With pivotal randomized trials under way, anti-melanoma agents continue to dominate the fast-growing arena of cancer vaccine research, but strategies targeting most major tumor types are moving rapidly into clinical testing.
A comparison of the basic competing vaccine designs allogeneic versus autologous reveals sharp disagreement among prominent investigators about what may work, and why. And, although laboratory studies are gradually sketching a clearer picture of cancer immunity that may one day favor one approach over another, the playing field in 1999 seems wide open to vastly different approaches.
Surprisingly, given the heavy tilt toward melanoma vaccine research, the first approval from the Food and Drug Administration may go to a colon cancer vaccine instead. Scientists at Intracel, a Rockville, Md., biotech firm, report that a phase III clinical trial, based at the Vrije Universiteit in Amsterdam, of the company's OncoVAX product showed the vaccine reduced recurrence by 61% in patients with stage II colon cancer. If and when FDA approval is granted, Intracel plans to establish hospital-based "OncoVAX centers" in areas with high colon cancer incidence. Intracel's regional targeting is driven by logistics: OncoVAX is an autologous vaccine that must be made individually from each patient's tumor, requiring tissue and vaccine to be shuttled between hospital and lab.
David Berd, M.D., of the Thomas Jefferson University in Philadelphia, developed an autologous vaccine approach now in trials for melanoma and ovarian cancer. While conceding that the autologous approach is more laborious, he believes it is the only one that can work based on current understanding of the biology involved.
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"The best vaccine would be something in a bottle that everybody could get. The problem is that no such thing exists," he said. "In animal systems, most successful work has been with syngeneic tumors, which are equivalent to human autologous tumors. There may, in the future, be a one-size-fits-all vaccine that works, but there isn't yet. So you can wait until one becomes available, or you can work with what you have. And we think the autologous vaccine works."
Antoine Ménoret, Ph.D., of the University of Connecticut in Farmington, shares this pragmatic view. In an article co-authored with Rajiv Chandawarkar, M.D., of Akron General Medical Center in Ohio, in the December 1998 Seminars in Oncology, he states that "anti-tumor immunity is private . . . reminiscent of the uniqueness of DNA or that of fingerprints." Thus, the authors write regarding the quest for an allogeneic vaccine, such "an ideal and ubiquitous `curative potion' is highly relevant for infectious diseases wherein antigens are shared among different patients . . . but seems utopian in cancer, where antigens are specific for each individual tumor and are poorly characterized."
But Philip O. Livingston, M.D., of Memorial Sloan-Kettering Cancer Center in New York, has a different view. He is skeptical of autologous vaccines because there is no satisfactory way to know, and to assay, how they work on a molecular level.
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In Berd's vaccine, made by Kansas City, Mo.-based AVAX Technologies, cells taken from patients' cancerous lymph nodes are coupled to dinitrophenyl, one of a group of immune-boosting molecules called haptens. Based on encouraging results in phase II trials (see News, April 17, 1996, and Journal of Clinical Oncology, June 1997), a phase III trial began in September 1998 at 25 centers. Berd believes the same technique may work in many cancers, and he said preliminary results on ovarian cancer patients have been encouraging and may also lead to larger trials.
One Advantage
"One of the advantages of an autologous vaccine is that you can apply it to any tumor type without changing the technology, as opposed to a purified antigen, which might only be designed for only one tumor," Berd said. "We can rapidly test this in a variety of tumor types, and we intend to go through most of the common tumors and perform phase I trials to see how it looks."
Another autologous vaccine strategy, pioneered in the laboratory by Pramod Srivastava, Ph.D., (now at U.-Conn. with Ménoret) is the use of heat shock protein-peptide complexes. Molecular chaperones that perform a variety of crucial cellular functions, including antigen presentation, HSPs bind to a vast array of peptides that collectively represent the antigenic profile of the cell or the tumor from which they are derived. Srivastava and co-workers have successfully treated a variety of tumors in mice with HSP peptide complexes.
Now, phase I/II clinical trials of HSPPC-96, a product of Antigenics, New York, are under way in gastric, renal cell, and pancreatic cancers and melanoma at Sloan-Kettering; the University of Texas M. D. Anderson Cancer Center, Houston; and Johannes Gutenberg-University Hospital in Mainz, Germany.
