Phase I/II Results Promising for Live Listeria Cancer Vaccine

Newswise — Phase I/II trial results have shown that the live Listeria cancer vaccine, Lovaxin C, is safe for humans, according to data being presented at the 2008 Annual Meeting of the American Association for Cancer Research. In addition, four women with end-stage cancer in the cervical cancer trial experienced tumor reductions.

"We are using Listeria to deliver tumor-specific antigens to the immune system in a manner that we feel results in maximal immune and tumor-clearing response," said John Rothman, PhD, 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 instruct the immune system what to attack. Listeria thrives within APCs and Advaxis' Lovaxin vaccines have the ability to direct a strong immune attack against whatever tumor target is bioengineered into the vaccine. Lovaxin C is engineered as a therapy for people who have cancer caused by HPV.

"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 advantage of millennia 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 NSAIDs and anti-emetics. Patients in the highest dose group had the same, but more severe, dose limiting, symptoms.

All 15 patients were used to assess safety, and Rothman used the RECIST criteria to assess the tumors in the 13 patients available for the efficacy analysis. At the end of the study, five patients had progressed, seven were stable, and one patient had an apparent partial response. Three of the seven stable patients had tumor reductions of about 20 percent.

The apparent partial response patient — who had failed 2 courses of chemotherapy and a course of radiation prior to entry in the study was stage IVb at trial initiation — was removed from the trial early when her positive response was observed and before a confirmatory scan could be performed. She was given six chemotherapy courses and a radical hysterectomy. Currently, she is tumor- free with normal hematology. All of her labs are within normal limits. At the time of this writing, 6 of 13 patients evaluable for efficacy are still alive. Median survival at the last assessment on February 29, 2008 was 424 days for the six survivors and a median survival for all treated patients of 327 days for all treated patients. 2 patients were stage IIIb at the time of their first dose and 12 were stage IVb, and one was not known.

The company will continue to study Listeria. A trial on early-stage cervical intraepithelial neoplasia will start in a few months, and the company is collaborating with the Gynecologic Oncology Group on another cervical cancer trial. The company also hopes to have a prostate construct in the clinic soon. Rothman said.

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