Conventional vaccines have virtually wiped out some diseases that were once epidemic. Could the next generation of vaccines make cancer a thing of the past? Dr Sarah Houlton reports
Public health was revolutionised by vaccines. From Jenner's smallpox vaccine, invented at the end of the 18th century, through the pioneering work of Louis Pasteur in the century that followed, to the vaccines that have been developed in more recent years to prevent childhood illnesses and the likes of polio and influenza, vaccines have become an important tool in the prevention of disease.
Now, however, a different sort of vaccine may be able to have dramatic effects on the course of disease. In much the same way that a prophylactic vaccine stimulates the immune system to create antibodies that prevent disease, therapeutic vaccines are designed to trigger the body to make antibodies that will kill infectious agents such as viruses, or cancerous cells.
Cancer vaccines, in particular, have received a great deal of attention in recent years. They treat cancer by stimulating the immune system to destroy cancerous cells without harming normal cells, giving a much more targeted response than standard chemotherapy or radiotherapy where healthy cells surrounding the tumour are likely to be damaged too.
The basic approach is to attack antigens on the surface of cancerous cells to trigger the immune response. These antigens, usually proteins or carbohydrates, are found exclusively on cancer cells, and not healthy ones. Because the body does not normally see a tumour as foreign, the immune system leaves it alone. Tumours can also have reduced levels of antigens, meaning the body is less likely to reject it. Specifically targeting tumour antigens gets around these problems, and kick starts the immune system into action.
There are several strategies that can be used. Unique tumour antigens can be targeted. The antigens can be modified to make them more immunogenic, either by delivering a modified gene to the cell in a targeted viral vector or adding genes for immunostimulating molecules into the vector alongside genes for the tumour antigen. Another strategy is to use the antigens to attach a further molecule that the immune system clearly sees as foreign, thus triggering a response.
Many companies - particularly small biotechs - are working on cancer vaccines of various types. One of these, San Francisco-based Cell Genesys, has several vaccines in clinical trials. Its GVAX cancer immunotherapies take genetically modified tumour cells that have been altered to secrete granulocyte macrophage colony stimulating factor (GM-CSF). This hormone systemically activates the immune system to recognise and destroy cancer cells. Because whole tumour cells are used, the company believes the response will be more robust as the specific antigen does not need to be identified.
Thus far, the company has tried its vaccines in prostate, lung, pancreatic and kidney cancers, plus melanoma and myeloma. The furthest advanced is its prostate cancer immunotherapy, which is currently in Phase III. It comprises two genetically modified prostate cancer cell lines, and is being developed for use after hormonal therapy in advanced stage prostate cancer, and in May was awarded fast track status by the US FDA.
Two Phase III trials are under way, which are ultimately intended to enrol around 1200 men with metastatic hormone refractory prostate cancer. The first will compare GVAX with the standard treatment of docetaxel plus prednisone in chemotherapy naïve asymptomatic patients without cancer-related pain. The second will be a similar comparison with patients who are symptomatic and have pain.
Its GVAX lung cancer vaccine is slightly different: the vaccine is made by modifying the patient's own tumour cells after it has been surgically removed. Phase II trials are being carried out, including one in patients with non-small cell lung cancer (NSCLC) who are receiving GVAX either alone or in combination with low dose cyclophosphamide, and another which is focused on the NSCLC subtype bronchoalveolar cancer. In a Phase I/II trial in 33 patients with NSCLC, three achieved complete response, two of whom had this subtype. Median survival was significantly higher in those patients whose vaccine products secreted higher levels of the hormone GM-CSF.
Genitope, based in Redwood City, California, is also working on vaccines that are based on a patient's own tumour cells. MyVax Personalised Immunotherapy combines a tumour protein with an immunologic carrier protein, and is administered along with an immunologic adjuvant. The tumour-derived protein, or idiotype, is an antibody expressed by the tumour cells. The foreign carrier protein is itself a strong antigen, and increases the immunogenicity of the patient-specific idiotype. Genitope is currently using keyhole limpet haemocyanin as the carrier protein. The third component, the adjuvant, enhances the immune response to the two proteins, and it is using GM-CSF.
active immunotherapy
Although this type of active immunotherapy was first investigated in the late 1980s in non-Hodgkin's lymphoma (NHL), its development has been limited by manufacturing difficulties. Genitope has overcome these problems with a proprietary gene amplification process, Hi-GET, to make the cell lines needed to produce the tumour-derived protein.
