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5/12/2003

Cancer Vaccines Offer New Treatment Modality

Cheryl A. Thompson

The newest weaponry in the war on cancer recruits patients’ immune systems to aggressively seek cells bearing a marker distinct to a cancer-causing virus or malignant neoplasm and destroy the target wherever it exists. Known as cancer vaccines, these agents can be classified by their purpose: prophylactic, or vaccines in the classic sense, preventing the development of cancer cells; and therapeutic, treating existing cancer cells, including metastases.

First on the market. One prophylactic cancer vaccine has been available in the United States for more than two decades. Hepatitis B vaccine and its predecessor, plasma-derived hepatitis B virus vaccine, protect recipients against a liver cancer linked to infection with the virus.

According to the American Liver Foundation, hepatocellular carcinoma accounts for less than 1% of cancer cases in the United States but up to 50% of cancer cases elsewhere. This disparity, the foundation said, is believed to be caused by the relatively low percentage of hepatitis B virus carriers in the United States compared with levels elsewhere.

Produced using recombinant DNA technology, hepatitis B vaccine contains a viral surface antigen, hepatitis B surface antigen, but no nucleic acid, thus eliminating the possibility of infection from the vaccination process itself. Hepatitis B surface antigen is the marker that the human immune system most readily recognizes as the virus’s calling card. Adsorption of the antigen to aluminum hydroxide increases the likelihood that the immune system will produce antibodies to the viral marker.

Customized attack on a lymphoma. At least two therapeutic vaccines against advanced stage follicular lymphoma have reached Phase III clinical investigation. Both vaccines are conjugates of the malignant B lymphocyte’s tumor antigen, its idiotype, and keyhole limpet hemocyanin (KLH), a large protein that the human immune system more readily identifies as foreign.

“The tumor antigen is unique to each patient’s tumor,” said Larry W. Kwak, head of vaccine biology at the National Cancer Institute (NCI) in Bethesda, Maryland, and principal investigator of one of the ongoing Phase III studies. “This is the flip side of having an antigen that is truly tumor specific. [The tumor antigen] will vary from lymphoma patient to lymphoma patient, so a customized product needs to be made for each patient that comes along.”

Preparation of the vaccine takes about three months, said Kwak, starting with isolation of the patient’s tumor antigen from a biopsy sample of an affected lymph node.

According to the clinical trials database hosted by NCI, both Phase III studies involve patients who have not previously received biologic therapy or chemotherapy.

Participants in the NCI-sponsored study, conducted at six extramural sites and the Bethesda campus, undergo six months or so of cyclical treatment with prednisone, doxorubicin, cyclophosphamide, and etoposide. Six months to a year after the end of chemotherapy, patients with a complete response are randomly assigned to receive s.c. injections of their customized vaccine or KLH, which serves as the placebo vaccine, on day 1 of months 1, 2, 3, 4, and 6. Both groups also receive sargramostim to stimulate helper and killer T lymphocytes for assault for four days with each vaccination.

BioVest International Inc. of Englewood Cliff, New Jersey, produces the vaccine for NCI under a cooperative research and development agreement, according to the company.

The other study, sponsored by Genitope Corporation of Redwood City, California, involves 24 sites in the United States and Canada. Patients undergo six months of cyclical treatment with cyclophosphamide, vincristine, and prednisone. Six months after the end of chemotherapy, patients with a partial or complete response are randomized to receive s.c. injections of their customized vaccine or KLH alone on day 1 of weeks 0, 4, 8, 12, 16, 20, and 24. As with the other study, patients also receive sargramostim.

“The optimal clinical setting to administer these vaccines is a minimal residual disease setting,” Kwak said, not in patients with advanced tumors.

Vaccine administration after a complete response to standard chemotherapy removes residual tumor cells, he said. Those residual tumor cells, he explained, are responsible for the inevitable recurrence of follicular lymphoma in all patients who stop treatment after their initial complete clinical response to chemotherapy.

Enhanced effects with dendritic cells. Taking advantage of a rare group of highly efficient antigen-presenting cells known as dendritic cells is another method to increase the immune system’s recognition of cancer cells.

While effective at activating killer T lymphocytes against most antigens, normal dendritic cells do not seem to capture tumor antigens and present them for destruction. Researchers have overcome this problem by loading the tumor antigens on dendritic cells, creating dendritic cell vaccines.

The NCI clinical trials database listed one dendritic cell vaccine in Phase III investigation for the treatment of cancer, but the institute’s commercial partner said it had suspended the 17-site study and withdrawn the investigational new drug application in November 2002 because of financial problems.

According to information from Northwest Biotherapeutics, in Bothell, Washington, and the NCI database, preparation of the dendritic cell–recombinant prostate-specific membrane antigen vaccine proceeded as follows: A patient with metastatic adenocarcinoma of the prostate whose disease progressed despite antiandrogen therapy underwent leukapheresis. The white blood cells were shipped to a processing center where the peripheral blood mononuclear cells were isolated and then grown in a culture medium with interleukin-4 and sargramostim to cultivate dendritic cells. These dendritic cells were loaded with recombinant prostate-specific membrane antigen, which, Northwest said, appears on nearly all prostate cancers in significantly higher numbers than on normal prostate tissue.

