Boost­ing check­point in­hibitor ef­fi­ca­cy via the mi­cro­bio­me

Con­tribut­ing au­thors: Pe­ter Bak, PhD, Jonathan Bar­ry, MD and Yechan Kang

The lat­est gen­er­a­tion of can­cer treat­ments im­munother­a­pies—a class of drugs called check­point in­hibitors—has rev­o­lu­tion­ized can­cer treat­ment. When they work, their re­sults are as­tound­ing, but their ef­fec­tive­ness is an all-or-noth­ing propo­si­tion: not every can­cer type is re­spon­sive to im­munother­a­py, and even in those tu­mors where im­munother­a­py rad­i­cal­ly changed the stan­dard of care, on­ly a frac­tion of pa­tients re­spond to treat­ment. Faced with this tan­ta­liz­ing—yet frus­trat­ing—ev­i­dence physi­cians and re­searchers are search­ing for ways to deep­en re­spons­es to im­munother­a­pies and find a rea­son why some re­spond to ther­a­py, and some don’t. Along the way, an un­ex­pect­ed fac­tor has emerged—the mil­lions of bac­te­ria liv­ing with­in the hu­man body.

Sev­er­al re­search teams, work­ing with check­point in­hibitors (CPIs) in mice, have found that fe­cal trans­plants from CPI-re­spon­sive an­i­mals con­ferred CPI ef­fi­ca­cy to mice pre­vi­ous­ly un­re­spon­sive to CPIs. The flur­ry of re­sults in ba­sic re­search has caught the eye of VCs, who have in­vest­ed ~$500M in these com­pa­nies over the past two years. As a mark that this sci­ence is en­ter­ing “prime­time,” some com­pa­nies have al­so raised mon­ey from the pub­lic cap­i­tal mar­kets, most re­cent­ly Evelo, who closed an $85 mil­lion IPO in May 2018.

Along with these ad­vances in ba­sic and ear­ly clin­i­cal sci­ence, the FDA has be­gun the process of sort­ing out when bac­te­ria can be con­sid­ered a “pro­bi­ot­ic” ver­sus a “drug,” and if the lat­ter, how they might be con­sid­ered with­in the es­tab­lished drug de­vel­op­ment path.

In 2016, the FDA took ini­tial steps to pave a reg­u­la­to­ry path­way for mi­cro­bio­me ther­a­pies with the pub­li­ca­tion of CMC (Chem­istry, Man­u­fac­tur­ing, and Con­trol) guide­lines for Live Bio­ther­a­peu­tic Prod­ucts (LBPs). An LBP is de­fined as a prod­uct that 1) con­tains live or­gan­isms; 2) is ap­plic­a­ble to the pre­ven­tion, treat­ment, or cure of a dis­ease or con­di­tion of hu­man be­ings; and 3) is not a vac­cine. This guid­ance was dis­cussed at an FDA work­shop held in Sep­tem­ber 2018, gath­er­ing clin­i­cians, re­searchers, in­dus­try ex­perts, and pa­tient ad­vo­cates to dis­cuss key is­sues around clin­i­cal, man­u­fac­tur­ing, and reg­u­la­to­ry is­sues as­so­ci­at­ed with mi­cro­bio­me ther­a­pies. In brief, mi­cro­bio­me ther­a­pies will be reg­u­lat­ed as bi­o­log­ics, re­quir­ing an In­ves­ti­ga­tion­al New Drug (IND) ap­pli­ca­tion and clin­i­cal tri­al da­ta with stan­dard clin­i­cal tri­als with stan­dard out­comes for ef­fi­ca­cy and safe­ty, when the spon­sor makes claims re­gard­ing the im­pact of a bac­te­r­i­al prod­uct on a dis­ease state.

In ad­di­tion to the reg­u­la­to­ry con­sid­er­a­tions that must be tak­en in­to ac­count when con­sid­er­ing the com­mer­cial­iza­tion of these tech­nolo­gies, the ex­tent to which patents may be used to se­cure mar­ket ex­clu­siv­i­ty loom large. This top­ic is com­plex and mul­ti­fac­eted, with im­pli­ca­tions that span reg­u­la­to­ry and in­vest­ment con­sid­er­a­tions.

While many of the on­go­ing in­dus­try and aca­d­e­m­ic-spon­sored tri­als are look­ing to prospec­tive­ly demon­strate an im­pact of FMT or bac­te­r­i­al cul­tures on pa­tient out­comes, two key fun­da­men­tal ques­tions are top of mind for clin­i­cians: why there is dis­cor­dance be­tween bac­te­ria species and CPI re­spons­es? And, what is the de­fin­i­tive mech­a­nis­tic link be­tween changes in mi­croflo­ra and treat­ment re­sponse?

