By David N. Leff
If you or someone close to you had late-stage cancer ¿ and your druthers ¿ would you opt for well-established therapies or an experimental mode of treatment?
At the Clinical Center of the National Cancer Institute (NCI) in Bethesda, Md., several hundred metastatic melanoma patients a year sign up for the latest modalities that have worked well in tumor-ridden mice.
¿What we are trying to do here at NCI,¿ observed cancer vaccinologist Nicholas Restifo, ¿is to develop treatments for patients whose conventional therapies have failed.¿ He is a principal scientific investigator at NCI¿s Surgery Branch. His laboratory focuses on synthetic and recombinant anti-cancer vaccines.
Restifo and Steven Rosenberg, who heads the Surgery Branch, are co-senior authors of a paper in the current Proceedings of the National Academy of Sciences (PNAS), dated March 16, 1999. Its title is: ¿Vaccination with a recombinant vaccinia virus encoding a self¿ antigen induces autoimmune vitiligo and tumor cell destruction in mice: Requirement for CD4+ T lymphocytes.¿
¿I work in the lab on the basic science aspects,¿ Restifo told BioWorld Today, ¿and then Steve and I develop experimental treatments. He heads the whole Surgery Branch, but here spearheads the actual patient side of the equation.¿
In that equation, metastatic melanoma is a key factor. Because it progresses with aggressive speed, and defies all conventional therapies, this lethal malignancy makes a uniquely useful model for studying cancers in general. Moreover, it afflicts laboratory mice, who serve as ideal preclinical surrogates for the human condition.
¿For a decade,¿ Restifo recounted, ¿we at NCI have been trying to develop therapeutic vaccines to make cancers go away. In various immunotherapy efforts in general, and metastatic malignant melanoma in particular, we¿ve noticed that some of the patients get vitiligo. That is, they lose the pigment in some areas of their skin. The melanoma tumors themselves are very pigmented,¿ he added. ¿That¿s where the disease gets its name; the melanin pigment is black.
¿But patients with some of the tumors that we could actually get to go away, using various experimental immunotherapies, sometimes got vitiligo ¿ bleached, white patches of skin and hair. We also observed that if a person had the vitiligo skin condition, the tumor seemed almost always to go away.
¿So we decided to run a prospective study,¿ Restifo went on, ¿and sure enough when we did that every patient who developed vitiligo had a positive response to our experimental treatment. Cosmetically, it¿s not a very beautiful side effect, but it didn¿t hurt the people. It wasn¿t life-threatening.¿
He pointed out that ¿there are pigment cells in your eyes, which is why your pupils are so black. You don¿t see any problem with the eyes. Or with the black substantia nigra of the brain. Nigra¿ means black. And that wasn¿t destroyed.¿ (See BioWorld Today, Oct. 7, 1994, p. 1.)
¿All in all,¿ Restifo observed, ¿vitiligo looks like a relatively benign side effect ¿ a good tradeoff. If you¿re dying of metastatic melanoma, it¿s not so bad to have a cosmetic problem.
¿Simultaneously,¿ he continued, ¿we were trying to figure out what the heck the immune system was recognizing on these tumor cells. The lead was development of vitiligo, an important key to the riddle.¿
So workers at the Surgery Branch set about cloning the gene products that the immune defenses recognized on the tumors. They made a library out of the melanoma cells and went through it, ¿initially one at a time,¿ Restifo recalled. ¿Three technicians transfecting cells night and day, probing those libraries, identifying genes.¿
They ended up identifying a handful of antigens that immune-system cells recognized on melanoma cells. These were enzymes in the synthesis pathway of melanin pigment, which acts to color normal as well as malignant melanocytes.
¿So we took all those genes that encode enzymes in the melanin biosynthesis pathway,¿ Restifo narrated, ¿and made a complementary DNA library out of a mouse melanoma. We used it to probe that library with individual human genes we had identified that were recognized by the human immune system. And we picked out all those genes, five in number.
¿Then we inserted those mouse genes ¿ similar to the ones in humans ¿ into recombinant vaccinia viruses. We wanted to test the hypothesis that associated melanoma with vitiligo in humans, and see if that would help us make a vaccine against melanoma.
¿And sure enough,¿ he went on, ¿when we vaccinated mice with these recombinant viral vaccines, all of them failed except for one. And that was one encoding an antigen called tyrosinase-related-protein-1 (TRP-1), which we found was the money protein. It prevented tumor growth in mice injected with aggressive melanoma cells.
¿That was the most exciting thing,¿ Restifo recounted, ¿Those same mice that developed vitiligo could resist challenge with the experimental murine melanoma. That was the linkage we were looking for between vitiligo and melanoma. We couldn¿t do that in people,¿ he pointed out. ¿We could notice that both effects were sometimes seen together in humans, but we were never able to link them quite so powerfully.¿
Folks Are Really Like Mice
Restifo continued: ¿So, as we always do, we developed our treatments first in mice. Now we¿re going to do it in patients. We¿ve already been in the clinic with similar strategies. We do have the human version of the murine gene that we¿re working with here, TRP-1 ¿ the subject of this paper ¿ but it is not yet in production. It¿s a little bit away from human trials right now. We¿re not on the threshold, but we¿re going to push it hard, because if human beings are anything like mice, and they really are, this may also work better in people than existing therapies.¿
Then Restifo changed the subject. ¿There¿s the other side of the coin ¿ autoimmune disease. It¿s long been speculated that viruses can cause those in people. That viruses cause multiple sclerosis or systemic lupus, for example.
¿We here have clearly caused an autoimmune disease in mice, vitiligo, with our vaccinia virus vector. So these findings may have implications for such diseases, even common things like rheumatoid arthritis. We don¿t know whether infectious agents cause that arthritis, but it¿s a very hot new area.
¿Our attempt was to cause an autoimmune disease in the service of destroying cancer. The rheumatologists¿ objective is to stop autoimmune diseases. Once we understand the autoimmunity mechanism,¿ Restifo concluded, ¿we can knock out the cells ¿ maybe the T cells ¿ that are at fault.¿