HALIFAX, Nova Scotia - Determining the best antigen presentation to elicit a broad immune response in humans is an enormous challenge in preventing cancer, said Randal Chase, president and CEO of Pasteur Merieux Connaught Canada (PMCC).

Chase spoke at Dalhousie University, in Halifax, where two research teams from the medical school there will study basic interactions between the immune system and cancer cells in an effort to uncover ways of stimulating an enhanced immune response against largely refractive cancer cells.

The researchers will be part of the PMCC vaccine network assembling researchers from Canada and around the world in an effort to find, develop and market therapeutic vaccines for cancer. The C$350 million (US$222.6 million), 10-year cancer vaccine research program was announced by PMCC in June 1997. The federal government's Technology Partnerships Canada program is contributing up to C$60 million towards the initiative in the form of a repayable investment. The network is expected to eventually involve an estimated 60 organizations across Canada.

Research has shown that there are a host of tumor-associated antigens (TAAs) - proteins displayed on the surface of cancer cells, but rarely seen on normal cells. These proteins, which vary depending on the type of cancer, are PMCC's targets. The problem is to alert the immune system to lock on to the target proteins and kill the cells to which they are attached. One of the key objectives of the program is to develop therapeutic vaccines that simultaneously target several TAAs.

Using PMCC's “prime-boost“ technology, the vaccines will help the patient's own body eliminate the cancerous cells after conventional treatment has removed most of the tumor. The goal is to prevent not the disease itself but the relapses and deaths that often follow treatment.

The Dalhousie research becomes the second program to be enrolled and supported by the Cancer Vaccine Network, Chase said. The University of Manitoba became the first member of the network in June. Its research effort, led by internationally acclaimed scientists Leigh Murphy and Peter Watson, is focusing on the genetics that underlie the progression of breast cancer.

A team led by Dalhousie Associate Professor Jean Marshall will study the chemical signals given off by immune cells in response to certain DNA sequences. Another team, led by Dalhousie associate professors Jonathan Blay and David Hoskin, will try to understand how certain molecules within a tumor act to suppress the immune system. The groups will receive C$380,000 in funding support from the network over the next two years.

Marshall's research group will focus on CpG motifs, short nucleotide sequences known to enhance immune responses. Her goal is to see how mast cells and peripheral blood monocytes respond to these CpG motifs. Mast cells play a part in allergic and inflammatory responses, while peripheral blood monocytes ingest foreign particles, such as bacteria and tissue debris. They communicate with each other and with other segments of the immune system by releasing cytokines.

Since mast cells are potent, long-lived resident tissue cells, present at the sites of infection and tumor growth, modulation of their responses could have profound effects on immune responses and inflammation. The aim of the research will be to develop new approaches for exploiting the immunoregulatory potential of the mast cell and to increase understanding of cytokines' role in disease.

The Goal: Reactivate Killer T Cells

In the long run, Marshall says, the knowledge gained from her research may enable scientists to start a cytokine response that would trigger or bolster an immune system attack on tumor cells by killer T cells. That is exactly where the other research team will focus. Solid tumors (e.g., cancers of the breast, lung, colon and prostate) resist attack by the patient's own immune system and are also largely refractory to immunotherapy.

Led by professors Blay and Hoskin, the team will examine how certain small molecules secreted by tumor cells act to inhibit the immune system's assault on a cancer. These low-molecular-weight immunosuppressive molecules are found within the tumor and somehow prevent killer T cells from working. Several of these molecules have been identified in tumor cells, but little is known about how they turn off the T cells.

Eventually, Blay and Hoskin hope, their research will lead to therapies that will reactivate the killer T cells and allow them to destroy a tumor.

Chase said the short-term goal of the Cancer Vaccine Network is to prove by the year 2000 that therapeutic vaccines can work in humans. The initial targets of the program are melanoma, colorectal cancer and bladder cancer. Other cancers, such as breast and prostate, will be targeted after researchers are satisfied they've proven the vaccine concept.

PMCC is a subsidiary of Paris-based Pasteur Merieux Connaught. *