A Phase I clinical trial to measure dose escalation and toxicityof a new radioimmunotherapy (RIT) treatment for lymphomahas astounded Mark Kaminski, the oncologist running thestudy.

None of the first 10 patients in the ongoing 18-month-old trialexperienced any side effects on climbing doses of theantibody/isotope covalent conjugate. But most of them did gainstriking remissions of their white blood-cell tumors.

"When we saw that astounding complete remission ratehappening in those patients," Kaminski told BioWorld, "weknew something was going on. That's why we reported the first10 patients in the New England Journal of Medicine (NEJM)."

Kaminski, who directs the Leukemia/Lymphoma Program atthe University of Michigan's Comprehensive Cancer Center, and11 co-authors, titled their interim report in Thursday's NEJM"Radioimmunotherapy of B-cell Lymphoma With [131I] Anti-B1 (Anti-CD20) Antibody."

Kaminski cited predictions that 40,000 new cases of non-Hodgkin's lymphoma will be diagnosed in the U.S. this year --independent of AIDS, for which lymphoma is part of thesyndrome. This reflects an increasing trend of the disease inthis country, he said, "and we don't know why."

B-cell lymphomas, which make up 80 percent of that 40,000-patient incidence, will take an estimated 20,000 lives this year.

"If you treated all B-cell lymphomas with standard therapy,"Kaminski said, "you'd have about a 50 percent cure rate, withsevere side effects." Such current methods include externalbeam radiation, chemotherapy, and, more recently, bonemarrow transplantation.

So-called "low-grade" lymphoma, which comprises about one-third of all cases, Kaminski added, "is slower-growing but,paradoxically, it's relentless. Patients can be treated and havesome remissions, but it constantly keeps on coming back untilit gets them." Kaminski has plans for this doomed subset.

The Michigan Phase I trial reported in NEJM employs an anti-B-cell monoclonal antibody to zero in on an antigen, CD20,decorating the surface of malignant B cells, and deliver a lethaldose of radioactive iodine. This I-131 isotope is commonly usedin nuclear medicine to ablate diseased thyroid glands.

The all-mouse antibody was developed a decade ago at Boston'sDana Farber Cancer Center, which licensed its production toCoulter Corp. of Hialeah, Fla. Coulter's manager of clinicalstudies, Stephan Glenn, a co-author of the NEJM paper, toldBioWorld that about four years ago he approached Kaminski atthe Michigan center, as well as Irwin Bernstein, head ofpediatric oncology at the Hutchinson Cancer Center in Seattle, topropose Phase I trials of the iodinated antibody against B-celllymphoma.

Bernstein's study is still in progress, with no data published.Kaminski's Phase I trial got fully under way 18 months ago,with a $1 million-plus grant from the National Cancer Institute.His progress report details the unexpected responses of the 10patients, all men who had failed primary chemotherapy. Five ofthem had low-grade lymphoma.

Following the experimental radioimmunotherapy regimen, fourachieved complete remission and two a partial response. Inthree, the disease progressed relentlessly, and the tenth had amixed response.

Tumors shrank greatly in 70 percent of the 10 and disappearedcompletely in 50 percent. Some patients remain entirely free ofdisease a year after treatment.

"The high rate of tumor responses so far in this ongoing study,together with the low level or absence of toxicity, is promising,"Kaminski wrote in the NEJM. "This therapy appears to offer atthe very least excellent palliation of disease and the potentialfor repeated treatments if relapse occurs."

With 23 patients now in the Michigan trial, Kaminski said,"Prior results are holding up, and it's my sense that they'reeven better." He observed that the dose-escalation toxicitystudy has been without significant side effects, while theradiation dose and amount of antibody continue to ramp up.Kaminsky predicted that "six or eight months from now, havingaccrued another 10 to 14 patients, we will reach a maximumtolerated dose, which can then be given in a Phase II type oftrial."

He surmised that the apparent efficacy of the regimen is duenot only to the ionizing radiation that kills tumor cells, but that"giving more antibody is really activating the immune systemto its 'nth' degree. Antibody itself is a very potent jump-starterof the immune system."

Confronting the Phase II outlook, Kaminski said, "We'reworking with Coulter to make sure that the pharmaceutical-grade antibody production continues. They're primarily adiagnostic company, and I think they're showing a lot ofcompassion to want to even get into therapeutics because it's alot of money."

Coulter's director of immunology, Bobbie Wallis, reassuredBioWorld, "We're not closing any doors on how to managelarge-scale antibody production. Since the NEJM paper we'vehad a flood of inquiries and we're looking at mass production ina different light."

David Goldenberg, chairman of Immunomedics of Morris Plains,N.J., is a founding father of RIT. His is one of half-a-dozengroups using iodinated anti-B1 antibodies against B-celllymphoma.

Goldenberg told BioWorld that "Kaminski has been getting niceresponses and has written a nice article. I'm very surprisedthat the NEJM took a paper reporting only 10 patients. We'vegot 10 patients also, with a 40 percent response rate."

In addition to Immunomedics and the University of Michigan,other players on the current RIT lymphoma scene include theHutchinson Cancer Center, the University of California, Davis,Stanford University, and the Sloan-Kettering Cancer Center inNew York.

Goldenberg said that the Hutchinson Center, the University ofMichigan, Immunomedics and UC Davis "are showing responsesin lymphoma patients refractory to other therapy. Thisreaffirms what Kaminski reported, and what I've said in otherarticles."

He added, "We've only looked at patients with refractory formsof treatment. The challenging question now becomes, What ifwe entertained RIT as an initial therapy? That's a reallyexciting question that could only be raised once someone hasshown some clinical response."

Now that he's shown it, Kaminski is eager to offer RIT as initialtherapy rather than, as in his Phase I trial, last-resorttreatment. His entering wedge is the low-grade patient withnothing to lose.

"If everything goes well," he told BioWorld, "one can really takethe tack of trying this in patients with low-grade lymphoma,for which there is no definitive or curative treatment."

He wonders if FDA would approve such a step. He noted thatthe FDA did authorize an anti-idiotype antibody trial inpreviously untreated patients with low-grade lymphoma, "so Iwould think that they might want to do this, too."

Kaminski said he "would be very interested" in offering RIT tothis patient group as soon as the current Phase I trial ends insix or eight months, and concurrently with the subsequentPhase II study.

He has one other role for RIT:

"Over the years we haven't seen the progress we thought wewere going to make with monoclonal antibodies. The lessons wecan learn from why this treatment is so successful inlymphoma can be used as a model for this approach in othercancers."

-- David N. Leff Science Editor

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