From radium to X-rays to isotopes, ionizing radiation isthe oldest form of tumor-zapping therapy _ other thanoutright surgery. Now, radiation has joined with twodisparate arms of biotechnology _ conjugated antibodiesand gene therapy _ to improve its cancer cure rate.

A human trial, reported in Aug. 5 The Lancet, hitched amalignancy-targeted monoclonal antibody to an isotopeof iodine that delivered high-dose radiation to late-stagelymphomas, and achieved major remissions.

Nude mice too turned in excellent results against a humantumor, reported in Nature Medicine for August, withradiation inducing gene therapy by turning on a cancer-killing cytokine, tumor necrosis factor.

Lancet's paper is titled: "Phase II trial of 131I-B1 (anti-CD20) antibody therapy with autologous stem celltransplantation for relapsed lymphomas." Its two co-first-authors, at the University of Washington, Seattle, arehematologist/oncologist Oliver Press and nuclearmedicine specialist Janet Eary.

B cells are the designated drivers of antibody formation inthe immune system. B cell lymphoma, in effect, turnsprecursors of B cells into single-cell tumors, whichproliferate in bone marrow, and build up mainly in thebody's lymph nodes.

With 30,000 new cases a year in the U.S., non-Hodgkin'slymphoma ranks fourth of all cancers in economicimpact.

As Eary explained to BioWorld Today, "it's a biphasicmalignancy, affecting younger adults and people inmiddle age. When their swollen but painless large lymphnodes prompt a diagnosis of lymphoma, chemotherapyusually brings about remissions, which may last months,before relapsing.

When that happens, late-stage therapy _ stillexperimental _ may try to cure the disease at its source,Eary said, "by targeted radiation to tumorous nodes,which incidentally damages the body's bone marrow."This draconian attack involves first extracting andfreezing a dollop of bone marrow, from which still-healthy stem cells can be rescued and eventually returnedto the patient.

The trouble with radiation is that it takes no prisoners,and rains friendly fire on healthy bodily tissues, such asliver and lungs, as well as on malignancies.

Eary's therapeutic strategy seeks to limit this wantondestruction, while maximizing tumor-directed radiation.She conjugates her high-energy source, 131I, directly toher B-cell-specific murine antibody, by covalent bindingwithout intermediate linker. "It's a robust antibody," sheobserved, "that binds about 90 percent of lymphoma Bcells."

In the just-reported Phase II trial, patients referred to herby clinician Oliver Press first spent four days under agamma-counting camera, after receiving a test injectionof the antibody-iodine combo. "This determined the bio-distribution," Eary explained, "which shows how much ofthe radiation dose the body's healthy organs pick up."That's how we calculated the individualized dose to giveeach patient."

Twenty-five individuals with relapsed lymphoma enteredthat trial, beginning five years ago. The preliminaryimaging phase found 21 of them had favorable bio-distributions; that is, more of the radiation reached tumorthan healthy tissue.

Each of these then received the full custom-calculatedtherapeutic dosage of 131I, aimed and fired by theattached antibody directly at the cancer's bull's eyes.Then, after their total-body radioactivity had declined tonear zero _ which took about 10 days in a lead-linedroom _ they got back the autologous hematopoietic stemcells kept on ice to replenish their bone-marrow.

Of those 21, 16 had complete remissions. Overall,counting an earlier Phase I trial, Lancet reported, thesuccess rate was "progression-free survival of 62 percent,and over-all 93 percent, with two-year follow-up."

Now a new trial is under way, Eary said, "addingchemotherapy to the antibody-associated radiation. Itbegan last winter, and so far has enrolled seven patients,as of last Friday."

Asked when this Phase II would reach its endpoint, Earyobserved, "You never know. When it gets done."

As for an eventual Phase III pivotal trial, she pointed out,"That would require a multi-institutional study, withpeople set up to give these extremely high doses of 131I,as well as bone-marrow stem-cell rescue."

From Antibodies In People To Gene Therapy In Mice

"Spatial and temporal control of gene therapy usingionizing radiation" is how University of Chicagoradiation oncologist Dennis Hallahan reports, in NatureMedicine, his group's killing of human epithelialcarcinomas growing in nude mice.

As the cytotoxic nose-cone of his three-stage missile,Hallahan, who is the paper's first author, armed a geneencoding tumor necrosis factor (TNF) with the gene foran all-purpose human early-growth-response promoter(Egr-1) .

Packaged in an adenovirus vector, he and his co-authorsinjected these sequences into the human tumorsimplanted in the hind limbs of nude mice. Theyimmobilized these animals in lucite chambers, andshielded their entire bodies with lead, except for thetumor-bearing limbs.

An X-ray generator aimed at the tumors irradiated themfour days a week to a total dose of 40 or 50 Gy (4,000-5,000 rad).

"The radiation," Hallahan explained to BioWorld Today"activates the gene transcription of TNF through the Egr-1 promoter. This combined the protein, which enhancesthe effects of radiation, with radiation's own effects."Continued radiation kept the promoter switch turned on,so TNF accumulated in the tumors.

"By localizing this cytotoxic gene therapy," he continued,"we were able to obviate the systemic toxicity one wouldget from the intravenous delivery of these cytotoxiccancer agents."

The combination of X-ray and gene therapy eradicated 12of 16 tumors treated.

"We have designed a Phase I clinical trial," Hallahansaid, "together with GenVec, Inc. of Rockville, Md. Thecompany will be submitting it to FDA and RAC[Recombinant DNA Advisory Committee], in time forRAC's December meeting."

He added, "We are trying to work out an agreement forGenVec to sponsor the trial financially, and provide theviral vector, in return for a license to our technology." n

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.