• 5/15/2007
  • web-based article
  • Dan Jones
  • Nature Reviews (www.nature.com)

With the approval of the first active immunotherapy pending, are we poised to enter the era of clinically effective cancer vaccines?

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). The Committee voted by 17–0 that Provenge was safe and 13–4 in favour of its efficacy in the treatment of metastatic, hormone-refractory prostate cancer. If things go in Dendreon’s favour, Provenge might be approved as soon as mid-May.

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 by Thierry Boon, a biologist at the Ludwig Institute for Cancer Research, Brussels, Belgium, 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.”

Translating this simple principle into clinically useful therapies is another matter though. And the heterogeneity of cancer throws up further hurdles to evaluating cancer vaccines — some 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.

In a Phase II trial reported in 2005, Onyvax-P slowed down the rise in prostate-specific antigen (PSA) levels in 40% of patients who had already received hormone treatment, which translated into an increased time to disease progression of 58 weeks. The Phase III trials are due to run for another year. “If we get good results, we hope to get it registered, in which case I’d immediately like to use the vaccine before hormone treatment — the current gold standard — on the grounds that if it is active after hormone treatment it is more likely to be so beforehand,” says Dalgliesh.

At the moment, most of the effort is being directed towards inducing a tumour-specific immune response, suggests Eli Gilboa, Professor of Microbiology and Immunology at the University of Miami, Florida, USA. But the induction of immunity is just one step — to engender protective immunity against cancer you also need to ensure the persistence of the vaccine-induced immune response in the cancer patient. Moreover, cancers can actively suppress the immune response. “The question is why tumours are able to grow unchecked,” says Gilboa. “Is it because they naturally elicit only weak immunity, or is it because they suppress immunity?” Gilboa argues that overcoming tumour-induced immune suppression is likely to be an important component in the fight against cancer.

It has become clear in recent years that tackling cancer will require more than merely priming the immune system with cancer antigens. “I think the whole field has come to the position that a cancer vaccine is one component of the whole equation,” says Neil Berinstein, Head of the Cancer Vaccine Program at Sanofi–Pasteur, Toronto, Canada. “We also need to manipulate some of the other pathways that are perturbed by cancer and which limit the quality of the immune response.”

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.”

The clinical evaluation of cancer vaccines has also been hampered by the patient populations available for study. “Cancer vaccine researchers are often at the back of the line when it comes to getting patients — you only get them after standard therapy, and by then the disease is far gone,” says Offringa. Seriously ill patients are unlikely to have the functioning immune systems required for an effective vaccine strategy. “After optimizing the technology, a major step forward in achieving efficacy with cancer vaccines will be applying them in patients with less developed disease,” predicts Offringa.

Despite the progress that has been made and the lessons that have been learned over the years, there are still basic questions about how to get the most out of the immune system using therapeutic vaccines. It is this lack of knowledge, rather than a flaw in the principle of cancer vaccines, that explains the poor results achieved with cancer vaccines over the past decade, Offringa suggests. “We’re only now truly beginning to understand how vaccines need to be composed, where they need to be administered and how often,” says Offringa.