Among allogeneic approaches, the primary distinction is between vaccines made, like autologous vaccines, from whole cells or cell extracts containing dozens or hundreds of (mostly unknown) antigens, and those made from one or a few antigens that have demonstrated immunogenic potential. Proponents of the first strategy generally believe tumor antigens are so poorly understood that it makes sense to cast a wide net, while investigators working with purified materials feel that knowledge of how a vaccine works is a key to improving its effectiveness.
Livingston and co-workers at Sloan-Kettering have focused their vaccine development on ganglioside antigens such as GM2, based on results from trials in the 1970s showing that these were the only antigens recognized by more than one melanoma patient.
They made an allogeneic vaccine by coupling GM2 to the carrier KLH (keyhole limpet hemocyanin, a mollusk protein), and QS-21, an immune-stimulating adjuvant derived from South American tree bark.
The GM2 vaccine, made by Progenics Pharmaceuticals, Tarrytown, N.Y., is being evaluated against interferon-alpha, the standard treatment for stage II and III melanoma, in an Eastern Cooperative Oncology Group phase III trial, and against placebo in a trial in Europe, Australia, and New Zealand, where interferon is not routinely used.
After the results of the GM2 vaccine trials are in, Livingston said, "the next question, even more important, is if you induce antibodies against several different antigens, can you have an impact on survival?" The Sloan-Kettering group is now organizing a polyvalent vaccine trial in both melanoma and sarcoma in which GM2 is joined by another pair of gangliosides, GD2 and GD3, that are expressed in those tumor types. Another planned trial in small-cell lung cancer patients will test a vaccine combining those antigens with fucosyl GM1, an antigen unique to SCLC.
Epithelial tumors such as breast and prostate tumors have a whole different set of antigens from melanoma and sarcoma, while SCLC shares some of each, Livingston said. "Our next trials are going to be in breast, prostate, ovary, small-cell [lung cancers], and they'll be polyvalent vaccines, hopefully four or five different antigens that we can consistently immunize against," he said, adding that the breast and prostate trials could begin in 1999.
Meanwhile, Biomira of Edmonton, Alberta, Canada, is starting a phase III trial for metastatic breast cancer patients using the company's THERATOPE® cancer vaccine, based on the abnormally expressed STn (Sialyl-Tn) antigen. About 75 sites in North America and Europe will participate.
Donald Morton, M.D., of the John Wayne Cancer Center in Santa Monica, Calif., began with the wide-net approach, developing his vaccine, CancerVax, from living whole melanoma cells. But as clinical trials proceed, Morton and colleagues are investigating what the vaccine is made of and specifically how it works.
They have identified 20 of its antigens, and in a phase II trial of patients with stage IV melanoma, published in the September 1998 Journal of Clinical Oncology, they examined the relationship between immune response to the vaccine and survival. They found that patients showing an immunoglobulin M (IgM) antibody response to one antigen, TA90, and a skin test demonstrating cellular immunity to the vaccine, had a 5-year survival rate of 70% and a median survival of 76-plus months, compared with 8% and 19 months for nonresponders on both measures.
"What was striking, and somewhat scary, is that patients who had an IgG response were not benefited by the vaccine; in fact, they didn't do as well" as IgG nonresponders, Morton said, "suggesting that some types of response are protective and others aren't." In the phase III trial of CancerVax now under way at 50 centers internationally, patients will be tested for antibody and skin test response during the first 3 months after vaccination.
If the earlier finding is confirmed, Morton said, "it will give us a monitor to determine whether the vaccine will work in a particular patient." Thirteen antigens in CancerVax have been found expressed in nonmelanoma tumors, Morton added, raising the possibility that the vaccine may work against these cancers as well. Phase II trials are being conducted in cancers of the colon, pancreas, and prostate.
On the horizon is a promising but untested strategy: vaccines using DNA as an antigen. These "naked DNA" vaccines, a serendipitous discovery in infectious disease research, have several potential advantages over traditional peptide-based vaccines which proponents believe may hold up in cancer applications also. They are relatively easy to make, handle, and store; and produce long-lived T-cell-mediated immunity.
Alan Houghton, M.D., of Sloan-Kettering, and colleagues successfully treated melanoma in mice with a human DNA vaccine. The researchers believe the human DNA differed just enough from native mouse DNA to trigger an immune response to the tumors. In a planned clinical trial of melanoma patients, Houghton's team will reverse the strategy, using mouse DNA to elicit a human immune reaction.
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