DNA vaccines: precision tools for activating effective immunity against cancer

Abstract

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.