Cancer vaccines on the horizon

On 29 March this year, the US FDA's Office of Cellular, Tissue and Gene Therapies Advisory Committee met to discuss the fate of Dendreon's leading cancer vaccine candidate Provenge (Sipuleucel-T). Provenge represents an extreme of 'personalized medicine'. Dendritic cells, which mop up antigens and present them to other cells of the immune system to stimulate a response, are taken from patients and then sent to one of Dendreon's repositories where they are treated with the prostate-specific antigen prostatic acid phosphatase (PAP), which is found in 95% of prostate cancers. On 29 March this year, the US FDA's Office of Cellular, Tissue and Gene Therapies Advisory Committee met to discuss the fate of Dendreon's leading cancer vaccine candidate Provenge (Sipuleucel-T). Provenge represents an extreme of 'personalized medicine'. Dendritic cells, which mop up antigens and present them to other cells of the immune system to stimulate a response, are taken from patients and then sent to one of Dendreon's repositories where they are treated with the prostate-specific antigen prostatic acid phosphatase (PAP), which is found in 95% of prostate cancers. Once returned to the patient, these activated dendritic cells should, in principle, activate T cells to attack and destroy cancer cells that are expressing PAP, leading to the eradication of the tumours.

The cell-based approach taken by Dendreon is one of several options being pursued by cancer vaccine developers. Another popular approach is to use viral vectors to deliver genes encoding proteins that stimulate the immune system to attack cancer cells. Since the first such tumour antigens were identified in the early 1990s enthusiasm for cancer vaccines has been steadily building. In both cases, the principle is the same. "You have to treat the immune system like a police dog," says Rienk Offringa, Head of the Tumour Immunology Group at the University of Leiden, the Netherlands. "Once it has the 'scent' of the tumour antigens it can look for cells that express them."

Some vaccines will be better suited for treating certain types of tumour than others. "It's horses for courses," says Angus Dalgliesh, Professor of Oncology at St George's University Hospital, London, UK. "It should be much easier to increase the time to disease progression and improve survival in cancers that develop more slowly and predictably, like prostate cancer."

Dalgliesh's spin-off company Onyvax currently has a prostate cancer vaccine, Onyvax-P, in Phase III trials. Onyvax-P comprises a series of cell lines representing different stages of prostate cancer (and different constellations of tumour antigens) that are administered to patients to stimulate their own immune system to mount an effective response against prostate cancer.

Since 1997, Sanofi-Pasteur has been running a cancer vaccine programme based on delivering genes that encode tumour antigens using modified canarypox viruses. Early experience with the vector system demonstrated the feasibility and safety of the approach, but clinical responses were infrequent. Since then, new vector systems have been developed which, although still reliant on pox-virus vectors, incorporate many other new features.

The latest generation of vaccine, which will be entering a Phase I/II trial in melanoma this summer, carries five melanoma tumour-associated antigens as well as genes encoding three co-stimulatory molecules that should make antigen presentation and immune activation more efficient. Along with this multi-pronged vector, patients will also receive immunomodulatory molecules such as granulocyte-macrophage colony-stimulating factor and interferon, which could make T cells more effective at attacking tumour cells. "This is the first time that this multi-antigen approach with co-stimulatory molecules and immunomodulators has been used anywhere," says Berinstein. "It's taken a long time to get here, but we think this will be a state-of-the-art cancer vaccine trial."