Pramod Srivastava, Ph.D., believes in paying attention to mice. And mice give him a lot of confidence that his heat shock protein vaccine should work in humans.
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In preclinical studies, the vaccine protected an overwhelming majority of mice from the recurrence of cancers. Although the human phase III trials of his vaccine are not complete, so far the data are consistent with the data from mouse studies.
"Were seeing what seems like clinical activity," Srivastava said of the studies in humans. In early, nonrandomized trials, he said, some patients have had complete responses, "and were seeing prolongation of survival in many kinds of cancersgastric, melanoma, and colon cancer[s]."
The vaccine consists of heat shock protein and its associated peptide complexes isolated from a patients tumor. Only a few micrograms of the vaccine are injected back into the patient. Patients with existing residual tumors are immunized as long as the vaccine supply lasts, and patients who appear to be disease free after surgery receive only a limited number of vaccine injections after surgery.
The power of the vaccine is that it contains a wide array of peptide antigens, which are unique to the given tumor. Because tumors contain random collections of mutations, the heat shock-associated peptides are a unique fingerprint of each cancer. This, in effect, makes them personalized vaccines for which the identity of the particular peptides or mutations is not required.
Background
The heat shock vaccine story began nearly 60 years ago with the observation that mice can be immunized against tumors; when mouse tumor cells are killed by irradiation and injected into the animal, the mouse does not develop cancer when it is injected with a live tumor. This is similar to the strategy used for smallpox and polio vaccines.
As a graduate student in India in 1980, Srivastava set out to identify what protected these mice from developing new tumors. "I was taking tumors and fractionating the proteins from the tumors on a column and then vaccinating animals with each fraction of protein, and trying to see which of them would prevent the animals from developing tumors."
He first identified a protein that would cause tumor immunity against rat liver cancer, then another that worked against a mouse sarcoma. By 1984, he discovered that both were heat shock proteins.
Heat shock proteins are one of the most abundant and highly conserved groups of molecules across species. The name is derived from the fact that they were first seen in 1962 in cells grown at elevated temperatures. They are induced by heat, low sugar levels, and other stress signals.
Heat shock proteins are found in every cell and, besides protection against stress, their many functions include chaperoning proteins between cell compartments, facilitating the folding and unfolding of proteins, and assembling protein subunits. The ability to generate immune responses against cancers may now be added to that list.
The problem is that it is difficult to imagine why such a common and important protein would induce an immune response in the body. Heat shock proteins from normal cells, for example, do not protect against cancer. And how could the vaccine show such specificityheat shock proteins from a particular cancer protect against only that cancer?
"When I would talk about my work [with heat shock proteins], people would ask me, very appropriately, how can you expect an immune responsetheyre so common," said Srivastava.
The answer did not come until 1992 when Srivastava discovered that the heat shock proteins were associated with peptides and that the combination of heat shock proteins and the peptides is responsible for the immune protection.
Further work in the last few years led Srivastava and his colleagues to the discovery of the mechanism responsible for the strong immune response seen in mice. It turns out that the vaccine is mimicking a long-established biological mechanism for eliminating damaged cells, known as the necrotic pathway. The process is the same in mice and humans. (See sidebar, p. 13)
Philip O. Livingston, M.D., at Memorial Sloan-Kettering Cancer Center in New York, said he thinks the idea of inducing an immune response with antigens that are unique to each tumor is powerful. "Everyone is excited by the scienceits quite elegant science," he said.
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Another issue is feasibilitywhether enough cancer cells can be collected to make the quantity of vaccine needed. "The issue is not only how much vaccine do you need per dose but how many doses and how long to continue treatment, and no one knows the answers," he said. He noted, however, that the trials so far have had an impressive track record for the percentage of eligible patients for whom the vaccine is successfully made.
Jeffrey S. Weber, M.D., director of the University of Southern California Norris Melanoma Center, Los Angeles, voiced some of the same concerns. "The obvious downside is that its difficult to isolate enough of a tumor under sterile conditions to extract the [heat shock proteins]. Ultimately, its not going to be practical to get your hands on that much tumor, especially early stage or smaller tumors. In other words, the tumor is not a renewable resource."
Weber suggested that this problem could be resolved by isolating mRNA from the tumor, making cDNA, and expanding it, to create a whole repertoire of mRNA that is expressed in an in vitro system to which heat shock proteins are linked.
In spite of the potential hurdles, Weber is impressed by the science. "If I were hunting around the melanoma world for new ideas or projects, I would certainly rank the issue of doing melanoma biopsies, extracting RNA, and making recombinant [heat shock proteins] high on my list," he added.
Now, vaccines using two different heat shock proteinpeptide complexes have been tested in rodents and humans. The early clinical trials include patients with cancers of the stomach, kidney, pancreas, and colon and melanoma and lymphoma. One phase III kidney cancer trial is ongoing and another involving melanoma patients is set to begin in the next few months.
Antigenics Inc., New York, is conducting the trials with investigators at Memorial Sloan-Kettering Cancer Center, New York; The University of Texas M. D. Anderson Cancer Center, Houston; the Johannes-Gutenberg University in Mainz, Germany; and the Istituto dei Tumori di Milano in Milan, Italy. The trials have accrued a total of about 300 patients so far.
"We dont know anything until we complete the randomized trial [that] were doing now," said Srivastava. "But the fact is that so far, the data are very consistent with the data weve seen in mice. The mechanism has been worked out for both, and the mechanisms are the same."
His colleagues express the same optimism, in spite of some potential shortcomings. "My bias has always been [that] if a real effect is demonstrated, people will figure out a way to make it work," Levitsky said.
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