From CASE Reports, Volume 13,3 (November 1998)

Molecular Chaperones

Breakthroughs by UConn Team May Hold Key to Virus, Cancer Vaccines

Molecular chaperones are special proteins that are present in every living cell, from bacteria to mammalian cells. The term “chaperone” conjures up an image of a teacher at a high school dance, and rightly so. The roles of the protein and the teacher are similar: to prevent undesirable interactions and promote desirable interactions. Some typical functions of molecular chaperones are to direct the correct folding of other proteins, and to guide their translocations within the cell.

“If these molecules are not around, many other molecules wouldn’t know quite what to do,” claims Pramod K. Srivastava, professor of immunology and director of the Center for Immunotherapy at the University of Connecticut.

Two Critical Discoveries

Srivastava and researchers in his laboratory have made two important observations about molecular chaperones. First, they discovered that a purified solution of chaperones obtained from cells also contains bits and pieces of a large variety of peptides derived from all of the proteins that the cell makes. “We can get a fingerprint of the cell in terms of its breakdown products,” explains Srivastava. “It’s like looking in someone’s garbage can. You can see what that person buys, eats, and wears.”

The second observation made by the scientists at Srivastava’s laboratory is that injection of the chaperone and its associated peptides into mice or rats induces a strong immune response, not against the chaperone itself, but against the peptide if it is recognized by the host as foreign. “For example,“ explains Srivastava, “if we purify chaperones from virally infected cells, we can get a strong immune response against the virus—we can use these chaperones as a vaccine against viruses. And we’ve found similar responses with cancer cells—we can use chaperones to create cancer vaccines.”

Srivastava’s group has repeated these observations, using molecular chaperones from cancers and virally infected cells as vaccines, in large studies in mice and rats. “We can prevent or cure primary and pre-existing metastatic disease in about 15 cancer models, including fibrosarcoma, melanoma, and colon, lung, and liver cancers,” he says. “And we’ve had success in animals with four viral models, including influenza, SV-40, vesicular stomatitis virus (VSV), and lymphocytic choriomeningitis virus (LCMV).”

The basic research to develop this technique was conducted in an academic setting, with funds from the National Institutes of Health (NIH). But Srivastava realized that he could not treat patients with material produced in a university laboratory, nor could NIH funding support clinical trials. So he and a business associate, Garo Armen, founded a company, called Antigenics, to develop and commercialize molecular chaperones as vaccines for cancers and viral diseases. Antigenics’ corporate offices are in New York and the research and development facility is in Woburn, Massachusetts. “We’d like to move the entire company to Connecticut, now that my laboratory is at the University of Connecticut,” says Srivastava.

Phase I Clinical Trials

The safety of using molecular chaperones as tumor vaccines was tested in a Phase I clinical trial in Berlin, in patients with a variety of cancers. “There was no toxicity,” says Srivastava. “It was like injecting a small amount of saline. The patients had no adverse reactions.”

“These are patient-specific vaccines,” he continues. “Each patient receives an injection of purified material derived from his or her own cancer, with no drug or chemical added.” To obtain the patient-specific solution, the surgeon removes the tumor from the patient, freezes it, and sends it by express mail it to the laboratories in Woburn. There, the chaperone and associated peptides are purified and returned to the clinical site. The patient then receives a subcutaneous or intradermal injection of the purified material—an outpatient procedure. “It takes about one day to purify the material,” claims Srivastava. “And it’s a relatively inexpensive process.”

More clinical trials are underway. Patient-specific molecular chaperone cancer vaccines are being tested in patients with pancreatic cancer at the Memorial–Sloan Kettering Institute in New York; in patients with B-cell lymphoma at the University of Connecticut Health Sciences Center; in patients with melanoma at the University of Texas’ MD Anderson Cancer Center in Houston; and those with stomach cancer in Berlin. A clinical trial in patients with kidney cancer also will soon be completed at MD Anderson.

“These are all unblinded, Phase I trials,” says Srivastava. “We’re still at the stage of proving the principle and testing safety, but we’ve seen immune responses in a number of patients. We’re beginning to think about a large, pivotal trial.”

Clinical Trial for Herpes Vaccine Due in 1999

The clinical development of molecular chaperones as vaccines against viral diseases is also moving forward. “Some time next year we’ll be starting a trial of a vaccine against the herpes virus,” says Srivastava. “This will be a disease-specific, rather than a patient-specific, vaccine, so the issues will be a little less complicated.” Rather than using the patient’s own cells, this vaccine will be produced in human cells infected with the herpes virus in vitro. The molecular chaperone and associated peptides will be isolated using procedures similar to those for the cancer vaccine, and the injection procedure will be the same.

“Since we aren’t using autologous material, that is, cells derived from the patient him/herself, we’ll be subject to different regulatory controls than with the cancer vaccine. But it is certainly still a simple, inexpensive, and quick way of developing highly effective vaccines,” says Srivastava. “I’ve been working on this concept for 18 years, and it’s exciting to see it being tested in the clinic.” — Lisa Christenson, science writer

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