The finding, published in the October issue of the journal Nature Chemical Biology, brings the scientists one step closer to a much-sought-after "cancer vaccine."
"In mice we can elicit very strong antibody responses and we have shown that the antibody responses are functional - that they can kill cancer cells," said lead author Geert-Jan Boons, Franklin professor of chemistry and researcher in UGA's Complex Carbohydrate Research Center.
Cancer cells originate in the body, and the immune system leaves them alone because it distinguishes between the body's own cells and foreign invaders such as viruses and bacteria.
Rather than using naturally derived and purified proteins and linkers, Boons and his team created a vaccine synthetically from scratch by stacking molecules together and arranging them in the appropriate configuration. In 2005, they created a fully synthetic vaccine that stimulated an immune response to the tumor-associated carbohydrate alone. The vaccine stimulated only low antibody levels, however, so the researchers began optimizing the components of the vaccine to elicit a stronger immune response.
Their optimized vaccine includes a tumor-associated carbohydrate that triggers the immune system's B cells, a part of a protein that triggers the immune system's T cells and a linker molecule that stimulates the production of generalized immune components known as cytokines.
The results of their three-pronged approach were astounding, particularly with respect to a critical component of the immune system known as IgG.
"When we tested our best vaccine we got really, really fabulous antibody levels that have never been seen before," Boons said. "The levels of IgG antibody production were 100 times better than with conventional approaches."
The vaccine has been successful in creating an antibody response that can kill cultured epithelial cells - those commonly involved in most solid tumors, such as breast and colorectal cancer - derived from mice and in stimulating an immune response in healthy mice. The researchers are currently testing the vaccine in mice with cancer, and Boons hopes to start phase I clinical trials in humans within a year.
Researchers from the University of Georgia and the Mayo Clinic in Arizona have developed a vaccine that dramatically reduces tumors in a mouse model that mimics 90 percent of human breast and pancreatic cancer cases—including those resistant to common treatments.
The researchers used unique mice developed by Sandra Gendler, Grohne Professor of Therapeutics for Cancer Research at the Mayo Clinic and co-senior author on the study. Like humans, the mice develop tumors that overexpress a protein known as MUC1 on the surface of their cells. The tumor-associated MUC1 protein is adorned with a distinctive, shorter set of carbohydrates that set it apart from healthy cells.
“This is the first time that a vaccine has been developed that trains the immune system to distinguish and kill cancer cells based on their different sugar structures on proteins such as MUC1,” Gendler said. “We are especially excited about the fact that MUC1 was recently recognized by the National Cancer Institute as one of the three most important tumor proteins for vaccine development.”
Gendler pointed out that MUC1 is found on more than 70 percent of all cancers that kill. Many cancers, such as breast, pancreatic, ovarian and multiple myeloma, express MUC1 with the shorter carbohydrate in more than 90 percent of cases.
Boons noted that MUC1 also is overexpressed in 90 percent of the subset of patients who are not responsive to hormonal therapy, such as Tamoxifen or aromatase inhibitors, or the drug Herceptin. These so-called “triple-negative” tumors are extremely aggressive and difficult to treat, Boons said, and a new treatment option is urgently needed.
“In the U.S. alone, there are 35,000 patients diagnosed every year whose tumors are triple-negative,” Boons said. “So we might have a therapy for a large group of patients for which there is currently no drug therapy aside from chemotherapy.”
Therapeutic vaccines received renewed attention last year when the Food and Drug Administration approved the first cancer treatment vaccine, a drug known as Provenge that is used to treat metastatic prostate cancer. Treatment with Provenge, which is manufactured in Georgia, requires clinicians to isolate immune cells from the patient and then to send the cells to a lab, where they are linked to a protein that stimulates the immune system. The cells are returned to the patient’s treating physician, who then infuses the drug over three treatments, usually two weeks apart.
Boons’ vaccine, on the other hand, is much simpler. It is fully synthetic, meaning that its components can be manufactured in a lab with assembly-line precision. The vaccine consists of three components—an immune system booster known as an adjuvant, a component that triggers the production of the immune system’s T-helper cells, and a carbohydrate-linked peptide molecule that directs the immune response to cells bearing MUC1 proteins with truncated carbohydrates.
Immune recognition of tumor-associated mucin MUC1 is achieved by a fully synthetic aberrantly glycosylated MUC1 tripartite vaccine.
The mucin MUC1 is typically aberrantly glycosylated by epithelial cancer cells manifested by truncated O-linked saccharides. The resultant glycopeptide epitopes can bind cell surface major histocompatibility complex (MHC) molecules and are susceptible to recognition by cytotoxic T lymphocytes (CTLs), whereas aberrantly glycosylated MUC1 protein on the tumor cell surface can be bound by antibodies to mediate antibody-dependent cell-mediated cytotoxicity (ADCC). Efforts to elicit CTLs and IgG antibodies against cancer-expressed MUC1 have not been successful when nonglycosylated MUC1 sequences were used for vaccination, probably due to conformational dissimilarities. Immunizations with densely glycosylated MUC1 peptides have also been ineffective due to impaired susceptibility to antigen processing. Given the challenges to immuno-target tumor-associated MUC1, we have identified the minimum requirements to consistently induce CTLs and ADCC-mediating antibodies specific for the tumor form of MUC1 resulting in a therapeutic response in a mouse model of mammary cancer. The vaccine is composed of the immunoadjuvant Pam(3)CysSK(4), a peptide T(helper) epitope and an aberrantly glycosylated MUC1 peptide. Covalent linkage of the three components was essential for maximum efficacy. The vaccine produced CTLs, which recognized both glycosylated and nonglycosylated peptides, whereas a similar nonglycosylated vaccine gave CTLs which recognized only nonglycosylated peptide. Antibodies elicited by the glycosylated tripartite vaccine were significantly more lytic compared with the unglycosylated control. As a result, immunization with the glycosylated tripartite vaccine was superior in tumor prevention. Besides its own aptness as a clinical target, these studies of MUC1 are likely predictive of a covalent linking strategy applicable to many additional tumor-associated antigens.
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