n e w s of t h e w e e k
ANTICANCER VACCINE Based on hexasaccharide, potential vaccine moves from synthetic lab to clinical trial
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nother therapy for cancer patients sible with the total synthesis of globo Η could be on the way. A new vac- by a team led by Danishefsky (C&EN, icine preparation is being tested Aug. 7, 1995, page 31). The synthesis, this month on 24 patients with early met achieved through glycal assembly, made astatic prostate cancer at Memorial Sloan- sufficient quantities of globo Η available Kettering Cancer Center in New York for various studies. To prepare the vac cine, the synthesis team attached a han City. Blending synthetic chemistry, immu dle to the hexasaccharide portion of the nology, and medicine, teams from three antigen through which it can be linked laboratories at the center developed the to a carrier protein. vaccine [Angew. Chem., 109, 66 (1997)]. Mice treated with the globo Η hexasac They were led by Philip O. Livingston, charide bound to the carrier protein key head of the Laboratory for Tumor Vaccin- hole limpet hemocyanin in conjunction ology; Samuel J. Danishefsky, head of the with an immunological adjuvant produce Laboratory for Bioorganic Chemistry and chernis- f try professor at Columbia | University; and Kenneth ^ O.Lloyd, head of the Lab- | oratory for Tumor Anti- ° gen Immunochemistry. | The vaccine consists κ of a synthetically pre- ° pared, complex hexasac- -Q charide linked to a carri- | er protein. The oligosac charide is identical to the carbohydrate region of an antigen called globo H, which is found on var Danishefsky's total synthesis of globo Η allowed ious types of tumor cells. Livingston (right) to develop anticancer vaccine. It is by far the most com plex synthetically prepared oligosaccha large amounts of IgM antibodies and some ride to be incorporated in a carbohydrate- IgG antibodies. The next hurdle was to de based anticancer vaccine. termine whether these antibodies would Globo Η was first isolated from hu recognize the antigen when they encoun man breast cancer cells. It also is found tered it on tumor cells. As Livingston ex on prostate, colon, and pancreatic cancer plains, some other attempts at anticancer cells, says Livingston. If successful, the vac vaccines had to be abandoned when it cine could be used against a variety of could not be shown that the antibodies in cancers. duced by the vaccine did, in fact, recog The role of antibodies in cancer thera nize the antigen on tumor cells. py is well established, notes Livingston. That doesn't seem to be the case here. Antibodies recognize antigens on tumor Several lines of evidence show that the cells, marking the cells for destruction by vaccine-induced antibodies in mouse sera other parts of the immune system. Fur indeed also recognize globo H on tumor thermore, he explains, carbohydrates are cells. The researchers also demonstrate the most numerous antigens on the sur that binding of the anti-globo Η IgM to tu face of tumor cells, making them logical mor cells triggers a process called comple targets for vaccine development. ment fixation, which culminates in de Developing the vaccine became pos struction of the tumor cell. Says Livingston: 8 JANUARY 20, 1997 C&EN
"The synthetic globo Η in the vaccine is being perceived correctly by the immune system and is inducing the type of anticancer-cell response we had hoped for." The vaccine is not expected to give long-term immunity, such as that con ferred by polio vaccines and the like. Ac tivating the part of the immune system responsible for such an effect requires larger amounts of IgG antibodies than the vaccine is producing. That's not surprising to Harold J. Jen nings, head of vaccine design at the In stitute of Biological Sciences at the Na tional Research Council in Ottawa. Be cause globo Η is a self-antigen—a part of the body's "self' rather than an invad ing foreign matter—it induces mainly IgM antibodies. Rather than conferring long-lived im munity, this vaccine could be a powerful tool to use in recovery from treatment of cancer, says Jennings. After an operation to remove a tumor, the preparation could be used to recruit the human immune sys tem to destroy any remaining cancer cells, thus preventing recurrence of the cancer. "If the vaccine can remove the last of the cancer cells, it's a tremendous step for ward," Jennings says. "The globo Η accomplishment is only the first step in an evolving anticancer vaccine program," says Danishefsky. "The full force of synthetic chemistry is being brought to bear on the carbohy drate tumor antigen problem." Maureen Rouhi
Feds crack down on CFC smuggling Six federal agencies are combining forces to strike a blow against the smuggling of chlorofluorocarbons (CFCs) into the U.S. This beefed-up effort, part of the new National CFC Enforcement Initiative, has resulted in charges against or arrests of individuals and companies in Houston, Los Angeles, Miami, Philadelphia, San Di ego, and Savannah, Ga. CFC smuggling has intensified in the past few years as U.S. production is phased out and use of more expensive alternatives ris es (C&EN, Sept. 16, 1996, page 18). "The U.S. has experienced a flood of illegal im ports of CFCs—through fraudulent mark ings of containers, fraudulent paperwork, smuggling, and other means," explains En vironmental Protection Agency Adminis trator Carol M. Browner. U.S. Attorney General Janet Reno