MyVax is currently undergoing Phase III trials in B-cell NHL and B-cell chronic lymphocytic leukaemia. The company recently reported long-term follow-up data on a Phase II trial in NHL, which showed that those given the vaccine had a significantly longer time to disease progression than those who received chemotherapy alone. In the open label Phase II trial, 21 patients with B-cell NHL who were in their first remission and had previously been given cyclophosphamide, vincristine and prednisone combination chemotherapy, or this combination plus doxorubicin, were given a series of five MyVax immunisations over a period of six months. Nine of the patients in the trial remained progression free up to 78 months after therapy, and the median time to progression was a little over three years. The FDA has granted it fast track status.
The liposome based vaccines being developed by Biomira in Edmonton, Canada, are a combination of an antigen, adjuvants and a lipomatrix. The tumour associate antigen in the combination, sialyl Tn, is a synthetic 25 amino acid sequence of the MUC1 cancer mucin. This is encapsulated in a liposomal delivery system which enhances the recognition of the cancer antigen by the immune system and facilitates better delivery.
The first of these vaccines to reach clinical trials, Stimuvax, is a liposomal vaccine specifically designed to generate a cellular immune response to the antigen mucin MUC1. The adjuvant is a naturally extracted lipid A, but the rest of the formulations that are in preclinical development use a synthetic analogue whose potency is similar.
A randomised open label Phase IIb trial was carried out in 171 patients with Stage IIIB and IV NSCLC who had completed their first-line standard chemotherapy, with or without radiation therapy, and whose disease was stable or had responded to treatment. The patients were given Stimuvax and best supportive care, or best supportive care alone. Subjects had a median survival of 30.6 months for those in Stage IIIB, and 13.3 in Stage IV.
The vaccine also has potential in prostate cancer. An open label Phase II safety and efficacy trial was carried out in 16 patients with prostate cancer who had undergone a radical prostatectomy at least six months before the trial but had continued to experience rising prostate specific antigen (PSA) levels. Subjects were first given a single dose of cyclophosphamide, which acted as an immunomodulator to enhance the vaccine's activity. Three days later, subjects were given the first of eight weekly Stimuvax vaccinations, followed by further vaccinations every six weeks with a maximum total of 15 doses over the course of about a year.
Although PSA levels did not decrease during the study period, they were stabilised in half of the patients in the first, weekly, vaccination phase, and remained this way in one of the patients by the end of the study. PSA doubling time was prolonged by more than 50% over the pre-trial times in six further subjects by the end of the trial.
Strasbourg, France-based Transgene is working on antigen specific vaccines. Its furthest advanced product, TG 4010, which is now in Phase IIb, is being developed to treat NSCLC, and is based on a recombinant vaccinia virus that expresses the MUC1 tumour associated antigen and human interleukin-2 to stimulate an antitumour immune response.
TG 4010 is based on the modified virus Ankara (MVA), which is a non-propagative highly attenuated vaccinia virus that was originally developed for immunising high-risk patients against smallpox. The MUC1 protein is a highly glycosylated mucin that is overexpressed in tumour cells in a less glycosylated form. As there are fewer sugar molecules crowding the tumour, new peptide and carbohydrate antigens are revealed that can be targeted by a vaccine. The vaccine is designed to induce a MUC1-specific cytotoxic T-lymphocyte and antibody response, plus a non-specific activation of the immune system via the virus infection and IL2 activation.
A Phase II study was carried out to assess its efficacy in combination with cisplatin and vinorelbine. The results compared favourably with the normal responses of patients given the combination chemotherapy. A tumour response rate of 37% was achieved, and 71% of patients achieved a partial response or stable disease for at least 12 weeks, and more than half of the subjects were still alive a year after starting the trial.
