Taking a jab at cancer by stimulating the immune system

Apr 18 2007

As the first FDA-approved cancer vaccine, designed to protect against human papillomavirus, has moved from scientific discussion to social debate, other vaccine studies are continuing to make progress.

While HPV vaccine efforts had the "benefit" of a viral source for the disease, other researchers are developing vaccines for cancers that are not virally based, in an effort to coax the immune system into attacking cancerous cells. Today at the 2007 Annual Meeting of the American Association for Cancer Research, presentations on ongoing HPV trials and other new approaches to stimulating the immune system are injecting momentum into cancer vaccine research.

Substantial impact on precancerous lesions and HPV infections through 5.5 years in women vaccinated with the HPV-16/18 L1 VLP AS04 candidate vaccine: Abstract 4900

Ongoing evaluation of a phase II trial of a human papillomavirus vaccine, developed to prevent cervical cancer, shows that the vaccine continues to protect against HPV types 16 and 18 at five and a half years into the study, according to researchers from the University of Louisville. Their findings also show that the vaccine offers significant cross-protection for HPV types 45 and 31.

The study follows 1113 women between the ages of 15 and 25 in North America and Brazil randomized to receive three doses of either the vaccine or the control. The vaccine, made by GlaxoSmithKline, which funded the study, is designed to protect against two strains of HPV, types 16 and 18, which together are thought to cause nearly 72 percent of all cases of cervical cancer.

At over five years into the study's follow-up, the researchers found that approximately 98 percent of subjects still maintained protection against HPV types 16 and 18. Regardless of HPV status, the vaccine also appears to prevent most occurrences of cervical intraepithelial neoplasia lesions , abnormal, precancerous cell growths found in the cervix.

They also found that the vaccination offered significant protection against genetically similar viruses. They determined the vaccine to be 88 percent effective against HPV type 45 and 54 percent effective against HPV type 31.

"Overall, it is not a surprise that the vaccine offers protection against additional types of human papillomavirus, as they are all related genetically," said Stanley Gall, M.D., professor at the University of Louisville. "However, as you get genetically farther from types 16 and 18, you would expect to see less cross-protection."

According to Dr. Gall, effective preventative treatment with the vaccine will depend on the long-term and broad protection the vaccine can offer against cancer-causing HPV types.

High Sustained Efficacy of a Prophylactic Quadrivalent Human Papillomavirus (HPV) (Types 6, 11, 16, 18) L1 Virus-Like Particle (VLP) Vaccine against Cervical Intraepithelial Neoplasia (CIN) grades 2/3 and Adenocarcinoma in situ (AIS): Abstract LB-187

Note: This is a placeholder abstract. Researchers will present follow-up efficacy data on an FDA-approved HPV vaccine. The full embargoed abstract will be available to reporters on Saturday, April 14.

Analysis of the immunological response to a MUC-1 loaded DC vaccine for human pancreatic cancer: Abstract 4896

Results from a Phase I study of a pancreatic cancer vaccine may offer clues toward promoting long-term survival from the disease, according to researchers from the University of Pittsburgh Cancer Institute.

The researchers gave a dendritic cell vaccine to 12 pancreatic cancer patients. Four of the subjects have shown no signs of recurrence in the three years since the study began.

"The trial was a look at the toxicity and feasibility of using a dendritic cell-based vaccine against pancreatic cancer," said Andrew Lepisto, Ph.D, post-doctoral researcher in the University of Pittsburgh's Department of Immunology. "While we are unlikely to run large-scale trials with this particular form of the vaccine due to difficulty in its manufacturing, we have learned a tremendous amount from the subjects that benefited from the trial, which may translate well into more practical vaccine formulations."

The dendritic cell vaccination strategy combines a cancer protein with the patient's own dendritic immune cells. These cells are antigen presenting cells that, in effect, advertise the presence of the antigen molecule to the rest of the immune system. The antigen, MUC-1, is a protein that is over-produced by pancreatic cancer cells. By presenting patients with MUC-1 on dendritic cells, the researchers expected that they could influence the white blood cells to attack pancreatic cancer cells.

The study data suggests that the key to the effectiveness of the vaccine could be in controlling the regulatory T cells, which suppress the immune system, says Lepisto. Prior to vaccination, the pancreatic cancer patients had significantly more regulatory T cells than normal, which then increased following each injection. Likewise, the patients also experienced an increase in effector T cells, white blood cells that respond against antigen.

"Our next step is to create a strategy that allows us to downplay the regulatory T cells while still benefiting from the increase of effector T cells," Lepisto said.

Each year, pancreatic cancer kills approximately 32,000 people in the United States alone. Pancreatic cancer is notoriously resistant to conventional cancer therapies and has one of the lowest five year survival rates of all cancers.

Wild type sequence p53 as a vaccination target for squamous cell carcinoma of the head and neck: Abstract 5113

Researchers from the University of Pittsburgh and the Gunma University School of Medicine have developed a vaccine that enlists multiple parts of the immune system into targeting p53 in head and neck squamous cell cancer. A phase I clinical trial of the vaccine is currently underway at the University of Pittsburgh Cancer Institute.

According to researchers, this is the first vaccine that takes a multi-pronged approach to stimulating the immune system with derivatives of wild type , or non-altered , p53, a tumor suppressor gene. Loss of suppressor function or alteration of the p53 gene factors into nearly 80 percent of human tumors. Tumor cells with altered p53 generally tend to accumulate the protein, which led the researchers to create a strategy that would allow the immune system to destroy tumor cells by targeting p53.

"Instead of creating a vaccine based on mutant p53, which would require a custom vaccine for every patient, our strategy is to target parts of the unaltered p53 protein that can best activate the immune system," said Theresa Whiteside, Ph.D., professor at the University of Pittsburgh School of Medicine. "We are using different unaltered portions of the p53 molecule to entice the immune system into attacking tumors."

According to the investigators, their vaccine uses three different p53-derived peptides to elicit responses from different aspects of immune system. The vaccine currently in trial uses autologous (patients' own) dendritic cells (DC) pulsed with a combination of three peptides: two that trigger cytotoxic T cells, which directly kill targeted tumor cells, and one peptide that stimulates helper T cells.

Altogether, it is an approach that not only excites the killer T cells into action, but also influences the helper T cells, which are instrumental in sustaining the killer T-cell response. The combined strategy has already shown great promise in studies using animal models and human cells in culture, according to the researchers.

The phase I trial, which will eventually enroll 24 patients with head and neck cancer, has three experimental arms, each including a DC-based vaccine containing p53-derived T cell-specific peptides. The three groups vary on whether the cytotoxic p53 peptides are delivered alone or in combination with a helper T cell-activating peptide that is either specific to p53 or not specific to p53.

"Despite great medical progress, the survival rate in head and neck cancer still remains very poor, at about 50 percent, and there is a definite need for new treatment modalities like vaccination," Whiteside said. "Targeting of p53, however, is a strategy that could also work in treating a number of different cancer types, since p53 loss of function is such a common feature of many cancers."