'Living drug' shows promise in early clinical trials.
Genetically engineered immune cells may have helped two patients with advanced prostate cancer to fight the disease, preliminary results suggest.
Prostate cancer kills more than 28,000 men in the United States alone each year. Although many patients have their prostate glands removed, the cancer can spread rapidly to other parts of the body, usually the bones. Current drug treatments, such as male hormone suppression therapy, often fail after just a few months.
The researchers extracted a type of white blood cell called T lymphocytes, or T cells, from the patients, who had already had their prostate gland removed. These cells normally fight infections, but the researchers used a virus to insert genes into the cells that would help them to target any remaining prostate cells. The modified cells were then injected back into the patients.
"T cells are the perfect killing machines," explains Richard Junghans, an oncologist at Roger Williams Medical Center in Providence, Rhode Island, and principal investigator of the study. "In one day, one T cell can kill 100 target cells. We want to use that power to fight cancer."
Reprogramming immune cells
Junghans' group genetically engineered the patients' T cells to recognize a protein found on the outer membrane of prostate cells called prostate-specific membrane antigen, or PSMA. The researchers then grew the engineered T cells until there were around a billion cells, then placed them back in the patients, hoping that they would seek out residual prostate cells and kill them.
The patients were taking part in a phase I clinical trial to test the safety of the technique and received only a low dose of the treatment. But Junghans' team found that the concentration of prostate-specific antigen (PSA) — a marker in the blood that correlates with the abundance of prostate-cancer cells — dropped by around 50% in one patient and by 75% in the other. The results were presented at the annual meeting of the American Association for Cancer Research on 19 April in Denver, Colorado. How effective the treatment really is will not be known until it is tested rigorously in future trials.
This treatment and a few others that are in phase I trials are the first to combine the genetic engineering of T cells with an new protocol that helps the infused cells to survive much longer. Earlier studies had shown that engineered T cells put back into circulation generally survive for only a few hours or days. But the new procedure conditions patients' bodies to make 'room' for the T cells by first knocking down the level of white blood cells with chemotherapy1. This way, the T cells can survive for months, and perhaps indefinitely.
Because the modified T cells are a 'living drug' that cannot be removed once infused into the body, the procedure is quite risky. The cells could, for instance, attack other types of healthy cells. In 2006, a trial using designer T cells targeted against kidney cancer had to be stopped and modified because the cells seemed to be attacking healthy liver tissue2.
"It is incumbent upon the investigator to perform due diligence to test all normal tissues in the body to make sure there is no cross-reactivity," says Junghans.
Mark Dudley, an immunotherapy researcher at the National Cancer Institute in Bethesda, Maryland, agrees that this is the biggest challenge for researchers designing T-cell therapies. He points out that the relatively small number of T cells used in the therapy can also be suppressed easily, or even wiped out, with certain drug regimens.
Even with the risks, however, Dudley says that personalized cell therapies such as this one are "the most exciting new technology out there" and have incredible potential. "We have every reason to believe that patients with any kind of cancer should be able to respond if the appropriate, cancer-specific T cells can be made."
Although these phase I results are encouraging, both Dudley and Junghans say that it is too early to tell whether the treatment was truly effective. Junghans says he won't be satisfied until he sees a 100% drop in PSA concentrations. "This approach is just too much work unless you are going for a real cure," he explains.
Dudley, M. E. et al. J. Clin. Oncol. 23, 2346-2357 (2005).
Lamers, C. H. J. et al. J. Clin. Oncol. 24, e20-e22 (2006).