In the Phase III study, patients were randomized to receive an intradermal injection of their vaccine or peripheral blood mononuclear cells at weeks 0, 4, 8, 12, 20, and 38.

Heat shock proteins. A customized therapeutic vaccine based on complexes of heat shock proteins and peptides from patients’ cancer cells is in Phase III investigation for the postsurgical treatment of kidney cancer without distant metastases and for the treatment of advanced melanoma.

All cells synthesize heat shock proteins in response to environmental stress, such as hyperthermia or hypoxia. Despite their name, these intracellular proteins serve under stress-free conditions as molecular chaperones, overseeing the assembly and folding of polypeptides and proteins and are always bound to a peptide, polypeptide, or protein.

According to Antigenics Inc. in New York City, the appearance of heat shock proteins and their charges outside a cell attracts the interest of antigen-presenting cells, which interpret the extracellular complex as the sign of a diseased cell in need of disposal. Following through on the initial action of antigen-presenting cells, the immune system hones in on cells bearing peptides identical to those in the complex.

Antigenics receives a portion of the patient’s excised kidney or melanoma metastasis, isolates complexes of heat shock protein gp96 and peptide, and produces Oncophage, a vaccine for administration when the patient has recovered from surgery.

According to the company, patients with kidney cancer receive one injection of their vaccine weekly for four weeks, usually starting within eight weeks after surgery. Patients then receive one injection every other week until their vaccine supply is expended.

Antigenics claimed in October 2001 that Oncophage was the first personalized cancer vaccine designated for fast-track status by FDA. At the time, the company said, the Phase III study of the vaccine for kidney cancer was under way at more than 100 sites in the United States and Europe.

The Phase III investigation of Oncophage in patients with metastatic melanoma is jointly sponsored by NCI and follows the same injection schedule as that of the other study. Whereas the kidney cancer vaccine trial has a placebo group that undergoes observation after surgery but does not receive simulated vaccine injections, the melanoma study has a comparative treatment—aldesleukin, dacarbazine, and temozolomide.

Prophylaxis as a backup to screening. Virtually all cases of cervical cancer can be traced to infection with a human papillomavirus (HPV), said Douglas R. Lowy, head of NCI’s cellular oncology laboratory, adding that infection is necessary but not sufficient for malignant growth to occur. HPVs also cause warts and some of the cancers of the mouth, pharynx, anus, larynx, vulva, and penis, he said, and are considered a sexually transmitted mucosal disease.

A vaccine to prevent HPV infection, Lowy said, would substantially decrease the number of abnormal Pap test results in the United States and, 20 or more years from now, reduce the development of cervical cancer in women who do not routinely undergo the screening. The goal would be to “try to prevent infection with the virus that causes the cancer.”

The Pap test screens for malignant and premalignant conditions in the female genital tract. A fairly new additional test, which also uses cells collected from the cervix, detects the presence of DNA from 13 HPV types associated with the development of cervical cancer. According to NCI, the Hybrid Capture 2 HPV DNA Test, by Digene Corporation in Gaithersburg, Maryland, tests for HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68.

Lowy heads one of the investigative efforts to develop an HPV vaccine based on L1, the virus’s major structural protein, although his candidate vaccine is not yet in Phase III testing.

“The key technological breakthrough that made the vaccine possible was the recognition that, if you express L1 in cells, it could self-assemble [into natural-looking pentamers] and form virus-like particles,” he said. “The virus-like particles morphologically look very similar to authentic infectious [viral] particles except that they don’t contain any DNA.”

Lowy said L1 virus-like particles are highly immunogenic, prompting the production of antibodies that interfere with binding of the intact virus to a patient’s cells and entry through a receptor.

A vaccine containing HPV-16 L1 virus-like particles prevented HPV-16 infection in all recipients, whereas infection developed in 5% of the women who received only the aluminum adjuvant. This 16-site study, supported by Merck Research Laboratories in West Point, Pennsylvania, and described in the New England Journal of Medicine,1 followed more than 1500 women, ages 16–23 years, for a median of 17 months after a three-dose vaccination series given over six months.

A vaccine targeting HPV types 6, 11, 16, and 18 is in Phase III testing, according to the parent company’s 2002 annual report.

Lowy said Merck added HPV-6 and HPV-11 virus-like particles to the vaccine to target the viral types responsible for genital warts. If this quadrivalent vaccine were tested in both sexes and found to prevent genital warts, he said, the company could market the product to men as well as women.

  1. Koutsky LA, Ault KA, Wheeler CM et al., for the Proof of Principle Study Investigators. A controlled trial of a human papillomavirus type 16 vaccine. N Engl J Med. 2002; 347:1645-51.