The Practical Dream of Cancer Therapies and Vaccines

By Jason Socrates Bardi

In the field of cancer research, to "cure" is, perchance, to dream.

To dream of helping the masses who are every year treated for cancer or of saving over 500,000 Americans who succumb every year to cancer. But believing in a cure is perhaps to slip into foolhardy fantasies. We may never find a single magic bullet that can successfully cure all types of cancer.

Immunology Professor Ralph Reisfeld freely admits to being a dreamer, although he is also enough of a realist to avoid using the word cure.

"In science you have to dream a little bit," he says. "My dream is to prevent cancer."

"And," he adds "if you can't prevent cancer, then at least you can help doctors treat it better. That would be a real boon for mankind."

Cancer is a quasi disease—actually over a hundred diseases caused by various sorts of mutations inside various cells in various tissues.

These mutations upregulate some genes, increasing the expression of metalloproteases for instance, and downregulate others, shutting off production of receptor proteins. After a certain number of such events occur, a cancer cell grows out of control, becoming what is known as a tumor. Tumors threaten the tissues where they are located. Worse, tumors can metastasize and migrate through the bloodstream to other tissues—the reality of malignant carcinoma that claims so many lives every year.

Immunotherapy—Helping the Body Do What it Should

One approach to cancer therapy that has evolved over the last few decades is the method of immunotherapy, which aims to give the immune system a push to start doing what it should be doing in the first place—killing cancer cells. Immunotherapy involves helping the T lymphocytes and other cells of the immune system attack and kill cancer cells, and it is best at killing small colonies of cancer cells before they grow into tumors.

One way in which this is accomplished is by presenting the immune system with tumor-specific antigen. Antigens are markers—proteins on the surface of a cancer cell, for instance—that are used by the immune system to distinguish one cell from another. Immunotherapy entails administering injections of the antigen and activating the immune system against it.

These injections enable the antigens to be presented by professional antigen presenting cells, which very effectively stimulate the immune system. After recognizing the antigens presented by the antigen presenting cells, the immune cells become activated and mount an immune defense, selectively attacking any other cells displaying the antigens—the cancer cells.

Since cancer cells are originally "self" cells, the trick is to find some antigen that they display, but which normal cells in the body do not. Fortunately, the mutations that cause cancer often cause distinct antigens to appear on the surface of cancer cells. Sometimes these antigens are overexpressed on cancer cells, decorating them much more so than normal cells, and sometimes the antigens are expressed only on cancer cells. But in any case, they mark the cancer cells, and when the immune system is stimulated to specifically attack cells with those antigens, the cancer cells can no longer hide behind their self faŤade.

"[Cancer] cells masquerade as self," says Reisfeld. "We do everything we can to take the mask off."

Reisfeld employs a technique called passive immunotherapy, which involves giving antibodies to a patient that are specific to tumor cell antigens. The antibodies bind to molecules on the surface of tumor cells and direct other, cytotoxic immune cells to them.

One such antibody he discovered is the monoclonal antiganglioside GD2, which is currently in Phase III clinical trials sponsored by the National Institutes of Health. GD2 targets the ganglioside proteins that are expressed on the surface of neuroblastoma tumors, the second leading cause of childhood cancer and one for which there is usually a poor prognosis.

"These children have been dying in far too large numbers," says Reisfeld, statistics that he hopes GD2 will change.

In the therapy, a recombinant protein is given to a patient intravenously. The protein is the antibody that is linked to the cytokine interleukin-2 (IL-2)—a molecule produced by immune cells that is important in cell growth, adhesion, and movement. IL-2 is a growth factor for immune cells, like T cells, macrophages, and natural killer cells. IL-2 binds to receptors on their surfaces, activates them, and helps them proliferate.

So the recombinant protein does four things. By virtue of its GD2 component, it finds the neuroblastoma tumor cells, binds to them, and attracts immune cells that can kill them. And significantly, because of the IL-2 component, the recombinant protein enhances this killing by activating the immune cells and inducing them to multiply at the site of the tumor.

"GD2 is almost like a guided missile to bring interleukin to the tumor," says Reisfeld.

Immunotherapy works best at slowing down metastasis in minimal residual disease, preventing the growth and spread of cancers. It is not designed to kill big, bulky tumors or address widespread metastasis. "There we need the surgeon, the radiologist, and the chemotherapist," says Reisfeld. "They do that."

One patient, he adds, has had great success since starting the treatment at the age of five. "Now he's 16 and a big boy," Reisfeld beams, pointing to a picture on his shelf of a boy, smiling.

How Much is an Ounce of Prevention Worth?

Reisfeld is also working on DNA vaccines as a possible way to prevent cancer.

The idea of the DNA vaccines is similar to that of immunotherapy. DNA encoding some antigen that will induce a cell-mediated immune response in which T cells are activated to kill cancer cells is injected into a patient so that the antigen can stimulate the immune system. The difficulty, again, lies in finding antigenic components of cancer that are not also present in normal cells, because the cytotoxic T cells will kill whatever they encounter that displays the antigen.

"T cells are mass murderers," says Reisfeld. "Once they begin to kill, they will continue killing."

One promising antigen is a protein called carcinoembryonic antigen (CEA) that appears in early development and soon disappears. In certain cancers, particularly on colon, lung, breast, and pancreatic cancer tissues, this protein is upregulated, though, and reappears specifically on them.

In studies conducted in Reisfeld's laboratory, DNA encoding the CEA antigen is inserted into replication-deficient Samonella typhimurium bacteria and then used in murine model systems. These bacteria are important because they direct the DNA to lymph nodes in the gut—the Peyer's patches where the bacteria die and release the DNA to be taken up by phagocytes, such as antigen-presenting dendritic cells and macrophages. The DNA is translated into protein which is digested in the proteasome of these cells and then presented to T-cells, as complexes with major histocompatibility antigens.

Once the dendritic cells present the antigen to selected T cells, the T cells are activated and proliferate. The T cells will then circulate throughout the body looking for that antigen, and when they encounter it on the surface of tumor cells, they will kill these cells.

The drawback of this approach is that if the antigens happen to be downregulated on the tumor cells, as they often are, then the tumors will be invisible to the passing killer T cells. One possible solution to this is to use the antibody/IL-2 in conjunction with the vaccine to further enhance the ability of the T cells to find the tumor cells. With the IL-2, any T cells that do manage to find some hidden tumor cells will receive the growth signal and expand further.

Reisfeld has tried this, and in some settings has been able to prevent the establishment of metastasis. "We're [now] trying to do this as effectively and as efficiently as we can," he says.

And, he adds, it is entirely possible that in this age of genomics new antigenic targets that are specific to tumor cells will be found in the next few years, which will lead to further possibilities.

"The real excitement is yet to come," he says.


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"In science you have to dream a little bit," says Immunology Professor Ralph Reisfeld. "My dream is to prevent cancer." Photo by Jason S. Bardi.