Good News for Immunostimulants

Epistemic Status: Moderate

Way back in 2015 I was writ­ing about 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, 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, is about to present its res­ults from two tri­als.

This Janu­ary, Stan­ford sci­ent­ists re­por­ted 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 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 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.