NEWS

Cancer Vaccines: Finding the Best Way to Train the Immune System

Bruce Goldman

Cancer immunotherapy has traditionally focused on forcing the immune system to hunt down so-called "shared antigens"—specific proteins that are overexpressed in tumors of a specific type—with the hope that the body’s own immune system will attack and destroy any cancer cell that overexpresses the antigen. The theoretical virtue of a shared antigen is that it can form the basis of a widely applicable, relatively inexpensive vaccine. Such an antigen can be precisely characterized, mass-produced, and metered out in carefully calibrated quantities.

Shared antigens have their drawbacks, though. They have been identified in only a relatively small percentage of tumor types and, even for those tumor types that have shared antigens, they are found on only a fraction of tumors.

And even when found, shared antigens have invariably turned out to be "self-antigens": that is, while abundant in tumor tissue, they are also expressed in healthy tissue. Carcinoembryonic antigen, or CEA, for example, is overexpressed in 95% of colorectal cancer cells, but is also found—albeit at lower levels—in colonic mucosa. That makes them weak antigens.

"Like many normal gene products, [these shared antigens have] already triggered autotolerance—they’ve caused the elimination of a large fraction of the immune cells that recognize them, which are just the ones you want to activate [for cancer immunotherapy]," said Eli Gilboa, Ph.D., professor of experimental surgery and director of the Center for Genetic and Cellular Therapies at Duke University, Durham, N.C.



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Dr. Eli Gilboa

 
Consequently, a great deal of thought has gone into resensitizing patients’ immune systems to shared antigens and using that for a vaccine. At the National Cancer Institute, Jeff Schlom, Ph.D., and his collaborators developed a vaccine by inserting the gene that encodes CEA into a safe but infectious and highly immunogenic poxvirus. When this vaccine was administered to patients with gastrointestinal malignancies, the investigators observed some induction of circulating CEA-specific T-cells—a promising sign.

Taking a different shared-antigen tack, Biomira, a Canadian biotechnology company, has beefed up the immunogenicity of MUC-1—a normally weak carbohydrate antigen overexpressed on many tumors—by chemically linking it to an extremely immunogenic carrier protein. When given as a vaccine, this formulation stimulates the formation of antibodies to MUC-1. Biomira is testing this vaccine in the biggest-ever phase III trials involving immunotherapy for metastatic breast cancer patients.

In recent years, though, some researchers have shifted their attention from antigens that are merely overexpressed in tumors to so-called "unique antigens" that are products of random mutations arising in the course of tumor cells’ uncontrolled cell divisions.

A cancer cell can host millions of mutant peptides, said Pramod Srivastava, Ph.D., professor of immunology and director of the University of Connecticut Cancer Center. "Each time a cell divides, it probably has about somewhere between six and 60 mutations," he said. "So any tumor ultimately acquires a huge number of them." The quirky proteins they encode are eventually degraded into peptide products that—if the immune system happens to notice—will be perceived as "foreign" and, therefore, likely to be far more immunogenic than shared antigens.



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Dr. Pramod Srivastava

 
"The immune system, presented with random mixtures of antigen, does not react to every antigen in the mixture, but preferentially responds to unique antigens that represent mutations in the tumor cells rather than to gene products present on normal cells," Gilboa said. This explains why a mouse injected with irradiated tumor material from another genetically identical mouse will prove resistant to a graft of the same tumor—but only to that tumor, and not to any other.

Targeting unique, tumor-specific antigens should, moreover, mean favorable side-effect profiles because normal tissue is left unharmed. The question is: How do you identify thousands of unique antigens—or even one of them—patient by patient? In each case, said Srivastava, "we know they exist, but they are not practically knowable."

There is at least one glaring exception to this rule. All cancerous cells in a patient with B-cell lymphoma are derived from a single malignant cell, so the immunoglobulins the malignant cells secrete—and those they retain on their surfaces—are identical. A group of investigators led by Ron Levy, M.D., professor of medicine and chief of oncology at Stanford University, has generated lymphoma vaccines by extracting tumor cells from individual patients and fusing them with immortalized myeloma cell lines. The resulting hybridomas produce vast amounts of this immunoglobulin, which can be manipulated into a vaccine that targets only that molecule’s unique antigenic determinants and subsequently causes the destruction of the malignant lymphoma cells that express it. Two phase III trials of this approach are now under way, one funded by NCI and the other sponsored by Genitope, a Redwood City, Calif., company.

Levy’s approach could be applied to other tumor types, such as T-cell lymphomas and chronic myelogenous lymphoma. But for most cancers, identifying patient-specific antigens is impractical if not impossible. Besides, if only a solitary, defined antigen is targeted, it is relatively easy for a tumor to evolve "escape variants," which evade immune detection by suppressing expression of the antigen.

Then again, it may be possible to kill two birds with one stone: Instead of picking patient-specific tumor antigens out of the heap, why not throw them all in and let the immune system itself settle the matter of which ones are worth attacking? This not only frees researchers from the onerous chore of identifying unique antigens, but greatly complicates a tumor’s effort to evolve escape variants. Srivastava and Gilboa are proponents of this philosophy.

