Yes, Virginia, there is a tumor-specific antigen.
Not just "tumor-associated," but absolutely exclusive to cancerousgrowths. And there's the catch: The antigen in question is not specificto tumors as a whole _ one molecule fits all _ but separately toeach individual's own private malignancy.
Which means that any attempt to enlist the body's immune systemagainst that antigen must do so one patient at a time.
That's just what oncologists at Stanford University have done. Theirreport on successfully tailor-making such immunotherapy for fourcancer patients appears in this month's Nature Medicine, titled"Vaccination of patients with B-cell lymphoma using autologousantigen-pulsed dendritic cells."
That article's senior editor is Ronald Levy, who heads the oncologydivision at Stanford's Medical Center. His double-barreled approachdeploys two elements: a patient-specific tumor antigen, and dendriticcells, a maverick component of the body's immune defenses.
"Although a part of the immune system," Levy told BioWorld Today,"a dendritic cell is not a B cell, not a T cell, not a macrophage.Rather, it seems to be the primary cell in the body that presentsprotein antigens, both allo [e.g., graft-rejection antigens ] and foreignproteins, to T lymphocytes."
To do this job, dendritic cells express major histocompatibilitycomplex (MHC) Class I and II molecules, with high efficiency. ClassI and II serve different T-cell types.
He and his team recruited this "immunologically powerful antigen-presenting dendritic cell" to enable his lymphoma patientscompetence to deliver their own tumor-specific antigens to cytotoxicT cells for destruction.
B Cells Go To Bud
"Every B lymphocyte in the body," Levy recounted, "has a uniqueantigen-binding receptor on its surface. It's made by a uniquecombination of separate genes that are rearranged in the DNA inevery cell, such that each one comes up with a different receptor."
He continued: "The B cell that gives rise to the lymphoma hasalready undergone that malignant transformation in its normal life,prior to becoming a tumor. So all the members of the subsequentprogeny of that original cell which became transformed have thissame unique immunogenic receptor.
"That allows us a special chance to target the tumor cells, and not thenormal cells," Levy said.
He and his co-authors took that chance by immunizing four B-celllymphoma patients, ages 34 to 59, with their own unique solid-tumorantigens.
First, the team removed samples of the tumors and created ahybridoma from the malignant cells. Generating those hybridomastook up to six months in culture.
"They make a unique antigenic product," Levy said, "essentially amonoclonal antibody, produced by the tumor cell. For us, it's ahandle that allows us to find and target that tumor cell."
To search for it, he modified a polymerase chain reaction testingprocess. "Its sensitivity," he observed, "is one tumor cell in 107 _literally, one in 10 million." Levy explained: "So you take a samplefrom the body, and if you have 107 cells in it, there's either going tobe a tumor cell there, or not."
Isolating the loner dendritic cells from patients' blood was a separatefeat: Achieving it, Levy observed, combined separating them by theirbuoyant density, and their adherence to plastic surfaces.
"When we got them freshly out of tissues or blood," he recalled,"they had a density similar to macrophages, and adhered to plastic.But as they differentiated in culture, not only did they lose thatadherence, but their density also changed, so we could separate themfrom macrophages."
Levy's team then infused the antigenic protein and immune-boostingdendritic cells as a combination vaccine designed to evoke animmune response against the tumor-specific antigens. The result: "Allfour patients developed measurable antitumor cellular immuneresponses."
Two patients experienced complete tumor regression, and remain freeof disease, one 24 months later; the other for over one year. Oneother registered partial regression.
Although tailor-making treatments for a single patient that requirehalf a year to prepare may seem clinically cumbersome, Levy madethe point that "while these patients are having their protein made,they remain on standard multi-drug chemotherapy regimens, whichalso take about six months to complete. About the time they'vefinished with their chemotherapy is about the time we're finishedmaking their vaccine."
Still, the Stanford oncologist allows that if this protein productionperiod could be cut to, say, one month, "it would make it cheaper,and permit us to do it for more patients."
His team is working on that. "Rather than making hybridomas, thereare ways of getting the genes for the antigen out of the patient'stumor, and expressing them in a recombinant host organism throughgenetic engineering," Levy observed.
There is also an alternative to the entire dendritic strategy. Lastmonth in Seattle, at the annual meeting of the American Society ofHematology, Levy reported on a clinical trial of 38 B-cell lymphomapatients "in which we coupled the unique protein chemically toanother protein, keyhole limpet hemocyanin, which is a strongimmune stimulator."
"We injected that material back in the patients while they were inremission," Levy went on, "and showed that half of the 38 patientswhom we vaccinated in this way made an immune response. Amajority of that half, remain disease-free. Most of the non-respondinghalf had their tumors come back."
Elsewhere in the Stanford Medical Center, infectious diseasespecialist Thomas Merigan, and Levy's co-author, Edgar Engleman,are using the dendritic-cell strategy against HIV infection. "Inongoing clinical trials ," Levy said, "they are incubating proteinsfrom the virus with dendritic cells and infusing them into patients totry to immunize them against the AIDS infection." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.