BY CHRIS VAUGHAN AND KRISTIN WEIDENBACH

This week dozens of Stanford cancer specialists joined thousands of colleagues from around the world at the American Society of Clinical Oncology annual meeting, held in San Francisco, May 12-15. The meeting is the year's largest forum for exchanging information to improve cancer treatment. Among this year's highlights were presentations on research conducted by Stanford investigators Lawrence Fong, MD, research associate; Michael Leong, MD, assistant professor of anesthesia; James Malone III, MD, staff physician; and Daniel Sze, MD, PhD, assistant professor of radiology, whose work was presented by collaborator Tony Reid, MD, of the Veterans Affairs Palo Alto Health Care System.

Vaccine is effective against tumors

Though methods of stimulating a patient's own immune system to fight cancer are showing promise against rare cancers such as lymphoma, cancer vaccines have met with little success against solid tumors. Now research associate Lawrence Fong, MD, and his colleagues have modified immune cells so that they can effectively attack colorectal tumors.

In a small, initial study on 12 patients with either end-stage colorectal cancer or lung cancer, the vaccine produced clinical benefits in four patients with colorectal cancer. In two patients the cancer completely regressed; one of those patients has been cancer free for a year, while the other has had a recurrence in a different location.

Fong and his colleagues based their treatment on the ability of a certain type of immune cell, known as a dendritic cell, to instruct other immune cells to hunt down specified compounds ­ acting much like a dog handler holding a piece of clothing under a bloodhound's nose. The researchers hoped to use dendritic cells to launch an immune attack against compounds produced by tumors. They started the treatments by harvesting dendritic cells from the patients. Then, since dendritic cells are rare in the blood, Fong and his team amplified the patients' supply of dendritic cells 20 times by using a blood growth factor called FLT-3 ligand.

Next the researchers altered the dendritic cells so that they displayed a protein called carcinoembryonic antigen, that is commonly overproduced by lung and colorectal cancers. Furthermore, this protein was engineered so that it would be more easily recognized by the body's immune system.

While Stanford researchers have previously shown that dendritic cells can be effective against lymphoma, the technique had not previously worked well against solid tumors. That's because solid tumors tend not to produce an immune response. Fong and his colleagues hoped that the manipulation of a cancer patient's dendritic cells would lead to an immune attack on the tumors.

When the modified dendritic cells were put back in the patients they did spur the immune system to attack the tumors in many patients. In those showing clinical benefit from the treatment, tumors either stopped growing, shrank or regressed completely. Fong says the results are very promising, particularly since the patients in this initial test were in the end stages of cancer. The next step is to test the new cancer vaccine in colorectal cancer patients who are less ill. - KW

Snail venom shows pain-killing potential

The venom of a deadly marine snail has produced a powerful tool for fighting pain, reported Michael Leong, MD, assistant professor of anesthesiology, and colleagues. They recently completed the first human tests of one of the toxin's chemical components, called ziconotide, and found that it relieves severe pain in cancer patients. Even more exciting is the fact that ziconotide is an analgesic instead of an anesthetic ­ it relieves pain without numbing or "putting to sleep" the affected area.

"This promises to be the first of a whole new class of pain drugs," said Leong. "We may be able to use it to treat people resistant to other types of drugs."

Ziconotide comes from the venom of predatory cone snails, which dart and paralyze passing fish before eating them. When researchers began studying the peptide they found that it works on the same parts of the spinal cord that have many receptors for morphine and other opioids. Further study revealed that ziconotide is a calcium channel blocker in neurons that transmit pain messages in the spinal cord. Administering the drug inactivates those neurons but leaves other nerves unaffected.

Leong and his colleagues tested ziconotide in a double blinded, placebo controlled trial on 108 cancer or AIDS patients with severe, chronic pain. They administered ziconotide through a catheter that dripped the drug slowly into the patients' spinal fluid.

Upon analysis of the drug trial data, the Stanford researchers found that ziconotide was highly effective in relieving pain, especially in the cancer patients. Pain relief didn't vary depending on the age or gender of the patient. Ziconotide also worked equally well whether or not the patient had previously been treated with morphine.

The researchers also observed that ziconotide seems to be effective in treating pain from nerve injuries as well as cancer pain. "We also think it might be a good neuroprotective agent for people undergoing heart-lung bypass" as part of an operation, said professor of anesthesia Raymond Gaeta, MD, who also took part in the study.