Although their actual approaches are quite different, both make use of dendritic cells’ key role in antigen presentation. Dendritic cells are the most efficient of the antigen-presenting cells and the only ones capable of generating a T-cell response, now believed by many to be a crucial component of cancer immunity.

Indeed, one major reason why the presence of foreign-appearing antigens on tumor-cell surfaces is often not enough to trigger a robust T-cell assault on the tumor is that those surface-membrane-bound antigens simply may never have found their way to a professional antigen-presenting cell. Gilboa and Srivastava both seek to jump-start immunity through the delivery of entire tumor-antigen libraries to dendritic cells.

Gilboa’s method involves extracting messenger RNA from as little as a needle-biopsy’s worth of tumor material, amplifying the mRNA via PCR, and incubating it with the patient’s own dendritic cells, which incorporate bits of it and produce the corresponding proteins. When these dendritic cells are reinfused into the patient, they display those proteins’ degradation-peptide products on their surfaces in association with an MHC molecule. T-cells responsive to altered or foreign peptides are in good supply, and are activated by dendritic-cell stimulation.

One of the beauties of this approach, Gilboa said, is that some of the RNA-pulsed dendritic cells can be stored, providing a potentially inexhaustible supply of tumor antigens for later use.

To prove the principle, Gilboa’s colleague Johannes Vieweg, M.D., associate professor of urology and immunity at Duke, led a phase I/II study of 13 patients with metastatic prostate cancer. Individual patients’ dendritic cells were pulsed with mRNA that coded for a single defined antigen, prostate-specific antigen (PSA), which is shared by healthy and cancerous prostate tissue alike. The outcome of the study established that mRNA-pulsed dendritic cells do in fact stimulate the immune response, so Vieweg launched another phase I/II trial among renal-cell carcinoma patients using dendritic cells incubated not with just a single shared antigen but with whole-tumor mRNA instead. Viewig said he finds the data thus far "very encouraging."

A big hurdle for using dendritic cells is the sheer complexity of culturing them. But the care and feeding of dendritic cells gets much less complicated if you leave them in the body. That’s where Srivastava’s trailblazing research on heat-shock proteins (HSPs) comes in. In 1980, Srivastava began a series of experiments on mice immunized with whole-cell lysates from a genetically identical tumor. These experiments led eventually to his isolation of HSPs as the agents responsible for the antitumor protection conferred on the recipient rodents. (See News, Jan. 2, p. 12.)

But the exact role of the HSPs was a great puzzle until Srivastava discovered that it is not the HSPs, but the peptides bound to them, that convey key antigenic information to the immune system. HSPs, by virtue of their role as multi-purpose intracellular chaperones, are capable of binding a wide variety of peptides produced by protein degradation within all cells. While they are abundant inside every cell of every organism, HSPs are never found outside of cells, except when a cell has undergone necrosis. When that happens, the cell’s contents are spilled into the surrounding medium. These contents include an abundance of HSPs that essentially hold a complete library of every protein-degradation peptide produced within the cell.

In 2000, Srivastava’s group identified a dendritic-cell receptor, CD91, with a strong binding affinity for HSPs. This binding triggers the dendritic cell to expeditiously usher in the HSP and its associated peptide, which it processes and prominently re-presents on its surface along with an MHC molecule and the requisite costimulatory molecules. If that peptide is just a run-of-the-mill self-antigen, it is ignored, because browsing T-cells have long since been depleted of the clones responsive to it. But if it is a unique antigen, its presentation on the dendritic cell greatly increases the odds that appropriate T-cells will be alerted and activated.

Antigenics, a company that Srivastava co-founded in 1994, makes personalized cancer vaccines by extracting HSPs from resected tumors. The company is close to the halfway mark in accruing roughly 1,000 patients for a phase III trial in renal cancer—among the largest ever initiated for an individualized cancer treatment—and has initiated another phase III trial in metastatic melanoma.

About two grams of tumor material is required now to make the HSP vaccines, limiting their scope to bulky tumors. But Antigenics has found a way to greatly amplify the amount of extracted material, permitting production of sufficient vaccine from a 200-milligram tumor sample, said Srivastava.

This would strongly expand the feasibility of HSP vaccines. "If they can reduce the required tumor-extract size by tenfold, they could make it practical," Levy said. As many as 80% of all tumors, instead of the current 15%, would be in reach. But even so, many cancer patients with very small tumors would remain unserved. For such patients, Gilboa’s RNA-amplification approach, if it works out, could be a godsend. If Antigenics’s proposed amplification of a patient’s tumor-antigen library is analogous to a vastly expanded print run for each of the tumor’s antigenic "books," Gilboa’s method is akin to storing the library online, using dendritic cells for computers running RNA software and printing out protein hardcopy as needed, now or later.

Any way you slice it, a patient-specific vaccine is going to be costly. But that is not the real problem, said Levy. "The real problem," he said, "is making these vaccines work. "Once they’re shown to work, people will get very clever at making them cost-effective to large numbers of patients."


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