The In­ge­nu­ity En­gine: Trans­la­tion­al Re­search and the Need for Speed

To­day, the world waits in des­per­ate hope for a coro­n­avirus vac­cine. Mean­while, peo­ple con­tin­ue to con­tend with oth­er se­ri­ous dis­eases such as can­cer and di­a­betes, which al­so re­quire new re­search in­no­va­tions. At City of Hope — a bio­med­ical re­search com­plex and Na­tion­al Can­cer In­sti­tute-des­ig­nat­ed com­pre­hen­sive can­cer cen­ter in South­ern Cal­i­for­nia — such in­no­va­tions and pa­tient care are con­tin­u­ing un­in­ter­rupt­ed. In large part, this is due to the in­sti­tu­tion’s recog­ni­tion that can­cer and oth­er ur­gent med­ical con­di­tions don’t stop for COVID-19.

When the pan­dem­ic be­gan to gain trac­tion in the U.S. in Feb­ru­ary, some of our sci­en­tists, in­clud­ing vi­rol­o­gist Don Di­a­mond, Ph.D., piv­ot­ed their re­search to tack­le SARS-CoV-2. Decades of keep­ing im­muno­com­pro­mised pa­tients safe in our pi­o­neer­ing Hematopoi­et­ic Cell Trans­plan­ta­tion Pro­gram, one of the largest of its kind in the U.S., has re­sult­ed in ex­ten­sive ex­per­tise in fight­ing vi­ral in­fec­tions, and pre­pared us to take on the coro­n­avirus.

Dr. Di­a­mond’s team pre­vi­ous­ly de­vel­oped the Triplex vac­cine for cy­tomegalovirus; this pro­gram has com­plet­ed phase 2 tri­als with very promis­ing re­sults; the vac­cine is cur­rent­ly the sub­ject of mul­ti­ple on­go­ing and planned stud­ies. Us­ing this as a start­ing point, the team set out to syn­the­size a new COVID-19 vac­cine.

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Sup­port­ing these in­ves­ti­ga­tors is a ro­bust re­search-and-de­vel­op­ment en­ter­prise, an over­ar­ch­ing in­sti­tu­tion-span­ning sys­tem that is tai­lor made to ac­cel­er­ate in­no­va­tions from the lab to pa­tients. This in­cludes every­thing rang­ing from fund­ing sup­port to ac­cess to coun­sel from in­ter­nal and ex­ter­nal drug de­vel­op­ment spe­cial­ists. Our R&D ap­pa­ra­tus lever­ages the com­bi­na­tion of a fun­da­men­tal strength in ba­sic sci­ence and the pa­tient-care fo­cus of our com­pre­hen­sive can­cer cen­ter. City of Hope blends the best of aca­d­e­mics, med­ical care and biotech, a con­cept that we call the “R&D hy­brid.”

Suc­cess re­quires a con­ver­gence of key com­po­nents strate­gi­cal­ly aligned to break through bot­tle­necks, in­crease speed and meet pa­tients’ needs.

In­no­va­tion

City of Hope’s ground­break­ing trans­la­tion­al re­search his­to­ry in­cludes de­vel­op­ing the tech­nol­o­gy un­der­ly­ing syn­thet­ic hu­man in­sulin, a break­through in di­a­betes man­age­ment, and mon­o­clon­al an­ti­bod­ies, which are in­te­gral to wide­ly used, life­sav­ing can­cer drugs such as trastuzum­ab, rit­ux­imab and ce­tux­imab. Build­ing on that lega­cy, more than 1,000 re­searchers pur­sue a va­ri­ety of cre­ative ap­proach­es, with ar­eas of ex­cel­lence in­clud­ing the de­vel­op­ment of bi­o­log­ics, small-mol­e­cule drugs and cel­lu­lar ther­a­pies. These ef­forts have gen­er­at­ed more than 450 patent fam­i­lies, with many more on the hori­zon.

Cre­at­ing a crit­i­cal con­tin­u­um to link the lab and the clin­ics can en­able R&D pro­grams to trans­late in­no­va­tion in­to nov­el treat­ments. This has led to City of Hope op­er­at­ing more than 500 clin­i­cal tri­als this year, en­rolling more than 6,200 pa­tients.

One re­cent ex­am­ple draws up­on 20-plus years of lead­er­ship in ad­vanc­ing CAR T cell ther­a­py. In a March 2020 Sci­ence Trans­la­tion­al Med­i­cine pa­per, mol­e­c­u­lar bi­ol­o­gist Chris­tine Brown, Ph.D., The Her­itage Provider Net­work Pro­fes­sor in Im­munother­a­py, and neu­ro­sci­en­tist Michael Bar­ish, Ph.D., re­port­ed promis­ing lab re­sults for an en­tire­ly new strat­e­gy for pro­gram­ming CAR T cells. The team aug­ment­ed the T cell with a pep­tide se­quence from chloro­tox­in (CLTX), a com­po­nent of scor­pi­on ven­om that has an affin­i­ty for brain can­cer cells.

CLTX-CAR for glioblas­toma was re­cent­ly li­censed to a biotech com­pa­ny for fur­ther de­vel­op­ment, and first-in-hu­man clin­i­cal tri­als of the treat­ment are un­der­way.

More broad­ly, our re­searchers con­tin­ue to ad­vance 46 drugs cov­ered by ac­tive INDs. Nine­teen of these INDs are for CAR T cell ther­a­pies as well as the de­vel­op­ment of CAR nat­ur­al killer (NK) cells, a group of in­nate im­mune cells, to treat glioblas­toma and oth­er can­cers. Mus­tang Bio, Inc., has a broad col­lab­o­ra­tion with City of Hope that in­cludes ex­clu­sive li­cens­es to five clin­i­cal-stage CAR T pro­grams.

