Experimental Vaccine Produces Colorectal Cancer Responses

SAN FRANCISCO—A new approach to stimulating the immune system against a cancer antigen has produced a clinical response in a small number of colorectal cancer patients enrolled in a phase I/II trial, according to a poster presented at the 37^th Annual Meeting of the American Society of Clinical Oncology (ASCO).

Lawrence Fong, MD, of Stanford University Medical Center, reported that researchers were able to increase dendritic cells as much as 20-fold within the patient, remove the dendritic cells from the patient’s blood and load them with an epitope derived from carcinoembryonic antigen (CEA), then deliver them back to the patient in a vaccine.

The vaccine led to dramatic tumor regression in two patients with advanced colorectal cancer. One had been cancer free for almost a year at the time of the presentation, and the other had a recurrence at 10 months. Two other colorectal patients had stable disease after treatment, and another had a mixed response, Dr. Fong said. No effect was seen in two lung cancer patients in the 12-person study.

"It’s feasible, safe, and appears to do what we had hoped," Dr. Fong told ONI. He expressed optimism that tumor immunology is moving forward after years of frustrated efforts. "We can actually prime an immune response," he said. "We can teach the immune system the things we want to teach it."

Since dendritic cells are rare in the blood, the first step in the process was to give the patients Flt3 ligand, a hematopoietic growth factor that fosters growth of dendritic cells.

"We present this as a new way of generating dendritic cells for vaccines, which is completely contrary to what everybody else is doing and, if anything, is a little simpler," Dr. Fong said. He said that researchers usually grow dendritic cells outside the patient’s body in a petri dish.

After 10 days, the dendritic cells were removed from the patients’ blood and loaded with the epitope, which is similar to CEA. The researchers then returned the cells to the patients in a vaccine.

Tricking the Immune System

The goal, Dr. Fong said, was to trick the immune system into attacking CEA. "T cells see CEA as something that is normally in our bodies, and they wouldn’t typically attack it. So in order to turn on the T cells, we immunize with something that is just a little different from CEA," he said. Once the modified epitope triggers an immune response, the immune system can target CEA because it is so similar to the epitope.

CEA is overexpressed in more than 90% of colorectal cancers, 70% of non-small-cell lung cancers, and about 50% of breast cancers, Dr. Fong said. Consequently, a vaccine that targets CEA could be applicable to some of the top cancer killers in the United States. He described the phase I/II results as "ground to stand on" for additional work.

Dr. Fong cautioned that developing a cancer vaccine for FDA approval will take years of research. He also predicted, however, that the process may be speeded up by new tools that can reveal how minor adjustments in experimental vaccines affect the immune system. For example, his group used a tetramer test developed at Stanford to correlate clinical responses with in vivo changes caused by the epitope vaccine.

"Now, hopefully, we can continue to make consistent incremental progress because we have better tools for understanding what we are doing," he said.