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Talactoferrin Alfa (TLF): Mother’s Milk Becomes Cancer Treatment

January 26, 2008 - 5:29 pm email to a friend printer friendly view / write comments

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Dr. West

We’ve covered several novel agents for treating lung cancer, but a new one that has shown promise in early studies and now is the subject of larger phase III trials is a drug called talactoferrin alfa (TLF), from a small company based in Houston called Agennix. I think it’s possible that much of the reason there hasn’t been much buzz behind this treatment, despite the very intriguing results, is that this agent is so different from the mechanisms we know well already, like blocking angiogenesis, inhibiting EGFR, combining these approaches, etc. And the fact that this is a small company far from the big pharma and biotech hubs like New Jersey and the Bay Area probably contribute; in addition, all of the results thus far have been generated out of India, which has many lung cancer patients but few recognized leaders in the field, so there hasn’t been an identifiable spokesperson to introduce the lung cancer world to the novel agent and concept of TLF. But let’s try to remedy this situation, because I’m inclined to keep my eye on it for the next few years.

TLF is an oral protein that is a recombinant product that is structurally identical in all material respects to human lactoferrin, an important immunomodulatory product that is expressed throughout the body in immune cells. As the name implies, it is found in highest concentration in breast milk, and it is important in contributing to the development of an infant’s immune system. The largest component of the immune system is actually the “gut-associated lymphoid tissue” (GALT), where the cells of the immune system interface with vast amounts of new proteins from the outside world (food). TLF is purported to work by getting taken up by the immune cell centers of the gut, called Peyer’s patches, where they induce immature dendritic cells, which are some of the heavy lifters teaching the rest of the immune cells what to focus on and what to ignore, to mature. Although the immune system is very complicated, the end result is that TLF can activate dendritic cells of the immune system and thereby lead to increased immune function against tumor cells.

(Click on image to enlarge) Please don’t worry if you don’t “get” these immune system principle: I show the figure in case people are interested, but it’s not on the quiz. Your immune system is like your television — you don’t need to know how it works to be able to use it. Suffice it to say that there are several lab-based studies with animal models of cancer that support this immunostimulatory role for TLF. But the real issue is what it does in humans.

Importantly, with approximately 500 patients receiving TLF over the past several years, no obvious side effects have been noted, in contrast with other “targeted approaches” in which side effects ranging from a serious rash to life-threatening bleeding are ongoing challenges. The phase I (safety) work in humans gave some signals of activity among NSCLC patients, among whom several had a prolonged survival of a year or longer despite having progressed on prior treatment (abstract here).

But in the last couple of years the results of two phase II randomized trials in advanced NSCLC have been reported, and they both appear provocative. At ASCO 2006, one study by Wang and colleagues (abstract here) reported the results of a randomized phase II trial of standard first-line chemo with carbo/taxol every three weeks along with either TLF daily or placebo. It was a “double-blinded trial”, so neither the physicians nor the patients knew whether they were receiving the active drug or placebo. A total of 110 patients were enrolled, among whom 100 had a scan six weeks (2 cycles) later to assess response. In this study, response rate (RR) was the primary endpoint, and this was strikingly higher in the recipients of TLF combined with chemo compared with chemo and placebo:

The bars on the left include all patients who started the trial (for which the results were not quite statistically significantly different, p < 0.08), but when only the patients who got to their first follow-up scan were included (the evaluable patients), the differences were more pronounced and actually statistically significant (p < 0.05). And progression-free and overall survival also appeared notably superior with TLF added to chemo.

When you add a third agent to a standard chemo doublet like carbo/paclitaxel, it generally adds side effects, whether that's adding avastin, or erbitux, a third conventional chemo agent, or whatever else you're interested in. One of the curious findings in this trial with TLF was that the side effects (typically referred to as toxicity or adverse events) were actually lower in the recipients of active TLF compared with placebo recipients, looking at all reported adverse events/side effects (left) or just the more serious (grade 3 or 4) ones (right):

Very curious. Presumably, enhancing immune function translates to fewer side effects from standard chemo.

While these results are impressive, this trial was presented as just a poster at the ASCO meeting in 2006, and it didn’t receive much attention when many physicians and the media focused on multitargeted agents like sutent and nexavar, and we tried to figure out how best to use drugs like tarceva and avastin. This was only a 110 patient study, but if the TLF results were true, this approach could have a real impact.

We got more information from another trial this past year, so I’ll continue with that along with the future plans for TLF in my next post.