In­fra­struc­ture

Hav­ing this in­fra­struc­ture in place is crit­i­cal to dri­ving in­no­va­tion. Three on-site GMP man­u­fac­tur­ing fa­cil­i­ties can pro­duce any of the ther­a­pies that sci­en­tists can en­vi­sion for use in clin­i­cal tri­als. And more than 20 core labs of­fer ad­di­tion­al ex­per­tise and equip­ment that are es­sen­tial to this trans­la­tion­al con­tin­u­um, from gene edit­ing to struc­tur­al bi­ol­o­gy to an­a­lyt­i­cal phar­ma­col­o­gy. With these ca­pa­bil­i­ties close at hand, in­ves­ti­ga­tors are bet­ter equipped to ad­vance their ideas with speed.

Be­yond the tra­di­tion­al re­search ca­pa­bil­i­ties, our sci­en­tists ad­di­tion­al­ly ben­e­fit from ex­per­tise rarely seen in an aca­d­e­m­ic set­ting: ex­pe­ri­enced drug de­vel­op­ment ex­perts who work hand-in-hand with re­searchers, along with a reg­u­la­to­ry af­fairs team that helps nav­i­gate the reg­u­la­to­ry process.

In­te­gra­tion

Us­ing the R&D hy­brid mod­el, re­searchers whose projects are eval­u­at­ed us­ing rig­or­ous cri­te­ria may be of­fered the op­tion to fun­nel their sci­ence in­to a mile­stone-dri­ven drug de­vel­op­ment process de­signed to short­en the time be­tween dis­cov­er­ies in the lab to the time when they can be­gin first-in-hu­man clin­i­cal tri­als.

This ap­proach to R&D can mean that an in­no­v­a­tive dis­cov­ery might be spun out in­to a start­up com­pa­ny or li­censed to an ex­ist­ing bio­phar­ma­ceu­ti­cal com­pa­ny. The ul­ti­mate goal is speed­ing new dis­cov­er­ies to pa­tients by fast-track­ing com­mer­cial­iza­tion of po­ten­tial­ly life-chang­ing new ther­a­pies.

In June, a nov­el gene ther­a­py for B-cell lym­phoma, CpG-STAT3siR­NA, de­vel­oped by im­mu­nol­o­gists Hua Yu, Ph.D., Bil­ly and Au­drey L. Wilder Pro­fes­sor in Tu­mor Im­munother­a­py, and Marcin Ko­rtylews­ki, Ph.D., was li­censed to Sco­pus Bio­Phar­ma. Be­cause of this col­lab­o­ra­tion, this team is on track to launch a first-in-hu­man tri­al ear­ly next year.

In­vest­ment

Ear­ly-stage projects and lat­er-stage trans­la­tion­al in­ves­ti­ga­tions of­ten get a boost from in­ter­nal fund­ing for drug de­vel­op­ment, which is con­sid­er­able in scale. As part of our R&D hy­brid mod­el, pro­pos­als are vet­ted with the help of ex­perts who have been and are suc­cess­ful in ven­ture cap­i­tal, biotech and phar­ma, who al­so fol­low and ad­vise on the project along its mile­stone-dri­ven de­vel­op­ment path.

Phil­an­thropy al­so can play a cru­cial role in dri­ving this trans­la­tion­al sci­ence. For ex­am­ple, re­search ded­i­cat­ed to the de­vel­op­ment of CpG-STAT3siR­NA re­ceived fund­ing through the Toni Stephen­son Lym­phoma Cen­ter at City of Hope. Grants from the Ben and Cather­ine Ivy Foun­da­tion and Gate­way for Can­cer Re­search helped fur­ther stud­ies of CLTX-CAR and the Mar­cus Foun­da­tion sup­ports CLTX-CAR clin­i­cal tri­als.

Hope as an In­ten­tion

Fi­nal­ly, there is an in­tan­gi­ble that breathes life in­to these R&D ef­forts: an un­wa­ver­ing in­sti­tu­tion­al com­mit­ment to turn sci­ence in­to prac­ti­cal ben­e­fit. City of Hope fac­ul­ty, staff and sup­port­ers em­brace that mis­sion be­cause we see mov­ing re­search rapid­ly to help pa­tients as an in­te­gral com­po­nent of com­pas­sion­ate care. Across the in­sti­tu­tion, re­searchers are fo­cused on de­vel­op­ing drugs that re­ceive Food and Drug Ad­min­is­tra­tion ap­proval and reach the mar­ket to im­prove pa­tient lives. In this way, City of Hope’s en­tre­pre­neur­ial spir­it is an out­growth of its hu­man­i­tar­i­an roots, which date back more than a cen­tu­ry.

As for Dr. Di­a­mond’s coro­n­avirus vac­cine work, ini­tial lab da­ta is show­ing promise. Be­cause the vac­cine will be man­u­fac­tured in-house, it will be able to move to clin­i­cal tri­als lat­er this year — tur­bo-charg­ing a process that tra­di­tion­al­ly takes sev­er­al years.

Whether it is can­cer, di­a­betes or COVID-19, pa­tients need so­lu­tions to­day. With time of the essence, this R&D in­ge­nu­ity en­gine dri­ves us to­ward our goals of has­ten­ing ef­fec­tive treat­ments and cures and trans­form­ing the fu­ture of pa­tient care.

For more in­for­ma­tion, vis­it city­ofhope.org.