Re­gard­ing the for­mer, each of the stud­ies con­nect­ing CPI re­spon­ders and non-re­spon­ders to the pres­ence of spe­cif­ic bac­te­ria has iden­ti­fied a dif­fer­ent genus and species of bac­te­ria. As one physi­cian put it: “What we have right now is a lot of as­so­ci­a­tion stud­ies that do not agree with each oth­er, nor make sense.” While mul­ti­ple rea­sons may ac­count for these dif­fer­ences, such as the way species were iden­ti­fied (e.g. dif­fer­ences in spe­cif­ic ge­net­ic eval­u­a­tion, var­i­ous stool col­lec­tion tech­niques, and dif­fer­ences in ge­og­ra­phy, etc.), it begs the ques­tion of whether treat­ment will need to be specif­i­cal­ly tai­lored to in­di­vid­ual groups of pa­tients based on race, ge­og­ra­phy, di­et, etc.

While physi­cians re­al­ize the in­flu­ence of bac­te­ria may be mul­ti­fac­to­r­i­al, and some for-prof­it de­vel­op­ment-stage com­pa­nies may have gen­er­at­ed pro­pri­etary da­ta, this is seen as a stage-gat­ing step for many physi­cians be­fore they would rec­om­mend a mi­crobe-based treat­ment.

With ini­tial sci­en­tif­ic re­ports as a back­drop, sci­en­tists, clin­i­cians, and in­vestors are rac­ing to un­der­stand how the tril­lions of bac­te­ria liv­ing with­in us be har­nessed to fight can­cer. There are still nu­mer­ous ques­tions leav­ing one won­der­ing if the in­vest­ment has out­paced the sci­ence:

  • While or­ga­ni­za­tions may be right­ly keep­ing da­ta pri­vate, clin­i­cians and ba­sic sci­en­tists agree that there is a panoply of ways in which a bac­teri­um could en­hance – a de­tailed mech­a­nism may be nec­es­sary to give on­col­o­gists com­fort with de­ploy­ing a new ther­a­py, with the un­der­stand­ing a mi­cro­bial tar­get­ed ther­a­py could me­di­ate its ef­fect through mul­ti­ple paths. How­ev­er, Vedan­ta and their aca­d­e­m­ic col­lab­o­ra­tors re­cent­ly pub­lished a re­port high­light­ing the ef­fect of de­fined con­sor­tia of bac­te­ria on CD8 T cells (­­ti­cles/s41586-019-0878-z)
  • With a dis­ease such as can­cer where the pri­ma­ry goal of the treat­ing physi­cian is to erad­i­cate the grow­ing tu­mor, the long term ef­fects of mi­crobe-based in­ter­ven­tions on gut, meta­bol­ic and CNS health have yet to be enu­mer­at­ed. To ap­pre­ci­ate this per­spec­tive one need not look fur­ther than the va­ri­ety of oth­er dis­ease ar­eas com­pa­nies are tar­get­ing with bac­te­r­i­al based ther­a­pies
  • From a cor­po­rate and in­vest­ment per­spec­tive the is­sue of mar­ket ex­clu­siv­i­ty will need to be care­ful­ly eval­u­at­ed. Tra­di­tion­al patent pro­tec­tion may not be avail­able to some ther­a­pies cur­rent­ly in the clin­ic, and there­fore ad­di­tion­al mech­a­nisms (e.g. Or­phan Drug Des­ig­na­tion) and cre­ative patent cov­er­age must be con­sid­ered.

Re­gard­less, the po­ten­tial re­turn on in­vest­ment is stag­ger­ing. Cur­rent mar­ket lead­ers in the CPI space have re­cent­ly post­ed up­wards of $8 bil­lion in sales with­in the cur­rent in­di­ca­tion set.

Even in the most re­spon­sive tu­mors, a sub­set of pa­tients re­spond; the ma­jor­i­ty of pa­tients do not re­spond and dis­con­tin­ue treat­ment. There­fore, a mi­cro­bial treat­ment that im­proves re­spons­es may be an ex­treme­ly valu­able as­set in its own right and to the val­ue to com­pa­nies that cur­rent­ly mar­ket CPIs as a prod­uct that al­so in­creas­es the uti­liza­tion of CPIs with­in es­tab­lished mar­kets. Even more tan­ta­liz­ing is the op­por­tu­ni­ty to open up tu­mors where re­spons­es to im­munother­a­pies have been his­tor­i­cal­ly poor. Tu­mors such as Glioblas­toma mul­ti­forme, ovar­i­an can­cer, pan­cre­at­ic can­cer—some of the fastest-grow­ing tu­mors—have not been re­spon­sive to sin­gle-agent CPI in­ter­ven­tion.

With such clin­i­cal and eco­nom­ic po­ten­tial, the next few years will be crit­i­cal in as­sess­ing whether the fas­ci­nat­ing ear­ly stage da­ta will trans­late to mean­ing­ful pa­tient out­comes, mak­ing ‘mirac­u­lous’ the stan­dard of care.

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