Immunotherapy: enlisting the immune system to fight cancer

SAN DIEGO – Researchers are directing the body’s immune system to shrink tumors and prevent new ones from forming. Data presented at the 2008 Annual Meeting of the American Association for Cancer Research, April 12-16, detail how cellular strategies and new vaccines are changing the cancer treatment landscape.

The first use of a live listeria cancer vaccine in man: Abstract 225

Phase I/II trial results have shown that the live Listeria cancer vaccine, Lovaxin C, is safe for humans. In addition, three women in the cervical cancer trial had approximately 20 percent tumor reductions, researchers report.

“We are using Listeria to deliver tumor-specific antigens to the immune system in a manner that results in maximal immune and tumor-clearing response,” said John Rothman, Ph.D., vice president of clinical development at Advaxis, which is developing Lovaxin C.

The trial included 15 women with progressive, recurrent or advanced cervical cancer. All patients had failed chemotherapy, radiotherapy or surgery. The women had metastatic disease and most were stage IVb.

Listeria monocytogenes infects antigen presenting cells (APCs) — “a very special piece of immune real estate,” Rothman said. These cells consume foreign invaders and instruct the immune system to attack them. Listeria thrives within APCs and thus directs an immune response.

“We bioengineer Listeria both to attenuate it and to cause it to secrete a tumor-specific antigen fused to a listerial protein, which makes it more effective than Listeria that just secretes the tumor antigen,” Rothman said. “By doing this we focus a very strong immune attack against the antigen in question, which is typically specific to a tumor.”

“What we’re doing is taking a lot of evolution that enabled Listeria to infect human immune systems, and an equal amount of evolution that enables humans to get rid of Listeria once this occurs. We are then co-opting and redirecting all of these complex immune responses and targeting them against cancer,” Rothman said.

The researchers divided the patients into three groups of five; each group received two doses of either 1x109, 3.3x109 or 1x1010 units of Listeria at three-week intervals. They administered ampicillin five days after each dose, first intravenously and then orally for 10 days.

Each patient developed flu-like symptoms, including fever, chills and nausea with or without vomiting. In the lower doses, these symptoms were treated with non-prescription non-steroidal anti-inflammatory drugs (NSAIDs) and anti-emetics. Patients in the highest dose group had the same but more severe symptoms.

Rothman used the RECIST criteria to assess the tumors in 13 patients. At the end of the study, five patients had progression of their cancer, seven were stable, and one patient showed a partial response to the therapy. Three of the seven stable patients had tumor reductions of about 20 percent.