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Combating cancer

Targeted vaccine therapies offer alternatives to existing treatments

An abstract image created in tapestryCancer is a disease characterised by the uncontrolled proliferation of abnormal cells. Approximately 7.9 million deaths were attributed to cancer in 2007 (according to the World Health Organisation), making it one of the leading causes of death worldwide. Cancer claims the lives of more than 150,000 individuals in the UK every year.

Standard therapies for cancer include chemotherapy, radiotherapy and surgery, and although the efficacy of these therapies has been proven, they have certain limitations. Radiotherapy and systemic chemotherapy destroy both normal and cancerous cells and are associated with a range of toxicities. In addition, available therapeutic options are not suitable for all patients.

To circumvent these problems, researchers have focused on the development of new targeted therapies. Cancer vaccines are targeted therapies that use the body's immune system to prevent or treat cancer. Prophylactic vaccines are designed to prevent the development of cancer by targeting cancer-causing viruses in healthy individuals. Therapeutic cancer vaccines are designed to elicit an immunological response against cancer cells in patients with existing disease.

To date, only two prophylactic cancer vaccines have been approved by the US Food and Drug Administration (FDA): the hepatitis B vaccine for the prevention of liver cancer, and the quadrivalent human papillomavirus vaccine (Gardasil) for the prevention of cervical, vulvar and vaginal cancer. Although no therapeutic vaccines have been approved by regulatory authorities in the EU or US, several are being investigated in clinical trials.

Therapeutic cancer vaccines
All cells have unique proteins on their surfaces, known as antigens. Therapeutic cancer vaccines are designed to stimulate an immunological response by making cancer-specific antigens more 'visible' to the body's surveillance system. This is achieved by administering vaccines containing tumour antigens, antigens that have been modified to make them more 'visible' to the immune system, antigen-presenting cells (such as primed dendritic cells), or anti-idiotype antibodies (antibodies with antigen-binding sites that mimic or look like tumour antigens).

In order to heighten the immunological response, substances known as adjuvants are added to the vaccines; commonly used adjuvants include cytokines, proteins, bacteria, viruses and certain other chemicals. Therapeutic cancer vaccines can be made from the patient's own tumour antigens or cells (autologous vaccines), or from those of someone else (allogeneic vaccines).

B-cell lymphoma vaccine
Biovest International and the National Cancer Institute (NCI) are developing BiovaxID, an autologous idiotype vaccine, for the treatment of B-cell lymphoma. BiovaxID is designed to stimulate a patient's immune system to specifically target, recognise and destroy cancerous B-cells which may remain in the body following chemotherapy.

It is the only hybridoma (fusion of human lymphocytes and cancer cells) cancer vaccine that contains a high-fidelity copy of the complete idiotype; this is believed to be instrumental in eliciting a complete immunological response, and in training the immune system to maintain a response in the event of disease recurrence.

Results from a pivotal multinational phase III trial, in patients with newly diagnosed follicular non-Hodgkin's lymphoma in complete clinical remission after chemotherapy, showed that the vaccine prolonged cancer-free survival by 13.6 months or 44 per cent. At 36 months, 61 per cent of patients receiving the vaccine were cancer-free, compared to 37 per cent of patients receiving control therapy (keyhole limpet haemocyanin and granulocyte macrophage-colony stimulating factor).

BiovaxID has been granted orphan drug status in the European Union (EU) and fast-track status in the US for the treatment of follicular non-Hodgkin's lymphoma. In the future, this vaccine could be developed for the treatment of other B-cell lymphomas.

Dendreon Corporation's sipuleucel-T (Provenge), which is the first in a new class of active cellular immunotherapies, uses live antigen-presenting dendritic cells to stimulate the patient's immune system. Currently in the late phase of development for the treatment of androgen-dependent or androgen-independent prostate cancer, sipuleucel-T selectively targets prostatic acid phosphatise, an antigen expressed in 95 per cent of all prostate cancers.

In the US, sipuleucel-T has been preregistered for the treatment of androgen-independent prostate cancer in patients with asymptomatic, metastatic disease. US regulatory filing for sipuleucel-T was based on data from two phase III trials (D9901 and D9902A) in patients with advanced disease. Registration will also be based on results from the phase III, double-blind IMPACT trial in 512 men with metastatic, androgen-independent prostate cancer. An interim analysis of data from the IMPACT trial showed a 20 per cent reduction in the risk of death in sipuleucel-T recipients compared with placebo recipients; these results are consistent with those from an integrated analysis of data from the previous phase III trials. Final results from the IMPACT trial are expected in the second half of 2009.

Positive interim results have also been reported in the phase IIIb PROTECT (PROvenge Trial of Early Prostate Cancer Treatment) trial, which is investigating the efficacy of sipuleucel-T in men with early-stage, non-metastatic, androgen-dependent prostate cancer. With a total of 176 patients enrolled in 19 sites, recruitment has been completed and final data analysis is expected in mid-2009.

Heat shock proteins (HSP) serve as 'molecular chaperones' and link with a broad range of peptides derived from intracellular protein degradation, including antigenic peptides from tumour cells. Vitespen (Oncophage; Antigenics) is an autologous cancer vaccine comprising purified HSP gp96 which is designed to deliver its attached antigenic tumour peptides to antigen-presenting cells in vivo, and subsequently induce an immunological response. Vitespen theoretically contains all the antigenic determinants from a particular tumour and circumvents the need for identification of specific antigens for individual cancers. Vitespen is in clinical development for renal cell carcinoma, metastatic melanoma, non small cell lung cancer and glioma.

In a phase III trial, Vitespen did not significantly improve recurrence-free survival (primary endpoint), compared with observation, in patients with a high risk of recurrence following surgery for renal cell carcinoma. However, analyses excluding data from patients with residual disease at baseline (a trial exclusion criterion) showed that Vitespen improved recurrence-free survival in intermediate-risk patients with no residual disease. Based on these results, the Russian Ministry of Public Health granted marketing approval for this indication, and the US FDA granted permission for the vaccine to be exported to Russia. Regulatory submissions have also been made in the EU.

The pipeline is replete with noteworthy therapeutic vaccines such as the autologous tumour cell bacillus Calmette Guerin vaccine OncoVAX (Vaccinogen) for the postsurgical treatment of colorectal cancer, and the gioblastoma multiforme vaccine DCVax-Brain (Northwest Biotherapeutics). Other promising vaccines, currently being evaluated in phase III trials, include MVA-5T4 [TroVax; Oxford BioMedica, sanofi-aventis] for the treatment of renal cancer, and BLP25 liposomal vaccine [Stimuvax; Oncothyreon, Merck KGaA] and belagenpumatucel-L [Lucanix; NovaRx Corporation] for the treatment of non-small cell lung cancer.

Rigorous testing is required in order to prove the efficacy of a cancer vaccine and determine its role in relation to established therapies. Vaccines such as CancerVax (Canvaxin), Genitope Corp (MyVax personalised immunotherapy), Favrille Inc (FavId), Therion (Panvac), CG 8123 (Gvax; Cell Genesys) have not been as successful, and development of these vaccines has been terminated based on poor phase III results.

Although there is increasing representation of cancer vaccines in later stages of the pipeline, the ultimate fate of these vaccines will largely be determined by the results of ongoing trials.

The Author
Pipeline was written by Liana Siqueira of Adis International using data derived from Adis Clinical Trials Insight and R&D Insight. For further information on Adis services, please contact Camille Scot-Smith on 020 7981 0733.
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22nd February 2009


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