LONDON _ Israeli researchers have developed avaccine that can cure mice of lung cancer, raising hopesthat it may one day be possible to cure human cancersusing the same approach.
The vaccine eliminated the cancer at an advanced stagewhen metastases _ deposits of malignant cells thatspread throughout the body from the primary tumor _already formed. Some of the mice were still alive 500days after receiving the vaccine and the researchersconsider them effectively cured.
Most efforts to develop vaccines against cancer are aimednot at preventing the disease but at stimulating theimmune systems of people with cancer to attack themalignant cells. This would allow the immune system to"mop up" metastases once the primary tumor has beenremoved by surgery.
Unfortunately, in most cases, tumor cells fail to stimulatethe immune system effectively. Scientists have thereforebeen searching for unique characteristics present ontumor cells which they could incorporate in vaccines andthus kick the immune system into action.
Ofer Mandelboim, Lea Eisenbach and their colleagues atthe Weizmann Institute of Science, in Rehovot, Israel,solved the first part of this problem last year. Theyreported in Nature that they had identified a mutation in aprotein that is present on the membranes of lung cancercells. The protein, connexin 37, also is present on normallung cells, but that found in the mouse, Lewis lungcarcinoma, has a mutation that results in a single aminoacid substitution. Tests carried out by Eisenbach's teamand reported in the same article showed that a peptide ofeight amino acids, which includes the substituted aminoacid, can induce cytotoxic T lymphocytes in mice whichcould recognize and destroy the tumor cells.
Now, the Israeli team reports that incorporating asynthetic version of this peptide into a vaccine canprevent metastatic spread of the cancer in mice. Writingin the November issue of Nature Medicine, Eisenbachand her colleagues report that most mice cured using thisapproach achieve long-term survival in an article titled"Regression of established murine carcinoma metastasesfollowing vaccination with tumor-associated antigenpeptides."
If an antigen is to stimulate cytotoxic T lymphocytes, itmust first be "presented" by a cell in conjunction withsurface proteins called major histocompatibility complexclass I proteins. So a virus-infected cell, for example, willbreak down the foreign viral proteins and export peptides(fragments of the proteins) to its surface. A similarprocess occurs when tumor cells express aberrant self-proteins.
Families of peptides which share common structuralfeatures will bind to one type of MHC class I while othersbind to other types.
Peptide-Loaded Cells Induced Attack On Tumors
Eisenbach and her colleagues chose antigen-presentingcells called RMA-S. These express the correct majorhistocompatibility antigen but do not normally displaypeptides because the cells are incapable of processingproteins. However, they can be "loaded" with the mutantsynthetic peptide from the outside. Tests showed thatthese peptide-loaded RMA-S cells, injected into mice,were capable of inducing cytotoxic T lymphocytes thatrecognized and attacked the tumor cells.
"We then tried to do the real thing," Eisenbach said. Theresearchers inoculated tumor cells into the feet of mice;once the tumors had reached diameters of about 6millimeters, the tumor-bearing feet were amputated. Atthis stage, the mice had widespread metastases in thelungs.
Two days later, immunization began. In control mice thatreceived no further treatment, death followed after about35 days. But out of nine mice that received the vaccinemade from RMA-S cells loaded with the mutant peptide,seven were still alive, 500 days after the experimentbegan. The other two mice did not respond to thetreatment and died earlier.
"The take-home message here," Eisenbach said, "is that ifyou have the right peptide for the cancer, the treatmentcan be very effective. Even at a relatively advanced stage,a big fraction of this vaccinated group survived."Provided researchers can identify a suitable peptide onthe cells of the types of lung cancer that affects people, itshould be possible to transfer to a technique for treatmentof humans, she said.
Peers Say Approach Is `Worth Considering'
Other researchers agreed that Eisenbach's work lookspromising. Eli Gilboa, professor of surgery andimmunology, at Duke University Medical Center, inDurham, N.C., said what was "spectacular" about thestudy was that "it worked in such a difficult but relevantexperimental setting." The team attempted to cure miceof pre-existing metastases left behind after removal of theprimary tumor, he said, exactly mirroring the situation inhuman cancer patients.
"Neither this nor any animal study will tell us in absoluteterms whether this particular strategy or these particularobservations will translate to a human patient _ but theyprovide very good guidelines. By using a relevantexperimental setting and demonstrating some efficacy,this work increases our confidence that the approach thisgroup is developing is worth considering very seriously,"Gilboa said.
But Jack Strominger, professor of biochemistry atHarvard University, in Cambridge, Mass., sounds a noteof caution. He warns that mouse tumors often are easierto treat than human tumors. "I'm not certain that thismouse model can be translated to the human situation."
Nevertheless, Strominger said, "this particular paperillustrates how you can prevent metastases after surgicalremoval of the primary tumor. If _ and it's a big if _that can be repeated in humans, then it would be atremendous advance and you would save many lives."
Since submitting the paper to Nature Medicine, the Israeliteam has discovered that the same tumor antigen ispresent on a different type of lung cancer that affectsmice, and has isolated a second tumor antigen on the firsttype of lung cancer.
Eisenbach said: "One of the potential problems of usingjust one tumor antigen is that if you immunize but don'tmanage to eradicate all the metastases, you might get`escape variants' _ cells that do not express the antigenand therefore grow effectively. So having more than oneantigen from the same tumor might be very important."
The team has tested the second antigen as a component ofa vaccine and found that it, too, is quite effective.
"Now we are ready to begin experiments to find outwhether immunization with two different peptides ismore effective in getting rid of lung metastases thanimmunization with a single peptide," Eisenbach said. n
-- Sharon Kingman Special To BioWorld Today
(c) 1997 American Health Consultants. All rights reserved.