Cancer Vaccines Advance To Commercialization, But Challenges Lie Ahead in the Road to Success

07 June 2004 00:01  [Source: ICB Americas]

Despite significant commercial potential, cancer vaccines remain an elusive opportunity. Feliza Mirasol reports.

The market for cancer vaccines remains tentative despite significant commercial opportunity and serious unmet medical need in current oncology therapy. With no therapeutic vaccines yet licensed for the treatment of cancer in the US, the anti-cancer market provides a hopeful landscape for the latest wave of new medicines. However, the lack of any industry benchmark leaves room for doubt as to whether commercial success can be achieved.

Cancer vaccines are meant to serve one of two functions: treatment of an existing cancer (therapeutic) or prevention of cancer development (prophylactic). Research is currently underway to evaluate several different vaccines in large human trials to determine which of the two approaches are most effective for certain types of cancers, reports the National Cancer Institute (NCI).

According to the NCI, the only cancer vaccine licensed by the Food and Drug Administration is a prophylactic vaccine against hepatitis B virus, which is associated with liver cancer. “If clinical trial results are favorable, additional cancer vaccines may be approved for use in the United States within the next few years,” states the agency. Vaccines currently under investigation include antigen/adjuvant vaccines, whole-cell tumor vaccines, dendritic cell vaccines, idiotype vaccines, and viral vectors and DNA vaccines.

The progression to Phase III clinical development of many cancer vaccine candidates marks a significant shift in pipeline status and offers the promise of future success, despite the challenges. Vaccines in Phase III clinical trials for cancers include candidates from Antigenics Inc., Aphton Corp., Biomira Inc. and partner Merck KGaA, Cell Genesys Inc., Dendreon Corp., Genitope Corporation, Igeneon, and the NCI, among others.

Antigenics’s lead product, Oncophage (HSPPC-96), is a personalized cancer vaccine in Phase III studies for renal cell carcinoma (RCC) and for melanoma. Results from the RCC trial, which has 650 patients enrolled, are expected by the end of this year or in early 2005. Submission of a biologics license application (BLA) is expected by mid-2005, says a company official. In addition, Antigenics initiated a Phase II clinical trial for Oncophage in lung cancer, which will be conducted in the UK.

A personalized vaccine, Oncophage is produced from individual patients’ tumors that have been removed in surgery. Using a proprietary manufacturing process, Antigenics isolates from the tumor the heat-shock protein gp96 and associated peptides. The vaccine is manufactured and shipped back frozen to the patient for use upon recovery from surgery. Antigenics has a manufacturing facility in Lexington, Mass., where it recently relocated from its former site in Woburn, Mass.

Miami, Fla.-based Aphton Corp. has a cancer vaccine, G17DT, in Phase III studies for pancreatic cancer. Aphton has strategic alliances with Aventis Pasteur for treating gastrointestinal system and other cancers with G17DT in North America and Europe. In October 2003, the company announced positive clinical results from one of these trials, which demonstrated increased patient survival with G17DT versus treatment with a placebo. Aphton expects to report data from a second Phase III trial in combination with gemcitabine in the fourth quarter of this year.

The company has filed for regulatory approval of the vaccine in a monotherapy indication in Australia and is also exploring other countries where it can file for a similar claim. “However, in the US, the Food and Drug Administration has required us to conduct clinical studies in combination with gemcitabine, which is a standard approved cancer therapy, and we feel it is unlikely that we will get a monotherapy indication approval in the US without the data from the combination study,” states Patrick Mooney, president and CEO of Aphton.

“Given the high level of unmet need in pancreatic cancer, and the impressive results in clinical trials so far, [we] believe that [G17DT] has the potential to establish itself in the marketplace in combination with gemicitabine in the US, and perhaps as a palliative drug therapy because of its mild toxicity profile,” notes Datamonitor, a London, UK-based consulting firm. “However, Phase III results as monotherapy do not appear strong enough to support first-line approval for pancreatic cancer in place of gemcitabine. The marketing strength of Aventis and its established presence in both the cancer and vaccines market will prove invaluable in the marketing of [G17DT] as a cancer therapeutic.”

The vaccine consists of diphtheria toxoid and a portion of the gastrin 17 (G17) hormone, which are linked chemically to form a compound that neutralizes both G17 and another hormone, Gly-G17, to treat advanced pancreatic cancer. “G17 and Gly-G17 are believed to be central growth factors, or initiating signals, for cell growth, cell proliferation and metastasis in pancreatic, gastric, esophageal, colorectal and other gastrointestinal system cancers,” Aphton’s Mr. Mooney explains. G17DT “induces in patients antibodies that bind to both gastrin 17 and gly-gastrin and remove them from circulation before they can bind to the cancer cell and initiate cell growth. [The] specificity of targeting only cancer cells occurs because gastrin is not normally secreted and gastrin receptors are not normally found on cells in the GI system, unless they are malignant, or on the path to malignancy, except cells that are involved with normal acid secretion.”

