Lifesaving lessons from leukemia

A type of stem-cell transplant originally developed by center researchers to treat leukemia shows initial promise as a therapy for an aggressive form of kidney cancer, according to a new Clinical Research Division study.

The transplant eliminated or prevented worsening of metastatic renal-cell carcinoma in three of eight terminally ill patients enrolled in the study. Researchers are optimistic that with further refinement, the procedure could offer new hope for patients with the disease, for which no effective chemotherapy exists.

The study, published in the Dec. 1 issue of Clinical Cancer Research, involved a modified form of stem-cell transplant called a nonmyeloablative, or mini, transplant. The procedure involves treating patients with low doses of radiation and drugs to suppress their immune system, followed by a transfusion of adult stem cells extracted from the blood of a relative of matching tissue type. Unlike conventional stem-cell transplants, which require high doses of chemotherapy and radiation and usually weeks of hospitalization, mini-transplants often can be performed entirely in an outpatient clinic.

Exploring mini transplants

Previous Fred Hutchinson studies in which mini-transplants were used to treat leukemia and other blood cancers have shown that the procedure works because donor immune cells recognize the patient's cancer cells as foreign and target them for destruction. In the new study, the researchers for the first time have found donor immune cells that react against kidney-cancer cells.

"We are hopeful that once we understand how the donor immune cells control and eliminate the cancer, we can design a more effective transplant strategy that takes advantage of this immune-cell response," said Dr. Brenda Sandmaier, senior author of the study. "This is currently an active area of research in our laboratories."

Scientists in the Clinical Research Division and at other transplant centers have explored using mini-transplants to treat metastatic renal-cell carcinoma because the disease is one of a handful of cancers known to at least partially respond to therapies that boost the patient's immune system, said Dr. Scott Tykodi, a research associate in the Clinical Research Division and lead author of the study.

"About 15 to 20 percent of patients with metastatic renal cancer who are treated with interleukin-2 or interferon — substances that stimulate the immune system — have favorable responses," he said. "What's truly remarkable is that about 5 percent are completely cured. That is unusual for patients with most types of cancer that has metastasized. We'd like to extend these benefits to more patients by developing better immune-based treatments."

Preliminary promise

Renal-cell carcinoma strikes about 30,000 people in the United States each year. About half of the cases have already spread, or metastasized, to other parts of the body by the time a patient is first diagnosed, or will spread soon after diagnosis. Although their effectiveness is limited, interferon and interleukin-2 are currently considered the best treatments for the disease.

Several transplants centers recently have conducted preliminary clinical trials of mini-transplants in metastatic renal-cell carcinoma patients. On average, about 20 percent of patients in these studies have had a partial or complete response from the treatment. In those trials, patients required hospitalization to manage the toxic side effects of the procedure.

In the new study, Tykodi and Sandmaier, and Clinical Research Division colleagues Drs. John Thompson and Rainer Storb, tested whether the milder mini-transplant regimen developed at Fred Hutchinson for blood-cancer patients would be safe and effective for metastatic renal-cell carcinoma patients.

Eight patients with metastatic renal-cell carcinoma, ranging in age from 40 to 54, underwent the procedure. All received pre-transplant conditioning (radiation and the drug fludarabine) and the stem-cell transfusions as outpatients, although four of the patients required at least one subsequent hospitalization to treat infections or other complications that developed within the first three months.

In two of the patients, the cancer remained stable and had not worsened after a follow-up period of more than a year. In a third patient, the disease went into remission. The cancer continued to worsen in the five other patients, who died at a median time of 8 months after treatment. Four of the deaths were due to renal-cell carcinoma, and one resulted from pneumonia.

To learn more about why the procedure was effective for a subset of the patients, Tykodi and Dr. Hootie Warren examined immune cells known as T cells from the blood of the transplant recipients. In five of the eight patients, they detected T cells originating from the donor that reacted against the patient's own tissue. In the three patients who responded well to the treatment, some of these T cells were found to react against the tumor tissue.

Previous transplant studies with leukemia patients have found that even when patients and donors are carefully matched for the most important factors that control an individual's tissue type, many other subtle tissue-type differences exist between any two individuals — even siblings — except identical twins. These differences, which cause the donor immune cells to react against the patient, can have both positive and negative effects. When the reaction is against healthy patient tissue, it results in a sometimes severe complication called graft-vs.-host diseases (GVHD). When the reaction is against the cancer cells — known as graft-vs.-tumor effect — the transplant is often successful. Both reactions usually go hand in hand, such that patients who suffer from GVHD often reap the greatest benefits from the transplant. Two of the three renal-cell carcinoma patients who responded to the treatment also suffered from GVHD.

Key differences

Tykodi said that the key to improving the effectiveness of the mini-transplant for renal-cell carcinoma is to learn which differences between patient and donor are most important for the anti-tumor effect. Ultimately, patients and donors may be typed and matched according to achieve the most effective response.

In addition, the research team hopes to identify T cells that react uniquely against tumor cells and weakly or not at all against normal tissue. Once identified, these cells could be transfused into patients after the transplant to boost the procedure's effectiveness. In addition, these novel targets on tumors could be used to develop vaccines that could stimulate a patient's own immune response after transplant.