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Telling Friend From Foe

Roswell Park continues to explore cancer vaccines. How do they work?

From time to time cancer patients undergo what their doctors call spontaneous remission. They appear to be cured by some processes within their own bodies, without the usual therapeutic interventions. Scientists at the Roswell Park Cancer Institute (RPCI) are working to harness this sporadic process, making it into a reliable path to defeat cancer.

These spontaneous remissions are usually brought about by the immune system of the patient, which attacks and destroys the cancer cells. This is a rather spectacular achievement for the immune system, which has generally evolved to avoid immune interactions with our own bodies. Failure of the immune system to distinguish self frZom the outside world often leads to autoimmune diseases such as multiple sclerosis or rheumatoid arthritis.

So it is an obvious direction for cancer research to learn to harness the human immune system to attack cancer in a more reliable way. This pathway has many obstacles. How do we learn the ways in which cancer cells differ from ordinary cells, and how do we direct the immune system to make use of these differences?

Historically the most successful way to harness and direct the capacity of the immune system has been through vaccination, an area in which the RPCI has been making enormous strides. Scientists there have developed what is called a dendritic cell vaccine. This vaccine is in a small-scale clinical trial on patients with a variety of cancers, and has generated much excitement and interest. The project is led by Kunle Odunsi, MD, PhD. RPCI’s Therapeutic Cell Production Facility (TCPF), under the direction of Yeong “Christopher” Choi, PhD, houses the production of the vaccine. This state-of-the-art facility maintains strict sterility and tight control of cell growth conditions.

How do these vaccines work, and how do they solve the difficult problem of self versus non-self in the cancer context?

The world of invaders to which the human body is exposed has enormous diversity, and has changed quite rapidly over time. Industrial chemicals, processed foods, and pharmaceuticals are examples of substances that have entered the human realm only recently. So the immune system cannot work merely by having a library of specialized molecules or cells designed to attack invaders. It also needs the capacity and flexibility to attack invaders that it has not met before. One of the ways in which the immune system accomplishes this is by a pathway that involves several different families of cells. Dendritic cells circulate around the body and have the capacity to ingest and chop up protein molecules from some foreign invaders. The pieces of this foreign protein are then transported to the surface of the dendritic cell where they can be recognized by so-called killer T-cells. The dendritic cell is a kind of bulletin board, announcing what new invaders need attention today.

Killer T-cells are programmed to recognize proteins displayed on the surface of certain other cells, including dendritic cells. The killer T-cell family has great variety, with a few cells able to recognize each of many foreign protein types. Thus, there will be a few killer T-cells that recognize a particular protein fragment on a dendritic cell. This recognition process causes the killer T-cell involved to multiply rapidly, so the number of this kind of T-cell becomes very large. This newly expanded group of killer T-cells then seeks out other foreign cells, such as bacteria or cancer cells, that bear this same foreign protein on their surface, and kills them.

What makes a cancer vaccine possible is that many cancer cells show on their surfaces proteins that do not occur on normal cells. If we can target the immune system to this cancer-specific protein, we can attack cancer without attacking our own bodies. This is the basis of the RPCI scientists’ method. They have identified a protein nicknamed NY-ESO-1 that is expressed on the surface of cells in many kinds of cancer, but only rarely in normal cells. To make a dendritic cell vaccine, blood from cancer patient is collected and enriched to increase the population of dendritic cells. The surface of a cell is like its face, and dendritic cells will all have a family resemblance that allow them to identified and separated from other cells by a device called a sorter.

The RPCI group then “posted” the NY-ESO-1 protein on the surface of dendritic cells taken from a patient—the bulletin boardallowed the cells to multiply, and injected these cells back into the patient. Sure enough, the expected population of killer T-cells appeared, and attacked the cancer cells displaying NY-ESO-1 on their surface.

This is a personalized vaccine, made with each patient’s own dendritic cells. And it can be generalized to use other cancer-cell proteins in addition to NY-ESO-1. Therein lies the excitement. Time will tell how fruitful this approach will really be, but it is off to a great start.

Eaton Lattman, PhD, is director of the Hauptman Woodward Research Institute.This column is one of an occasional series exploring news about science and technology in and around Buffalo.

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