Meanwhile, Cell Genesys Inc. is moving forward with plans for the first of two Phase III clinical trials in hormone-refractory, metastatic prostate cancer for its candidate, GVAX prostate cancer vaccine. Just last month, the company obtained a special protocol assessment from the FDA that indicated the trial will adequately support a BLA. Cell Genesys expects to begin this first trial by the end of the second quarter and to initiate the second trial in late 2004 or early 2005.

The company has clinical trials underway of its other GVAX vaccines in multiple cancers, including prostate, lung, pancreatic, leukemia and myeloma. Cell Genesys’ GVAX cancer vaccines are whole-cell vaccines comprised of tumor cells that have been genetically modified to secrete granulocyte-macrophage colony-stimulating factor, an immune stimulatory hormone.

Dendreon Corp.’s lead product candidate, Provenge, recently completed a Phase III trial in advanced prostate cancer and is currently in two other separate Phase III clinical trials. One, in asymptomatic, metastatic, androgen-independent prostate cancer, stems from the previously completed study, which demonstrated an average 89 percent overall increase in survival time. Results of the follow up Phase III trial, if successful, will serve as the basis for a marketing application, says the company.

The second trial underway is in early stage, androgen-dependent prostate cancer. Provenge is also being used in a Phase II clinical trial by the NCI for testing in combination with Genentech Inc.’s Avastin (bevacizumab) for this same indication. Provenge works by stimulating the immune system to attack cells that express prostatic acid phosphatase, “a protein that is expressed on approximately 95 percent of prostate cancer cells,” says Dendreon.

Genitope Corp. just closed registration for its Phase III clinical trial at the end of March. The company is evaluating its lead candidate, MyVax (formerly referred to as GTOP-99), in patients with previously untreated follicular non-Hodgkin’s lymphoma (f-NHL). The trial is designed to test whether MyVax, a vaccine-like treatment that is both patient-specific and tumor-specific, can delay or even prevent recurrence of f-NHL in patients undergoing a period of remission after an initial course of chemotherapy. “The goal [is] to demonstrate a significant improvement in the progression-free survival time,” states the company.

MyVax is manufactured using a tumor-specific marker expressed on the patient’s malignant B-cells, which acts as a fingerprint unique to each patient. The therapy is then used to stimulate the patient’s own immune system to recognize these tumor cells as foreign and to attack the malignant growth while leaving healthy cells intact.

Igeneon, a European biopharmaceutical company in Vienna, has also initiated two additional Phase III clinical trials for its cancer vaccine candidate, IGN101. The first is a placebo-controlled study in metastatic colorectal cancer. The second is a controlled study in adjuvant breast cancer, which the company says is the first pivotal trial worldwide with a breast cancer vaccine in the adjuvant setting. A placebo-controlled Phase II/III trial in adjuvant non-small cell lung cancer (NSCLC) is ongoing.

IGN101 stimulates the immune system by triggering a response to epithelial cell adhesion molecule, a membrane protein that is almost always expressed, and often over-expressed, on epithelial cancer cells, Igeneon points out. The vaccine targets the selective destruction of disseminated tumor cells and may prevent or delay metastases formation.

The advancement to Phase III clinical development, though a success in itself, still poses other crucial challenges to further development. One is the underlying potential for failure at this late stage.

An example of such a setback is Biomira and Merck KGaA’s lead product candidate, Theratope. The partners reported results last summer from a Phase III clinical study of Theratope in metastatic breast cancer. Theratope did not meet the two pre-determined statistical endpoints of time to disease progression and overall survival that the companies had been seeking in the trial. However, a final analysis of the data showed a favorable trend toward improvement in survival in a subset of patients who received hormonal treatment following chemotherapy and who took the vaccine, say the companies.

“Based on our assessment of the data to date, we are not planning to seek a registration for this product at this time,” stated Biomira president and CEO, Alex McPherson, at the 26th Annual San Antonio Breast Cancer Symposium held in December 2003. “We do, however, believe that there may be scientific rationale from these Phase III data to continue with the development plans for Theratope. Once our strategy has matured, we intend to discuss our plans, which may include a registration trial, with the regulatory authorities.”

The target indications for which Biomira is positioning Theratope are highly competitive, notes Datamonitor. “Even with the marketing back-up of Merck KGaA, gaining physician attention for Theratope in a market dominated by early- and mid-life cycle immunotherapies including Herceptin and Erbitux for breast and colorectal cancers, respectively, in addition to other vaccines competing for the colorectal indication, [will] be extremely challenging.”

Despite the setback, Biomira and Merck KGaA are bolstered by favorable results from a Phase IIb trial of another candidate, BLP25 liposomal vaccine, in NSCLC. The study showed an overall improvement in patient survival by over four months. Biomira is scheduling for the manufacture of new vaccine supplies in preparation for a potential multinational registration trial. Additionally, the companies are conducting Phase II studies of Theratope in women with metastatic breast cancer being treated with hormone therapy and in men and women for the treatment of colorectal cancer.

Antigenics’ Oncophage, in Phase III clinical for kidney cancer and melanoma, is a personalized vaccine produced from the patient’s own tumor cells.

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