Journal Article

DNA vaccines: precision tools for activating effective immunity against cancer

Ottensmeier, Christian H., Rice, Jason, Stevenson, Freda K.

2008

Overview

Key Points Preventative vaccination against infectious organisms has had a dramatic effect on public health. Therapeutic vaccination against cancer is more challenging but, armed with new immunological insight and genetic technology, aims similarly to harness the power of the immune system, in this case to destroy or suppress tumour cells. Passively transferred antibodies and T cells are clearly able to attack human cancer cells in vivo and are included in treatment protocols for some cancers. Active vaccination would generate these effector pathways, together with immunological memory that is able to continuously detect and remove any emergent cancer cells. Tumour antigens are being rapidly revealed, and can be expressed on cell surfaces or, more commonly, as peptides in association with the major histocompatibility complex class I (or II) molecules. DNA vaccines can be designed to activate antibody and/or T-cell responses, providing focused immune attack on selected antigens. DNA vaccines offer a precise but flexible strategy for delivering antigens to the immune system, and additional sequences encoding molecules to manipulate outcome can be included. The problem of translating success in preclinical models to patients seems to be overcome by using electroporation, which dramatically improves performance and is now in clinical trials for prostate cancer. The key to bypassing immune tolerance and activating high levels of anti-tumour antibody or cytotoxic T cells lies in inducing CD4 + T-cell help. Sequences derived from microbial antigens can be incorporated into anti-tumour DNA vaccines, a strategy which mobilizes help for anti-tumour responses from the large non-tolerized anti-microbial repertoire. Clinical trials are the real test, but the current question is largely of efficacy rather than toxicity. New thinking is informing pilot trial design within a highly regulated environment, and immunological assays that can be predictors of clinical outcome are developing rapidly. DNA vaccines against cancer allow a high degree of molecular precision, but until recently translation into the clinic has been difficult. Advances in delivery techniques are now allowing them to fulfil their potential. DNA vaccination has suddenly become a favoured strategy for inducing immunity. The molecular precision offered by gene-based vaccines, together with the facility to include additional genes to direct and amplify immunity, has always been attractive. However, the apparent failure to translate operational success in preclinical models to the clinic, for reasons that are now rather obvious, reduced initial enthusiasm. Recently, novel delivery systems, especially electroporation, have overcome this translational block. Here, we assess the development, current performance and potential of DNA vaccines for the treatment of cancer.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: Animals / Antigen Presentation / Antigens / Antigens, Neoplasm - metabolism / B-Lymphocytes - metabolism / Biomedical and Life Sciences / Biomedicine / Cancer / Cancer Research / Cancer vaccines / Cancer Vaccines - therapeutic use / Care and treatment / CD4 antigen / CD4-Positive T-Lymphocytes - metabolism / Clinical trials / Cytotoxicity / Deoxyribonucleic acid / DNA / DNA vaccines / Dosage and administration / Drug Design / Electroporation / Forecasts and trends / Humans / Immune System / Immunological memory / Immunological tolerance / Immunology / Immunotherapy / Lymphocytes T / Major histocompatibility complex / Models, Biological / Neoplasms - genetics / Neoplasms - immunology / Neoplasms - therapy / Nucleotide sequence / Prostate cancer / Public health / review-article / Tumors / Vaccines / Vaccines, DNA - chemistry / Vaccines, DNA - therapeutic use