) in metastatic renal cell cancer.
Administration of gene therapies that boost cytokines may be a source of future investigation.
Specific immunotherapy targets TAA, which are present specifically in cancer cells, presented on major histocompatibility complex (MHC) molecules, and able to be recognized by immune effector cells. Examples of specific immunotherapies follow.
- If MHC epitopes are known for a particular TAA, injections of peptides with appropriate adjuvant (IFN-1, for example) may be used.
- Synthetic peptides are widely available and safe through intradermal or subcutaneous routes.
- Their use is limited by the need for known epitopes of TAA.
Tumor cell lysate preparation
- Extracts of a patient’s own tumor cells are either reinjected, pulsed, or fused with antigen-presenting cells (APCs).
- Obviates need to specify TAA.
- Labor-intensive preparation and the requirement of prepared cancer tissue limit widespread use, although streamlined protocols for vaccination may make this modality more attractive in the future.
- One phase III randomized control trial (RCT) showed an increase in progression-free survival in a group of patients with stage III renal cell carcinoma; other trials have been reported.
Vaccination with recombinant DNA expressing genes known to be up-regulated in malignancies has been used as a targeted vaccination tool. Presentation of antigenic proteins then occurs after delivery of genetic information through a vector approach.
Recognition of antigenic material induces cytotoxic and humoral responses that slow progression of the tumor. Targets using this approach include the following:
- Carcinoembryonic antigen (CEA), a tumor marker expressed on most gastrointestinal malignancies. CEA-positive malignancies have been targeted in numerous clinic trials.
- Her2/neu, the epidermal growth factor receptor expressed on breast, stomach, and pancreatic cancers. Notably, humoral response to her2 may be effective in slowing tumor progression.
- MAGE-1, which is an embryonic gene product associated with malignant melanoma.
DNA vaccines are useful because they afford a high degree of specific protein expression and MHC presentation without knowledge of epitope binding. Limitations of DNA vaccines include the requisite for TAA to be known for specific tumors and obstacles associated with vector delivery of DNA.
Dendritic cell vaccination
To optimize the immune response to TAA vaccination, investigations aiming to optimize antigen presentation are under way.
Dendritic cells (DCs) are potent antigen-presenting cells (APCs) due to their expression of high levels of costimulatory molecules and MHC complexes. Their role in th1 immunity and the direction of T-cell responses to tumor vaccines make them ideal targets for cancer immunotherapy. Cultured DCs take up exogenous antigen or can be transduced with DNA vaccines through a variety of methods including viral vectors.
Elucidation of techniques for large-scale storage and expansion of DCs has made clinical trials involving autologous DCs loaded with peptides or transduced with TAA possible.
TAA-specific cytotoxic T cells may be isolated and expanded for infusion; this technique specifically targets TAA and produces a large number of TAA-specific T cells alternatively, T cells may be transduced with specific T-cell receptors through DNA incorporation or viral vectors.
Small studies have suggested that these methods produce effective antitumor immunity, but the clinical impact of such an approach is not known.
Modulation of regulatory T-cell (Treg) response in cancer immunotherapy
evidence suggests that an inhibitory immune compartment consisting of CD4+CD25+ T cells suppresses immune responses, especially in the setting of self-vaccination (such as in TAA vaccines). Approaches to decrease this component of the immune response have undergone investigation. Denileukin diftitox (Ontak) has been used to eliminate CD25+ cells in an effect to accomplish this. Further investigation and use of therapies targeting this will likely be important in guaranteeing effective immunization against TAA.