By David N. Leff

Science Editor

When a body’s immune system becomes a loose cannon that aims friendly fire against its own cells, the upshot is autoimmune disease. Usually, the cannonballs are T lymphocytes, which shoot killer T cells at their hapless targets.

Of the top-listed 20 autoimmune diseases in humans, the best-known are insulin-dependent diabetes mellitus, multiple sclerosis, rheumatoid arthritis and systemic lupus erythematosus.

Last month, research immunologists at Stanford University announced that they had deliberately turned tumors in a dozen terminal-stage colon-cancer patients into autoimmune disease targets. Their contrarian strategy produced two remissions. The Proceedings of the National Academy of Sciences (PNAS), dated July 17, 2001, carries their report, titled: ”Altered peptide ligand vaccination with Flt3 ligand expanded dendritic cells for tumor immunotherapy.”

The paper’s senior author is immunologist Edgar Engleman, professor of pathology and medicine at Stanford. “Converting tumors into autoimmune targets is every immunologist’s hope and expectation,” Engleman told BioWorld Today. “Their efforts have produced promising data in other tumors,” he went on, “particularly melanoma and renal cancer, using approaches somewhat similar to ours. But those tumors have long been known to be potentially immunogenic. There have been instances where patients with melanoma, for example, saw their life-threatening tumors disappear altogether – presumably related to a spontaneous autoimmune response mounted by the patient.

“That doesn’t happen,” Engleman said, “in colon, breast or prostate cancer – the common solid tumors. The most interesting finding in our PNAS report is that this is the first time I know of that an immunotherapeutic approach to colon cancer actually showed a promising clinical outcome.”

Active Immunization Versus Passive

“In this particular case,” Engleman said, “we used a vaccine designed to make the patients’ immune system sensitized to the tumor. We weren’t actually administering the drug that killed the tumor. Rather, we were inducing the patient’s immune system to generate a response that ultimately attacked the tumor.

“This is called active immunization,” he said, “as opposed to passive immunization. The famous antibody that’s being used in lymphoma is a form of passive immunotherapy, because it’s administering an antibody that’s doing all the work. The patients’ bodies don’t have to generate the immune response in that case. But in our case they do.”

The epitopic bull’s eye of Engleman’s autoantibody is a glycoprotein called carcinoembryonic antigen (CEA). “It’s expressed in the growing embryo,” he said, “and in maturity seems to be expressed at low levels in the normal gastrointestinal tract and some other cell types. CEA,” he observed, “is one of the few proteins overexpressed by colon cancer, stomach cancer and lung cancer tumors. Over 90 percent of colon tumors overexpress CEA, so it makes a good immune target for us.

“We synthesized a small fragment of the CEA protein, which is quite large,” Engleman said, “and we changed the sequence by one single amino acid. We altered one of the nine amino acid peptides that we used, so that it would bind more tightly than the native sequence to cell receptors – the cells that were recognized – and kill the tumor cells. That seemed to make a big difference. It’s probably why we got the results we did, because it’s hard for the body’s immune system to mount an immune response to self tissues. The body is designed to go to great lengths to avoid that. And if something appears on the radar screen that we call self,’ then we don’t make a strong immune response to it.”

Thus equipped with a customized immune target and a government grant, the Stanford co-authors enrolled 12 patients in a Phase I/II study. “They were treated as outpatients,” Engleman related. “All the patients had metastatic cancer; the majority, colon cancer. In order to get into the study they had to have a CEA-expressing tumor, and were estimated to live long enough to receive the vaccine and give their immune systems the chance to respond to it. That meant a minimum six months of projected life span.”

Giving Treated Cells Back To Patients

“In this ex vivo treatment,” he said, “we isolated and manipulated immune-system dendritic cells – the main cell in the body that processes antigens and presents them to the T cells. So in fact we didn’t mobilize the conventional autoimmune T cells directly, but rather the cells that come earlier than the T cells. We isolated those dendritic cells from the patients’ blood, introduced the CEA antigen to the cells, and then gave the cells back to the patient by injection. It took about two days to process the cells, and be sure they’d be taken up the CEA. And those cells that we injected traveled back to the lymph nodes where they then presented the antigen to the T cells which – thus activated – went on to attack the tumor.

“Flt-3L is a ligand, a recombinant protein initially identified by Immunex Corp. [of Seattle],” Engleman noted. “They cloned the gene and expressed the protein. It activates bone marrow cells, which then produce more dendritic cells. These cells were released into the patients’ blood stream and we captured them. The patients in this study were pretreated for 10 days with Flt-3L, in order to expand the number of dendritic cells. We ended up getting 100 times more dendritic cells by using the Flt-3L in this manner. It’s not an approved drug, but an experimental protein. Flt is a ligand that binds to an enzyme on the surface of these bone marrow cells. It sticks out from the surface, but inside the cell it’s an enzyme that causes cells to multiply – to make more dendritic cells.”

Engleman allowed that “this was a very small study, and we only had a couple of patients to demonstrate the dramatic clinical response. One of them went into complete remission about a year and a half out. The other relapsed after a year or so. A few more of the 12 cancer patients demonstrated an immunization sensitivity. If it works for this solid tumor, the implications are that the overall approach could work for other solid tumors. We’re currently extending the study into lung cancer.

“It’s quite likely,” Engleman concluded, “that within a few years we will have approaches like this that are commercially available, so that cancer patients can be treated.”