U.S. Army Medical Research and Materiel Command

September 28, 2002

TWO NEW STRATEGIES MAY ENHANCE BREAST CANCER TREATMENT

Points of Contact:
Jennifer Goldberg phone 212/886-2200, email jgoldberg@cwg.com;
Gail Whitehead, Public Affairs Coordinator, phone (301) 619-7783, email gail.whitehead@amedd.army.mil;

Research Results from the "Era of Hope "Department of Defense Breast Cancer Research Program Meeting

ORLANDO, September 28, 2002 - Two studies presented at the "Era of Hope" Department of Defense Breast Cancer Research Program meeting describe how a specific genetic profile may identify patients most likely to respond to a leading breast cancer drug, and preliminary evidence demonstrated from a mouse model that an immune system-stimulating agent may offer intriguing treatment results.

Two Genetic Patterns Identify Likely Responders to Docetaxel Therapy

In a small study of pretreatment gene expression profiling, response to the drug docetaxel (TaxotereÔ) was predicted with 83% accuracy, reported researchers from the Breast Center at Baylor College of Medicine and the Methodist Hospital in Houston.

"Docetaxel is one of two main drugs used against breast cancer, and roughly half of all patients respond to it," explained Jenny Chang, M.D., assistant professor at Baylor. "A test that identifies likely responders and nonresponders may eventually improve outcomes by routing the best candidates to docetaxel therapy early and sparing other women exposure to a treatment that will be ineffective for them."

Dr. Chang and her colleagues examined gene expression patterns in breast cancer cells from 24 women before they received treatment with docetaxel, using a gene chip that measures 12,000 human genes. When gene expression was analyzed without knowing the treatment result, two distinct patterns emerged. Then, when treatment response to docetaxel was evaluated, 10 of the 13 patients with the first pattern had good responses, while 10 of the 11 patients with the second pattern were resistant to the treatment, giving an 83% predictive accuracy even in this small initial study.

A larger study of 100 patients, sponsored by the National Institutes of Health, is in progress to further refine and validate the results of this pilot study.

"If these genetic profiles are validated, they also have the potential to reduce treatment costs," added Dr. Chang.

Docetaxel is synthesized from a precursor compound extracted from the needles of the Pacific yew tree.

Immune System Stimulant Destroys Breast Tumors and Prevents Regrowth in Mice

A new immunotherapy designed to unleash disease-fighting T cells has been shown to eliminate established breast tumors in four out of five treated mice and reduced a tumor in the fifth to barely discernible size, according to research presented here today.

"When we reinoculated the four treated and tumor-free mice with live breast cancer cells, no tumor regrowth was seen," said Zoya R.Yurkovetsky, a Ph.D. student from the Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine. "This suggests that the treatment not only fights tumors but generates a long-lasting immune memory, which should protect the host in the same way that anti-infection vaccines do."

The researchers achieved these results with a single administration of genetically modified dendritic cells injected directly into the tumor, and closely reproduced the effects in three sets of experiments with no signs of toxicity. In control animals, the tumors steadily progressed. The investigators first created an adenovirus encoded to express a protein called CD40L as a vehicle for delivering the immunostimulant factor to the tumor, then demonstrated that this adenovirus significantly suppressed the growth of breast adenocarcinoma in mice compared with control groups. They then engineered immune dendritic cells to express CD40L protein. When these CD40L-expressing dendritic cells (DC/CD40L) were injected at the tumor site, they prompted strong antitumor immune responses that not only inhibited tumor growth but led to tumor regression.

"Interestingly, CD40L caused the dendritic cells to produce significantly more interleukin 12 (IL- 12) ¾ a potent immunostimulatory cytokine that has demonstrated antitumor activity in mice and humans ¾ and increase the antitumor properties of dendritic cells or CD40L in tumor-bearing hosts," commented Ms. Yurkovetsky. "Tumors suppress immune cells. We believe that both CD40L and IL-12 strongly increase the resistance of immune cells to that suppressive activity."

The Pittsburgh team plans to examine different breast cancer lines and mouse strains to rule out animal-specific effects, investigate the trafficking mechanism of dendritic cells in animals, and look for an antitumor effect in other cancers. In similar experiments involving colon cancer in mice, DC/CD40L greatly reduced the size of tumors but did not eradicate them, suggesting that further improvement of the approach is required. The researchers are also interested in exploring combination therapies, especially those that include IL- 12 and IL- 15, because of their reported antitumor activity.

"Era of Hope" is a forum for the presentation of research supported by the U.S. Department of Defense's Breast Cancer Research Program (BCRP), an unprecedented partnership between the military, scientists, clinicians, and breast cancer survivors. Since 1992, the BCRP has been working to prevent and cure breast cancer by fostering new directions in research, addressing underserved populations and issues, encouraging the work of new and young scientists and inviting the voice of breast cancer survivors to be heard in all aspects of the program. One of many congressional research programs managed by the U.S. Army Medical Research and Materiel Command, the BCRP has received more than $1.3 billion to date from Congress for innovative breast cancer research.

"Gene Expression Profiles for Docetaxel Chemosensitivity"
JC Cbang, E C Wooten. R Elledge, S G Hilsenbeck, A Tsimelzon, S Mohsin, P O'Connell
- Poster Session: Saturday, September 28, 3:35 p.m.-5:05 p.m., Posterboard P-5, Exhibit Hall A1

"Intratumoral Administration of Adeno CD40L or Dendritic Cells Overexpressing CD40L Elicited Effective Antitumor Immunity in Mice"
ZR Yurkovetsky, MR Shurin, PD Robbins
- General Session: Saturday, September 28, 3:35 p.m.-5:05 p.m., Room 106