Mayo Clinic Researchers Use Human Antibody To Cure Malignant Melanoma In Mice

In the July 15 edition of Cancer Research (http://cancerres.aacrjournals.org) Mayo researchers report three innovative discoveries that advance the emerging field of cancer immunotherapy. Cancer immunotherapy refers to scientist-controlled manipulations of the immune system to kill cancer cells without the toxic side effects of chemotherapy or radiation. These findings show that when administered intravenously, the human antibody can still induce immune response -- which suits it for potential therapeutic use as a drug for humans.

"What this current work demonstrates is that by using this antibody we can train the immune response to strike a new target," says Larry Pease, Ph.D., Mayo Clinic immunologist and lead investigator of the study.

The Discoveries

A novel way to fight cancer with the immune system

Treating live mice intravenously with a human antibody stimulates components of the immune system known as dendritic cells, which, in turn, changes the way dendritic cells interact with the T cells of the immune system. The result: a consistently strong -- and often curative -- treatment effect for malignant melanoma, a cancer that is newly diagnosed in approximately 51,000 people in the U.S. annually, and claims more than 7,000 lives a year in the United States.

New approach works to kill cancer in mice

The researchers created an anti-tumor immune response where none existed in nature. Under normal conditions dendritic cells are key players in initiating select immune responses -- responding to malignant melanoma just doesn't happen to be among them. Mayo Clinic researchers changed that. They trained T cells to seek and destroy malignant melanoma by inducing activity of dendritic cells by "cross-linking" structures on their cell surface. Cross-linking is a molecular manipulation that can stimulate cells.

Effectiveness

In the investigation, one group of mice was treated intravenously with the experimental cross-linking antibody therapy, and two control groups were treated with known antibodies that do not prompt cross-linking structures containing B7-DC. All groups had malignant melanoma tumors transplanted into them. They were then examined 17 days later for evidence of tumor growth.

Results showed that in the two control groups, only one of 26 (less than 4 percent) were tumor free. By contrast, 11 of 16 mice -- 69 percent -- were tumor free in the group receiving the experimental antibody treatment. In addition, the few mice in this group that did develop tumors experienced significantly inhibited tumor growth compared to controls.

In a second line of investigation animals received intravenous transplants of tumors that seeded their lungs with dozens of discrete foci of melanoma, modeling what happens during lung metastasis. After three days, some of these animals were treated with the B7-DC cross-linking antibody or a control antibody. They were evaluated for tumor growth when their untreated counterparts had developed more than 50 tumor nodules in their lungs.

Forty-eight percent of the animals (14 of 29) that received B7-DC cross-linking antibody treatments were tumor free when the experiments were ended three to four weeks after tumor engraftment. In contrast, all the mice that received control antibodies developed large numbers of tumors in their lungs. Furthermore, all of the 52 percent of animals that developed melanoma lung nodules developed substantially fewer tumors relative to the animals receiving irrelevant antibody, showing that treatment with B7-DC cross-linking antibody had a strong treatment effect even when animals were not completely cured.

Distinct from previous methods

The data reveal a dramatic improvement in anti-tumor abilities of dendritic cells stimulated with this human antibody. Following treatment the dendritic cells behaved differently when compared to dendritic cells stimulated by established methods.

"Essentially, we are inducing an immune response against a tumor where an immune response isn't normally happening," says Dr. Pease. "The human antibody induces strong tumor immunity when administered and without further interventions -- even after tumors are already established. This is an important milestone for any cancer therapy that will be useful for treating patients."

In addition to Dr. Pease, the coauthors of the article include: Suresh Radhakrishnan, Ph.D.; Loc Tan Nguyen; Bogoljub Ciric; Dallas Flies; Virginia P. Van Keulen; Koji Tamada; Lieping Chen and Moses Rodriguez, M.D. Their work was supported by grants from The Ralph C. Wilson, Sr., and Ralph C. Wilson, Jr., Medical Research Foundation, the Mayo Clinic Comprehensive Cancer Center and the National Cancer Institute of the National Institutes of Health.