Failure of cancer vaccines: The significant limitations of this approach to immunotherapy

Immunotherapy, has always represented a very attractive fourth-modality the rapeutic approach, especially in light of the many shortcomings of conventi onal surgery, radiation and chemotherapies in the management of cancer Subs ets of neoplastically transformed cells have been shown to (re-)express on their surface molecules which are not typically present on the surface of n eighboring normal cells. In some instances, especially in malignant melanom as, cytotoxic T lymphocytes (CTLs) directed against such tumor associated a ntigens (TAAs) have been isolated. The cancer vaccine approach to therapy i s based on the notion that the immune system could possibly mount a rejecti on strength response against the neoplastically transformed cell conglomera te. However dree to the low immunogenicity of TAAs, downregulation of MHC m olecules, the lack of adequate costimulatory molecule expression, secretion of immunoinhibitory cytokines, etc., such expectations are rarely fulfille d. Various approaches have been explored ranging from the use of irradiatio n inactivated whole-cell vaccines derived from both autologous and allogene ic tumors (even tremor cell fines), and genetically modified versions of su ch cellular vaccines which aim at correcting costimulatory dysfunction or a ltering the in situ humoral milieu to aid immune recognition and activation . Anti-idiotype vaccines, based on cancer cell associated idiotypes, have a lso been colored which aim at increasing immunogenicity through in vivo gen eration of vigorous immune responses. Dendritic cell (DC) vaccines seek to improve the presentation of TAAs to naive T lymphocytes Unfortunately, ther e is always the possibility of faulty antigen presentation which could resu lt in tolerance induction to the antigens contained within the vaccine, and subsequent rapid tremor progression. The theoretical basis for all of ther e approaches is very well founded Animal models albeit highly artificial ha ve yielded promising results. Clinical trials in humans, however have been somewhat disappointing Although general immune activation directed against the target antigens contained within the cancer vaccine has been documented in most cases, reduction in tumor load has not been frequently observed an d tumor progression and metastasis usually ensue, possibly following a slig htly extended period of remission. The failure of cancer vaccines to fulfil l their promise is due to the very relationship between host and armor: thr ough a natural selection process the host leads to the selective enrichment of clones of highly aggressive neoplastically transformed cells, which app arently are so dedifferentiated that they no longer express cancer cell spe cific molecules. Specific activation of the immune system in such cases onl y leads to lysis of the remaining cells expressing the particular TAAs in t he context of the particular human leukocyte antigen (HLA) subclass and the necessary costimulatory molecules. The most dangerous clones of tumor cell s however lack these features and thus the cancer vaccine is of little use. The use of cancer vaccines seems, at present, destined to remain limited t o their employment as adjuvants to both traditional therapies and in the ma nagement of minimal residual disease following surgical resection of the pr imary cancer mass.