A randomised open label multicentre Phase IIb study is now under way to formally evaluate its efficacy in combination with chemotherapy versus chemotherapy alone, and preliminary results are expected to be available early next year. Although the vaccine's evaluation is furthest advanced in patients with NSCLC, it is also being investigated in prostate cancer, and it also has potential in any other MUC1 positive tumour, notably breast, kidney, pancreas, stomach, ovary and colorectal cancers.
shock therapy
The approach being taken by Antigenics is based on heat shock proteins, a family of proteins that are thought to play a role in the presentation of antigens on the surfaces of cells. Also known as stress proteins, these proteins are present in all cells, and are induced when a cell undergoes various types of environmental stress, such as heat, cold and oxygen deprivation, but are also present under normal conditions where they are essential components in many of the processes a cell undergoes in its normal life, including helping the immune system to recognise disease cells.
The company has two vaccines currently in development, Oncophage and AG-858, which are designed to use the entire range of antigens from a patient's specific tumour to stimulate a strong immune response against the cancer. The Heat Shock Protein (HSP) technology works by mimicking the "danger" signal that is naturally triggered by extracellular HSPs. The two vaccines consist of HSP-peptide complexes that have been isolated from an individual patient's cancer cells, building up a "library" of abnormal peptides that is unique to the disease as it is manifested in that patient. When the cancer vaccines are injected into the body, this fingerprint of HSP-peptide complexes stimulates the immune system to target cancer cells that have the same collection of complexes.
Oncophage is the furthest advanced of the two vaccines, and the company recently reported data from a Phase III trial in patients with metastatic melanoma. In the multicentre open label trial, 322 patients with Stage IV melanoma were given Oncophage or the physician's choice of standard licensed cancer treatment. Patients given at least 10 doses of vaccine had their median survival extended by 29% compared with the control group.
A multicentre randomised open label Phase III trial has also been carried out in patients with kidney cancer. A total of 728 patients whose renal cell carcinoma was at high risk of recurrence after the kidney was surgically removed were enrolled in the trial, and half were given Oncophage vaccination. While more of the patients given Oncophage had died at the data cut-off point than those who had not, the company is encouraged that analysis of the data indicate that the vaccine appears to induce a 43% decrease in recurrence in patients in the earlier stages of the disease. The patients will continue to be followed up.
personalised approach
A different approach is being tried by Argos Therapeutics in the form of dendritic cell cancer vaccines. Dendritic cells capture, process and identify foreign bodies and alert the body's immune response, activating antibodies and T-cells to destroy the foreign material. The technology being developed by Argos loads dendritic cells with the patient's total tumour RNA, forcing the cells to recognise the complete antigenic repertoire of the tumour cells and creating an autologous vaccine that is personalised for the patient's specific disease. Because the vaccine contains all the antigens for the cancer, it means specific antigens do not need to be identified.
The starting point is to take precursors of the patient's dendritic cells and mature them. Their tumour RNA is then amplified, from the tumour site itself, metastases or even tumour cells that are present in the circulation. A single production run makes sufficient vaccine to treat the patient for several years, and only a tiny specimen of tumour is needed. Phase I/II trials are being carried out in patients with metastatic renal cell carcinoma, and trials are also planned for chronic lymphocytic leukaemia.
Dendritic cells also feature in the pathway of the non-patient-specific vaccines being developed by Cerus, based in Concord, California, based on Listeria monocytogenes bacteria. An attenuated strain of listeria is used to stimulate innate immunity by interacting with multiple pattern recognition receptors associated with antigen presenting cells, such as macrophages and immature dendritic cells. The dendritic cells are activated and mature, releasing cytokines and activating NK cells. Tumour antigens that have been engineered into the listeria are processed and presented by mature dendritic cells, priming tumour specific CD4 and CD* T-cells. These then recognise the malignant cells, leading to cytokine production and tumour cell destruction.
Phase I trials are planned in colorectal cancer that has metastasised to the liver, using the CRS-100 strain, after preclinical experiments suggested that it stimulates an anticancer immune response in the liver. Another product, CRS-207, combines the listeria technology with mesothelin, a proprietary antigen that is expressed in pancreatic and ovarian tumours. A third product that is in development, MEDI 543, is a combination of MedImmune's EphA2 antigen, expressed in a number of solid tumours such as breast, prostate, colon and metastatic melanoma, and Cerus" listeria technology.
With so many innovative approaches to developing vaccines against cancer, it can only be a matter of time before therapies that are more effective, but also do not cause the unpleasant side effects of standard chemotherapy or radiotherapy, enter the marketplace.