AFTER TESTS IN PETS, TRANSGENE PLANS PHASE IIHUMAN TRIALSOF IL-2 GENE TRANSFER
By David N. LeffScience Editor
The trouble with mice is that they're so unlike people.
This fact of life bedevils research oncologists, who implant humantumors into immunodeficient mice, and then try out experimentaltherapies. They know full well that the lab-bred little rodents haveradically different immune systems, and that transplanted tumors area far cry from spontaneous malignancies. But at the price, and forease of manipulation, these small animal models are just about theonly game in town.
Transgene S.A., of Strasbourg, France, has just introduced a newgame. It's based on the fact that dogs and cats, besides beingcomfortably bigger than mice, develop spontaneous cancers thatclosely resemble human tumor patterns.
Dogs acquire highly metastatic melanomas; cats, fibrosarcomas,which have a low rate of metastasis. Both have a dismal prognosis.
A paper in the December Gene Therapy, tells in its title the gist ofTransgene's large-animal strategy: "Gene therapy of spontaneouscanine melanoma and feline fibrosarcoma by intratumoraladministration of histoincompatible cells expressing humaninterleukin-2."
Molecular biologist Majid Mehtali, who directs gene therapyresearch at Transgene, is the paper's first author. "The results of thisresearch," he told BioWorld Today, "confirm for the first time, to ourknowledge, the safety and therapeutic potential of a gene therapystrategy in animals with spontaneous metastatic and nonmetastatictumors. That effect," he added," is shown on extended survival andfewer tumor relapses of a spontaneous cancer, not in mice, as is doneusually, but in domestic animals."
These preclinical results have already given rise to a pair of Phase Ihuman trials, one just completed in Switzerland, the other about toclose in France.
Under the Transgene protocol, pets with cancer brought by theirowners to France's celebrated school of veterinary medicine atMaison Alfort, on the outskirts of Paris, underwent surgery to excisetheir tumors, followed by radiation therapy to reduce residualmalignancy.
About half of them then received repeated injections of green-monkey kidney cells (Vero cells) genetically engineered to express athigh levels the human cytokine, interleukin-2 (IL-2), which has wellknown anti-tumor effects. The other half, as a cohort of controlanimals, got dummy injections, or none.
Box Score: Survival Up, Relapses Down
Cats followed up for 16 months, and dogs for 12, had fewer relapsesand increased median survival time than did controls.
Thus, half a year after treatment, 56 percent of control felines treatedby surgery and irradiation alone developed new tumors. In contrast,none of the Vero-treated cats suffered these sequelae. At 16 monthspost-therapy, 11 of 16 control cats (69 percent) relapsed, versus 5 of16 (31 percent) in the Vero cohort.
Six months after treatment, 12 of 16 (75 percent) control caninesdied, while only five (31 percent) succumbed in the treatment group.
One year out, 94 percent of control dogs were dead, but only 63percent of Vero-treated ones.
"We chose Vero cells," Mehtali said, "because they were usedpharmaceutically to produce the polio vaccines, which have beensafely injected into patients.
"By injecting the Vero cells into the tumors," he explained, "we firstinduce an inflammatory reaction against those cells. We also thinkthat the IL-2 is boosting this inflammation, as well as expanding anincreasing number of tumor-specific lymphocytes [T cells] that aregoing to kill the cancer."
He observed, though, that "we probably are just inducing naturalkiller cells [NKD], which are killing the tumors without creating anyimmune-response memory. These NKDs will not recognize anyrecurring tumors later on." He and his colleagues are working tosurmount this problem.
Transgene, Mehtali pointed out, acquired exclusive rights to this genetherapy technology from the Pasteur Institute in Paris. "The initialidea to use xenogeneic cells secreting cytokines for this particularapplication came from Philippe Kourilsky at the Pasteur."Immunologist Kourilsky is a scientific co-founder of the company,and a senior co-author of the Gene Therapy article.
Transgene's role in the research and application program, Mehtalisaid, "is to carry on the whole project in large animal models, makethe evaluation, then do the clinical trials."
The two Phase I human studies, at the Cantonal Hospital in Basel,Switzerland and the Curie Institute, in Paris, each enrolled ninepatients with end-stage, accessible solid tumors, such as melanoma,myosarcoma and head-and-neck cancer.
He observed that "Results are absolutely positive from the standpointof the treatment being safe and well tolerated." Although efficacywas not under study, he added, "We have encouraging results."
Tooling Up For Phase II Human Trials
The 18 Phase I subjects, unlike the dogs and cats, did not haveablative surgery and radiation before administration of the IL-2-secreting Vero cells. "If possible, in the Phase II trials," Mehtaliobserved, "we would like to go into patients at an earlier stage oftheir disease so we might treat them with either chemotherapy orradiation. But this, like the Phase II protocols altogether, is still underdiscussion."
For one thing, the group would like to add a second cytokine, gammainterferon, to the Vero package, to stimulate the expression of tumor-presenting antigens.
In the meantime, Transgene has already "produced, finished andtested the clinical materials."
Last month, Mehtali reported on Transgene's now-published animalstudy to the European Working Group on Gene Therapy, in Leiden,the Netherlands. He has since "received several letters from peoplethere who are interested in gaining access to the same animal model."
Mehtali observed: "In the young history of cancer gene therapy, mostof the protocols have been ex vivo transfers, in which we recover thetumor cells, manipulate them in the lab, transduce them with a gene,then infuse them back into the patient. That's quite complex, and alsoexpensive, because you are developing one product for one patient."
"For the biotech field, all future cancer gene therapy will need to bein vivo, using vectors or gene products that have been aliquoted andare ready to use. That's what we had in mind when developing thisparticular approach," he said. n
(c) 1997 American Health Consultants. All rights reserved.