The research was sponsored in part by Elan Pharmaceuticals. - CV

Early bone marrow transplant promotes lym

James M. Malone, III, MD, and colleagues have found that striking early and aggressively against a particular kind of lymphoma gives patients a better chance for survival than the gentler, standard approach to treatment.

Malone, a staff physician in the department of medicine's hematology division, and colleagues in the bone marrow transplant division have analyzed the experience of 45 patients treated for mantle cell lymphoma ­ a type of non-Hodgkin's lymphoma. They found that giving patients a bone marrow transplant to treat the cancer early in the course of their disease gave them a better chance for survival than using a transplant as a last resort after other treatments have failed.

The study was a joint project between physicians at the medical center and at the City of Hope National Medical Center in Duarte, Calif. Non-Hodgkin's lymphoma is a cancer of the blood's B cells. Malignant lymphomas are the most common type of cancer to affect people who are 20 to 40 years of age. Standard chemotherapy treatments are rarely successful for patients with this particular type of non-Hodgkin's lymphoma ­ half of the patients die within three years of diagnosis.

According to Malone, treatment for patients with this kind of lymphoma consists of chemotherapy, sometimes followed by an autologous bone marrow transplant, in which the patient's own blood-forming stem cells are harvested and then returned to the patient after he or she has received high doses of chemotherapy and radiation to kill the cancer cells. "Autologous transplantation has been utilized in these patients for some time, but it has been unclear if it is beneficial, and if so, in which patients," said Malone.

He and his colleagues studied 21 patients with mantle cell lymphoma who had bone marrow transplants at Stanford and 24 patients who had bone marrow transplants at the City of Hope between January 1993 and December 2000. They found that 94 percent of patients who received their bone marrow transplant early, when their cancer was first in remission, survived for at least three years, whereas less than 60 percent of patients who were transplanted later, after their cancer had recurred on one or two occasions, survived to three years. The researchers also found that the cancer was less likely to return in those patients transplanted early.

"People don't like to use a 'harsh' treatment, like a bone marrow transplant, early. They like to use 'gentle' therapies first," said Malone. "But we found that doing the transplant early had a significant impact on survival." - CV

Attacking cancer cells with a dose of virus

Researchers at Stanford and the Veterans Affairs Palo Alto Health Care System have developed a new cancer therapy that uses a virus to attack cancer cells. The therapy increases survival for patients suffering from gastrointestinal cancers such as colorectal, gastric or pancreatic cancers -- cancers that often metastasize to cause secondary tumors in the liver, which can be fatal within six months.

The therapy uses an adenovirus called Onyx-015 that has been engineered to be harmless to normal cells in the body but to grow unabated in tumor cells, eventually killing them. Half of the patients who received the highest dose of the virus survived for one year or more, reported the researchers.

"The therapy takes advantage of the fact that tumor cells are behaving abnormally," said Tony Reid, MD, PhD, a staff physician at the VA. "It is a very weakened virus. If you gave it to a healthy person it couldn't grow. But because a tumor cell is abnormal -- it is permissive -- it allows the virus to grow inside the tumor cell and take over the cell and kill it." Reid collaborated with Daniel Sze, MD, PhD, Stanford assistant professor of radiology, and colleagues to conduct the study.

The researchers injected the virus into the hepatic artery, which carries blood from the heart to the liver. A normal liver derives only one third of its blood supply from this artery; however, malignant tumors within the liver obtain almost all of their blood supply from the hepatic artery, making this blood vessel a prime portal for a cancer-fighting agent.

Patients in the study received a monthly infusion of the virus for two to six months. Six patients received low doses of the virus and 27 patients received the highest dose. "You have to start with very small doses to show that it's safe and work your way up slowly. We are encouraged by the survival data that we saw," said Reid.

The median survival time ­ the time at which half of the patients were alive and half had succumbed to their cancer ­ increased from 155 days for those receiving low doses of the virus, to 342 days for those receiving the highest dose. Patients experienced no adverse events that could be attributed to the infusion. The most common side effects were mild to moderate fever and fatigue.

Seventeen of the patients in the study were treated at the VA hospital. The remaining patients were treated by Reid's colleagues at the Mayo Clinic, Rochester, MN, and the MD Anderson Cancer Center, Houston, TX. The Onyx-015 was provided by Onyx Pharmaceuticals, Richmond, Calif. - KW