Karmanos Cancer Institute awarded $3M NIH grant to study triple-negative breast cancer

Oct 19 2010

Scientists at the Barbara Ann Karmanos Cancer Institute in Detroit have received a nearly $3 million, five-year research project (RO1) grant from the National Institutes of Health to study a potentially ground-breaking immunotherapy treatment for women with one of the deadliest forms of breast cancer – triple-negative breast cancer. The research is exclusive to the Karmanos Cancer Institute.

This grant supplements the $2 million, four-year NIH RO1 grant to Karmanos that funds a treatment protocol for women with HER2-negative metastatic breast cancer using targeted T cell immunotherapy.

Lawrence G. Lum, M.D., D.Sc., professor of Medicine and Immunology and Microbiology at Karmanos and Wayne State University School of Medicine and his research team are conducting a Phase II clinical trial to test the efficacy of anti-CD3 x anti-Her2/neu bispecific antibody (Her2Bi)-armed activated T cells immunotherapy on women with stage II and III HER2/neu (0-2+) and hormone receptor negative breast cancer (triple negative breast cancer), in combination with neoadjuvant chemotherapy which kills cancer cells and reduces tumor size.

Researchers believe this trial will help determine if this treatment combination increases the complete pathological response – meaning the elimination of all disease -- at the time of surgery. A total of 40 patients will be accrued for this study.

"This grant from the NIH speaks to the truly innovative research being conducted at Karmanos and establishes the Institute's leadership role in creating cancer care standards that other hospitals will follow in the future," said Gerold Bepler, M.D., Ph.D., president and chief executive officer, Karmanos Cancer Institute. "Every day, our basic scientists and clinicians conduct exciting research found no where else in the country."

The therapeutic method, which enables the human body to rid itself of cancerous cells, could one day have tremendous impact on women battling triple-negative breast cancer, according to Dr. Lum. The targeted T cells not only kill cancerous cells but also enhance the body's ability to detect those cancerous cells. This could lead to long-term, anti-cancer immunity to prevent the recurrence of cancer.

Many women with triple-negative breast cancer are not helped by traditional chemotherapy methods. The incidence of triple-negative breast cancer is also very high in black women, according to Dr. Lum. Tumors are more aggressive and there is more disease when the cancer is discovered.  

The principal investigator on the breast cancer immunotherapy protocol is Zeina Nahleh, M.D., associate professor of Medicine and co-leader of the Breast Oncology Multidisciplinary Team at Karmanos and Wayne State University School of Medicine. Zaid Al-Kadhimi, M.D., assistant professor of Medicine at Karmanos and Wayne State is the research co-investigator assisting Dr. Nahleh with clinical protocol.

The Karmanos Cancer Institute is the only cancer center in the United States offering bispecific antibody-targeted T cell immunotherapy. Dr. Lum is the inventor of these bispecific antibody-armed T cells.

Cancer cells with low hormone receptor status, or none at all, are very difficult to treat since they have few or no receptors that are responsive to traditional chemotherapy antibodies. Less than 25 percent of all patients with triple-negative breast cancer respond well to chemotherapy and surgery, according to the research, and many suffer from a poor prognosis following treatment. The relapse rate is 80 percent.

"We're targeting a group that no one else can treat. We're trying to increase the complete pathological remission rate," Dr. Lum said. "Only about 20 percent of the women are HER2 positive (3+). That leaves about 80 percent of the women who can't get antibody therapy, such as Herceptin."  

Through immunotherapy treatment, Dr. Lum arms a woman's T cells with bispecific antibody that give the cells the ability to target and kill remaining cancer cells following chemotherapy, possibly prolonging her life and immunizing her against cancer relapse.

The first step in the process of arming T cells is extracting the cells through apheresis. The cells are then cultivated and expanded in the lab and armed with the bispecific antibody, which programs the T cells to attack the tumors.  Next, the armed T cells are frozen and preserved until they are ready to be infused into the patient after chemotherapy. A biopsy is performed following chemotherapy to see how much of the tumor was eliminated.

The research team checks the type and function of the lymphocytes in the tumor biopsy and determines the number of cancer tumor stem cells that are present. Patients will then receive four infusions of T cells, followed by surgery to remove the remaining tumor. At the time of surgery, the lymphocytes are tested for their function and the number of remaining cancer stem cells is evaluated.

In the Phase I clinical trial involving 19 women with all types of metastatic disease, Dr. Lum showed that infusions of Her2Bi-armed T cells are safe for the patient; induce immune responses that kill breast cancer cells; stabilize the disease; and promote a very promising, partial clinical response.

The results also indicate that targeted T cell infusions work to vaccinate the patient against their own tumors. Targeted immunotherapy in some instances improves overall survival of women, many of whom have received multiple therapies, according to Dr. Lum. The successful trial results also have allowed researchers to expand the study to the current Phase II and to study women with triple-negative breast cancers.

These exciting immunotherapy study results have garnered attention in the cancer research community. Dr. Lum was invited to present his results at the American Society of Clinical Oncology Breast Cancer Conference earlier this month in Washington, D.C.

"What we're hoping is that when you eliminate the remaining tumor through immunotherapy and vaccinate the patient against the tumor, we would then see an increased number of women who were cured at that point in time," Dr. Lum said. "You knew what the situation was before immunotherapy, and now you know the situation after. If we can double the number of women whose cancer is completely eradicated through immunotherapy, it would be a home run in how we treat women with triple-negative breast cancer."