By David N. Leff
Anticancer therapies, like cars and clothes, come in fashions or trends.
Half a century ago, penicillin — which cured infections as if by magic — set off the public demand for "miracle drugs" against cancer too. Interferon gamma (INFg) seemed like an answer to this prayer in the 1980s, and its cytokine inducer, interleukin-12 (IL-12) looked like a likely candidate in the 1990s.
"Interferon gamma is no longer being used in human anticancer trials," observed molecular hematologist/ oncologist William Lee, at the University of Pennsylvania, in Philadelphia. "It went through a flurry of clinical trials in the late '80s, maybe early '90s, and the results were generally disappointing. The toxicities were considerable. So I don't think anybody is really using it very much any more. INFg is also very hard to give, because its half-life of INFg is so short when you administer it."
As for the status of IL-12, "It's used as a direct anti-tumor agent," Lee continued. "The clinical trials have been done. They have not been reported. You'd have to talk to either Hoffmann-La Roche or Genetics Institute about that. I think they may be in the process of assessing or reassessing the use of IL-12 against cancer."
Lee is senior author of a paper in the just-released July issue of the journal Immunity (a spin-off of Cell), which reflects a new and little-suspected role for these two molecules. Its title is "Tumor cell responses to INFg affect tumorigenicity and response to IL-12 therapy and antiangiogenesis."
The question Lee and his co-authors posed was this: "In mouse models of cancer, IL-12 is a highly effective anticancer agent. We know that it acts through INFg for the great majority of its anti-tumor effects. We know that because if you administer anti-INFg antibody to a mouse, you eliminate most of IL-12's anti-tumor activity.
"We believed," he told BioWorld Today, "that a lot of this effect is through INFg/IL-12's inhibition of tumor angiogenesis."
Tumor Blood Supply A Popular Target
In recent months, attacking angiogenesis, to cut off a tumor's vital blood supply, has become the trendy high-fashion icon of anticancer therapy. (See BioWorld Today, July 16, 1998 and Dec. 2, 1997, both p. 1.)
Lee observed "that the principles of Judah Folkman and others working in the field — about inhibition of the growth of blood vessels feeding tumors — are very, very sound. What is at issue here is how are they best put into practice, and what are the limitations and toxicities."
He deplored "the way the field has been propelled into big lights, when it's probably not quite ready for prime time. Antiangiogenesis is very promising, but to the extent it conveys that you're going to have a no-cost way to cure all tumors, it's fantasy.
"What needs to be worked out are a lot of the details, to truly understand this approach to angiogenesis-inhibiting cancer therapy."
It was that exploratory approach that led Lee's lab and their research co-authors at the Philadelphia-based Wistar Institute to go after the IL-12/INFg antiangiogenesis connection.
Lee cited two reasons supporting their hunch:
"First, we know through in vitro assays and in vivo testing that IL-12/INFg does inhibit angiogenesis.
"Second, we have evidence that recombinant IL-12 is actually immunosuppressive around the time that you give it in high doses in vivo. It actually tends to suppress the cellular immune responses.
"So we thought," Lee observed, "that we'd essentially eliminated anti-tumor immunologic, antigen-specific, immune rejection mechanisms. And knowing that IL-12 does inhibit angiogenesis, we believed that this is one of the major mechanisms of its anti-tumor activity."
As Wistar immunologist Giorgio Trinchieri, co-senior author of the Immunity paper, commented: "The ability of tumor cells to produce angiogenic factors is well known, but their ability to produce anti-angiogenic factors is a new finding, which helps shed light on the mechanisms of cancer therapy."
In their experiments with tumor-bearing mice, the investigators sought to gauge the extent to which a tumor cell's response to INFg influenced IL-12's anticancer activity.
"So our strategy," Lee recounted, "was to render tumor cells unresponsive to INFg. Because all the tumor cell lines that we deal with in my lab respond to INFg, we didn't have a natural variant that didn't. Therefore, we had to create it. We expressed a dominant negative mutant INFg receptor.
"We mutated it so it was still competent to bind INFg, but could no longer transmit INFg signals inside the cell. And it blocked the ability of the normal receptor to do so. So it's negative because it's functionless. And it's dominant because it inhibits a functioning receptor on the same cells."
"We then took these carcinoma and melanoma tumor cells," Lee went on, "which we proved no longer responded to INFg in vitro, and put them into mice. As controls we inserted tumor cells which still responded to INFg. Then we treated these animals with IL-12, which induces the host to produce lots of INFg."
Interferon-Snubbing Tumors Defy IL-12 Therapy
"We found that the mice bearing the normal tumor cells, that could respond to INFg, had nice anti-tumor responses from the IL-12 injection. However, those that received the tumor cells that could not, had a very poor response to IL-12 anti-tumor therapy.
"These results," Lee observed, "bring up the principle that tumor cell responses to these biologic therapies may be as important as the host responses, in terms of causing the tumor cells to regress. And we think that a lot of this is due to blocking angiogenesis.
"In other words," he explained, "IL-12 induces angiogenesis inhibition, but a lot of it is due to the tumor cell responding to the INFg. The tumor cells actually produced angiogenesis inhibitory factors when they were stimulated by INFg.
"I don't think that there is a potential clinical application yet for these findings in terms of human cancers," Lee said, "because I don't know that the anticancer role of IL-12 has been established. Genetics Institute and Hoffmann-La Roche are currently evaluating their cancer trials with IL-12. So this is one case — not surprisingly — where things may work a lot better in mice than they work in humans.
"If there is a therapeutic implication," he concluded, "not direct but just implied, it would be that if you can get the tumor cells to produce antiangiogenic factors, you may be able to stop their growth."
Genetics Institute Inc., is located in Cambridge, Mass., and Hoffmann-La Roche Ltd. is in Basel, Switzerland. *