Thursday, March 22, 2018

What has Dr Faustman been up to so far?

Now and then, I review the literature and check if some progress has been made towards a T1D cure or, less ambitiously, towards the understanding of T1D pathogenesis. (spoiler: not much). While I try stay away from controversial topics, in the “cure” field, Dr DL Faustman is hard to avoid.

The Faustman saga for dummies.

A long, long time ago, Dr Faustman revisited the even older topic of the BCG/Diabetes relationship. While she did find some interesting stuff, she over extended herself with claims that proved to be wrong. The erroneous claims (nothing wrong with being wrong, this is how science works) and partial replication of her results by another team (same remark) led to a conflictual situation that created difficulties for her to get funding but also contributed to the emergence of a fan base that supported her. That fan base consists of a mix of conspiracy theorists who think she has a cure but that it is being suppressed and very rational and generous people who support her as they would support any other group working towards the “cure” moonshot. On the other hand, Dr Faustman’s communication style, her bold claims, especially in the fundraising effort directed towards her base, has irritated a lot of people. She’s a White Knight to some, a Dark Lord to others.
Link: the “permanent disease reversal” paper that started the controversy: in a nutshell, the splenocyte role could not be replicated.

Restarting the saga.

In 2012, a publication titled Proof-of-concept, randomized, controlled clinical trial of Bacillus-Calmette-Guerin for treatment of long-term type 1 diabetes restarted the fireworks. Without diving into the details of what this paper shows or doesn’t show, something that would be out of my league as far as the finer points are concerned anyway, one can risk a few comments.
  • the title of the article is extremely bold: treatment of long-term type 1 diabetes would be a major breakthrough, worthy of a Nobel prize.
  • the use of BCG, basically a common vaccine, opens the door to catchy headlines such as “could a simple vaccine cure type 1 diabetes?”
  • the number of patients involved in the clinical trial (n=85, but only n=6 actual) can be seen as insufficient. Additionally, the 6 patients were initially split in 2 groups of 3 (control/intervention), but were then reshuffled as a 3-1+1 as an EBV infection occurred. Obtaining statistically significant results, at least at the patient level, is just black magic. Yes, formulas will provide an answer, they always do but…
  • the methods are extremely well documented and the trial seems to have been conducted according to the highest standard (double checked with actual researchers who stated “if all papers were like this, that would be good”).

Typical reactions to the paper.

The non scientifically educated patient will start looking for places where he can purchase the BCG vaccine and expect a full recovery whereas the physicist will trash the paper as bogus research and a shameful misapplication of statistics to massage the data into the desired results. Bottom line: there we go again! White Knight or Dark Lord?
That being said, if one looks beyond the catchy, almost dishonest, title, if one ignores the patient outcome and statistical massaging, one could focus on the flow cytometry results (essentially counting cells) and see an interesting effect. Had the paper been titled something like “BCG vaccination increases apoptosis in Insulin reactive T cells”, I believe it wouldn’t have generated as many negative reactions or false hopes.

So what’s going on here?

The BCG vaccine is used as a TNF proxy. TNF (Tumor Necrosis Factor) has been shown to play a role in the evolution of Type 1 Diabetes, a “paradoxical role” as researchers say since it has been shown to be both protective and harmful. The problem is that you can’t just go around and inject Type 1 Diabetics with TNF: TNF is usually bad for you, one is unlikely to obtain approval for a clinical trial involving TNF injections. (anti-TNF of all kinds have revolutionized the treatment of many auto-immune arthritis). Therefore, BCG – a known to be safe vaccine and known  TNF trigger as most mycobacterium are – is used as a relatively mild shot at the insulin reactive T cells which are known to play a role in the T1D auto-immune reaction.

One additional interesting point is that there are, at least, two different TNF Receptors that are unequally distributed in different cell populations and that trigger different responses. TNFR2 is the receptor Dr Kaufman is interested in, as it is shown in this 2016 paper Treg activation defect in type 1 diabetes: correction with TNFR2 agonism.
A small explainer may be needed here:
  • cytotoxic T cells are involved in the auto-immune reaction that kills healthy cells (for example insulin reactive T cells).
  • regulatory T cells (rTregs) when activated (aTregs) may prevent or stop auto-immune diseases by keeping cytotoxic T cells in check (preventing them from activating or triggering their death).
  • Type 1 Diabetics seem to have a defect in Treg activation (they end up with less aTregs).
  • that defect seems to be significant because the number of aTregs seems to be inversely correlated with residual C-Peptide secretion and control.
  • TNFR2 agonism (that means stimulating the TNFR2 receptor instead of blocking it as an antagonist would) leads to more aTregs which could be good.
Once again, the title of the paper is a bit ambiguous, the aTregs “defect” mechanism of action isn’t that clear and its clinical impact is only inferred through association and correlation. The snapshot fits in the current movie of our immune system understanding but isn’t definitely proven to be the root cause of all ills.

Dr Faustman could indeed very well be on an interesting track, as she recently stated in this opinion piece TNF, TNF inducers, and TNFR2 agonists: A new path to type 1 diabetes treatment but one can’t help being a bit annoyed by the boldness of her claims compared the current level of evidence.

Some of her detractors could joke: “What next? Will she also treat cancer?”

Ugh, well, yeah, she could…  TNFR2: A Novel Target for Cancer Immunotherapy.

My own (worthless) opinion

Interesting research, despite the hype. This is an area that is definitely worth exploring and it is actively explored by many researchers in many different fields. A cure? Not within 5 years. Small steps in the correct direction? most probable.

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