When everyone first heard about the TeGenaro/TGN1412 Phase I disaster, the immediate question was whether it could have been prevented. As mentioned before, the main problem I had was that the volunteers seem to have been dosed fairly quickly, rather than waiting longer to see how the first patient did. That alone would have contained the tragedy to one person. But even then, we'd all be asking how that one case could have been avoided. I'm not well-versed enough in immunology to say for certain, but according to the Times of London, there's some earlier work that might have given everyone pause if it had been sufficiently appreciated.

They quote Angus Dalgleish, a British professor of immunology, as saying that he was amazed that the TGN1412 trial had been allowed, considering that at the ASCO meeting last year, a team from the National Cancer Institute presented the results of a study of an anti-CLTA4 antibody in cancer patients. They didn't see the catastrophic results of TGN1412, but the trial was rough enough. Nearly half of the patients in the high-dose group saw a harmful immune response - most of them recovered, but one needed surgery. That target is another receptor on the surface of T-cells, and it's involved in the same general activation/deactivation pathway that CD28 (TGN1412's target) is. CLTA4 activation blocks the activating effect of the CD28 pathway - in fact, it's only induced after the CD-28 receptor has been stimulated, and it seems to come on in order to damp it down. Immunology's full of these reverse-reverse things.

So one net result of either approach is to enhance CD28 signaling - TeGenaro's antibody strongly activates CD28 directly, and Medarex's inhibits its inhibitory pathway. Still, the two therapies were aiming at opposite endpoints: TeGenaro was mainly hoping to enhance the activity of regulatory T-cells (which would then decrease autoimmune activity) while the NCI group was hoping to generate a stronger overall immune response against renal tumors. Of course, it looks like the "stronger overall immune response" part of this pathway wins out.

Here's the abstract from the meeting, which tells us that the anti-CLTA4 antibody they're talking about is MDX-010, from Medarex. They've been working on it for years, and have (for example) reported similar results in 2004 in a study against metastatic melanoma. Their first attempts in this area were reported in 2003 in PNAS.

And it's still being studied - in fact, it's one of the more advanced things in Medarex's pipeline. Here's a trial that's in recruitment right now for late-stage melanoma, in combination with a potential melanoma vaccine, MDX-1379, and here's one for prostate cancer, in combination with androgen therapy. They wouldn't have made it to Phase III with this if they'd constantly seen the kinds of effects reported by the NCI group.

So the Times article is semi-right, although it gives the impression that there's this one study from last year that should have definitely raised the warning. But anti-CLTA4 therapy has been around for several years now, and it's well-represented in the literature. And it's still in advanced clinical trials, to boot. This is the sort of thing that both TeGenaro and the review board that approved its study would have been well aware of, and would have taken into account. It now appears that blocking CLTA4 is something that has to be approached with caution, while activating CD28 directly is disastrous, but I'm not sure that was obvious before this trial.