# Good News for Immunostimulants

_Epistemic Status: Moderate_

Way back in 2015 I was [writing about](https://srconstantin.wordpress.com/2015/10/28/bacterial-infections-and-cancer-remissions/) the connection between cancer remissions and the immune response to infection. To recap the facts:

*   A plurality of recorded spontaneous cancer remissions happened when the patient had a strong immune response (often with fever) to a bacterial infection at the tumor site.
*   William Coley’s bacterial therapies for cancer at the turn of the 20th century, while not tested to the standards of modern experimental methods, did seem to produce recovery rates comparable or superior to chemotherapy.
*   Endotoxin, a poisonous substance found in the outer membrane of Gram-negative bacteria, can cause tumor regressions.
*   TNF-alpha, an inflammatory cytokine involved in the body’s response to endotoxin, is equally effective at causing tumor regressions; it is too dangerous to give to patients systemically, but is an effective cancer treatment for advanced melanoma when used in isolated limb perfusion.
*   There are quite a few cases, both in animals and humans, of inflammatory cytokines causing complete tumor regressions in metastatic cancers, particularly when injected directly into the tumor.

At the time, I predicted that if only there were a delivery mechanism that could more effectively isolate inflammatory cytokines to the tumor site, it might work safely for more than just special cases like isolated limb perfusion; and that there might be some delivery mechanism that made a bacterial therapy like Coley’s toxins work.

The heuristic here was that when I went looking for the _biggest responses_ (remissions, complete tumor regressions) in the _toughest cases_ (metastatic cancers, sarcomas which don’t respond to chemotherapy), many of them seemed to involve this picture of acute, intense activation of the innate immune response.

It turns out that two new therapies with very good results pretty much support this perspective.

[CpG oligodeoxynucleotides](https://en.wikipedia.org/wiki/CpG_Oligodeoxynucleotide), a motif found in bacterial DNA, are the active ingredient in Coley’s toxins; they are the part of bacterial lysate that triggers the immunostimulatory effects.

Today, SD-101, a CpG oligodeoxynucleotide drug produced by the biotech company [Dynavax](http://www.dynavax.com/), is [about to present its results](https://globenewswire.com/news-release/2018/03/15/1437796/0/en/Dynavax-Announces-Acceptance-of-Two-Data-Abstracts-for-SD-101-in-Combination-with-KEYTRUDA-for-Presentation-at-the-2018-American-Association-for-Cancer-Research-AACR-Annual-Meeting.html) from two trials.

This January, Stanford scientists [reported](http://med.stanford.edu/news/all-news/2018/01/cancer-vaccine-eliminates-tumors-in-mice.html) that SD-101 combined with another immunotherapy — but no traditional chemotherapy — eradicated both implanted and spontaneous tumors when injected into mice, both at the injection site and elsewhere.

We’ll have to see the results of the human trials, but this looks promising.

Another drug, NKTR-214, is an engineered version of the inflammatory cytokine IL-2, designed to localize more effectively to tumors. The IL-2 core is [attached](http://sci-hub.tw/10.1158/1078-0432.ccr-15-1631) to a chain of polyethylene glycols, which release slowly in the body, preferentially activating the tumor-killing receptors for IL-2 and resulting in 500x higher concentrations in tumors than a similar quantity of IL-2 alone. This is the tumor-localizing property that could make inflammatory cytokines safe.

In patients with advanced or metastatic solid tumors, previously treated with PD-1 inhibitors, NKTR-214 resulted in [23% of patients](http://ascopubs.org/doi/abs/10.1200/JCO.2017.35.15_suppl.2545) experiencing partial tumor regression.

While this still doesn’t mean much chance of recovery, it’s still notable — \_any \_treatment for advanced cancers with more than a 20% response rate is remarkable. (Chemotherapy usually produces partial response rates in the 2-20% range for metastatic cancers, depending on cancer type and drug regimen.)

It’s early days yet, but I continue to think that immunostimulants have a lot of potential in cancer treatment.

Moreover, I think this is a little bit of evidence against the frequently heard claim that it’s impossible to “pick winners” in biotech.

The conventional wisdom is that you can’t know ahead of time which drugs that seem to work in preclinical studies (in vitro or in mice) will succeed in humans.

Most preclinical drug candidates \_do \_fail, it’s true. And there are a lot of reasons to expect this: mouse models are not perfect proxies for human diseases, experimental error and outright fraud often make early results unreplicable, and we don’t understand all the complexities of biochemistry that might make a proposed mechanism fail.

But the probability distribution over drug candidates can’t be _uniform_, or it would have been impossible to ever develop effective drugs! The search space of possibly bioactive molecules is too large, and the cost of experiments too high, to get successes if drugs were tested truly at random. We would never have gotten chemotherapy that way.

I think it’s likely that using the simple heuristic of “big effects in tough cases point to a real mechanism somewhere nearby” gets you better-than-chance predictions of what will work in human trials.