Sol­id Tu­mors: The Next Fron­tier of Can­cer Im­muno-ther­a­py

In the last decade, the realm of can­cer ther­a­py has tak­en ground­break­ing strides, with chimeric anti­gen re­cep­tor (CAR) T-cell ther­a­py be­ing one of the most promis­ing new types of treat­ment. Hav­ing shown po­ten­tial in treat­ing blood can­cers, CAR T-cell ther­a­pies are now set­ting their sights on a more com­plex ad­ver­sary: sol­id tu­mors. This ar­ti­cle ex­plains what CAR T-cell ther­a­py is, why sol­id tu­mors are such a chal­leng­ing tar­get, and how re­searchers can use ad­vanced in vit­ro mod­els to gain a more hu­man-rel­e­vant un­der­stand­ing of CAR T ef­fi­ca­cy.

Un­der­stand­ing CAR T-Cell Ther­a­py

At its core, au­tol­o­gous CAR T-cell ther­a­py is a form of im­munother­a­py where a pa­tient’s own im­mune cells are mod­i­fied to rec­og­nize and kill can­cer cells more ef­fec­tive­ly. This is done by adding a gene for a re­cep­tor, called a chimeric anti­gen re­cep­tor (CAR), which is de­signed to iden­ti­fy a spe­cif­ic tu­mor anti­gen. These mod­i­fied cells are in­fused back in­to the pa­tient, where they hunt down and kill the can­cer cells.

To date, re­searchers have suc­cess­ful­ly de­vel­oped six FDA-ap­proved CAR T-cell ther­a­pies for blood can­cers, in­clud­ing leukemia, lym­phoma, and mul­ti­ple myelo­ma. This has proved in­valu­able for those in dif­fi­cult-to-treat pa­tient pop­u­la­tions who ex­hib­it lit­tle to no re­sponse to con­ven­tion­al ther­a­pies.

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How­ev­er, these hema­to­log­i­cal ma­lig­nan­cies on­ly rep­re­sent a small por­tion of all can­cer cas­es and deaths—about 90% of can­cers are sol­id tu­mors. Un­for­tu­nate­ly, ef­forts to adapt CAR T-cell ther­a­py for sol­id tu­mors have, to date, proved in­ef­fec­tive.

The Chal­lenges of CAR T for Sol­id Tu­mors

High-mor­tal­i­ty, treat­ment-re­sis­tant sol­id tu­mors—in­clud­ing lung, breast, col­orec­tal, and pan­cre­at­ic can­cer—are prime can­di­dates for im­munother­a­py. How­ev­er, the rel­a­tive com­plex­i­ty of the het­ero­ge­neous sol­id tu­mor en­vi­ron­ment cre­ates nov­el im­muno­log­i­cal ob­sta­cles that are not seen in blood can­cers.

The chal­lenges are many, but a few high­lights in­clude:

  • Se­lec­tive Traf­fick­ing and Mi­gra­tion: For blood can­cers, im­munother­a­pies are ad­min­is­tered in the same lo­ca­tion where the can­cer­ous cells re­side—the cir­cu­la­to­ry sys­tem. But for sol­id tu­mors, this is just the start of the jour­ney. Af­ter be­ing ad­min­is­tered in­to the blood stream, the im­mune cells must se­lec­tive­ly traf­fic out of the vas­cu­la­ture at the site of the tu­mor and then mi­grate to the tu­mor tis­sue. This is a chal­leng­ing but crit­i­cal jour­ney, as the CAR T cells must reach the tu­mor in ad­e­quate num­bers to ef­fec­tive­ly kill the can­cer­ous cells while avoid at­tack­ing healthy tis­sue.
  • Tu­mor anti­gen het­ero­gene­ity: In hema­to­log­i­cal tu­mors, anti­gen ex­pres­sion is rel­a­tive­ly sta­ble and uni­form. But in sharp con­trast, sol­id tu­mors can ex­hib­it sig­nif­i­cant vari­abil­i­ty in anti­gen ex­pres­sion, both with­in a sin­gle tu­mor and be­tween pa­tients. This means that CAR T-cell ther­a­py tar­get­ing a spe­cif­ic anti­gen might on­ly at­tack cer­tain parts of the tu­mor, leav­ing oth­er parts un­touched. It may al­so present the need for a more per­son­al­ized or mul­ti-anti­gen-tar­get­ed CAR T ap­proach.
  • Tu­mor Mi­croen­vi­ron­ment (TME): The area sur­round­ing sol­id tu­mors is a unique cel­lu­lar and chem­i­cal land­scape, where in­hibito­ry im­mune cells, im­mune check­points, and cy­tokines cre­ate an en­vi­ron­ment that is nat­u­ral­ly hos­tile to im­mune cells, in­clud­ing CAR T-cell ther­a­py. This means that once CAR T cells reach the tu­mor, they can quick­ly be­come sup­pressed or in­ac­ti­vat­ed by im­muno­sup­pres­sive fac­tors in the TME, hin­der­ing their abil­i­ty to ef­fec­tive­ly de­stroy can­cer cells.

The Need for Hu­man-Rel­e­vant Re­search Mod­els

While en­thu­si­asm for sol­id tu­mor CAR T-cell ther­a­py is strong, FDA-ap­proved ther­a­pies have so far re­mained out of reach large­ly due to the chal­lenges de­scribed above. A ma­jor lim­it­ing fac­tor in over­com­ing these chal­lenges has been a lack of pre­clin­i­cal re­search mod­els that can ad­e­quate­ly recre­ate the com­plex jour­ney that CAR T cells must un­der­take in the hu­man body to be ef­fec­tive. The mod­els that re­searchers re­ly on for de­vel­op­ing im­munother­a­py fall in­to two main cat­e­gories: in vit­ro and an­i­mal mod­els.

2D cell mod­els of­ten in­clude tu­mor cell lines or pa­tient-de­rived organoids (PDO) cul­tured in a sta­t­ic dish, where the CAR T cells are ad­min­is­tered di­rect­ly to the tu­mor cells to eval­u­ate killing ef­fi­ca­cy. How­ev­er, these mod­els on­ly al­low re­searchers to eval­u­ate the end of the CAR T cell jour­ney and com­plete­ly ig­nore the as­pect of CAR T cell track­ing and mi­gra­tion.

An­i­mal mod­els re­main the cor­ner­stone of pre­clin­i­cal im­munother­a­py test­ing and have pro­vid­ed im­por­tant con­tri­bu­tions to hema­to­log­i­cal can­cer CAR T-cell ther­a­pies that are on the mar­ket to­day. One ex­am­ple is pa­tient-de­rived xenograft (PDX) mod­els, in which hu­man pa­tient-de­rived tu­mors are im­plant­ed in im­mun­od­e­fi­cient mice. How­ev­er, while an­i­mal mod­els en­able a more com­plete un­der­stand­ing of im­munother­a­py ef­fect—al­low­ing the CAR T cells to be in­tra­venous­ly ad­min­is­tered and traf­fic to the tu­mor as they would in hu­mans—they suf­fer from large species dif­fer­ences in re­spons­es and rel­a­tive­ly poor in­sights in­to mech­a­nism of ac­tion, lim­it­ing their suc­cess­ful trans­la­tion to hu­man clin­i­cal re­sponse.

To tru­ly un­der­stand the dy­nam­ics of can­cer im­munother­a­py for sol­id tu­mors and de­vel­op ef­fec­tive treat­ments, re­searchers need more ad­vanced mod­els that can cap­ture the com­plex in­tri­ca­cies of hu­man bi­ol­o­gy and im­mune re­sponse.

A Path For­ward for Sol­id Tu­mor Im­munother­a­py De­vel­op­ment

For CAR T-cell ther­a­py’s po­ten­tial to be ful­ly re­al­ized in sol­id tu­mors, it is vi­tal that its ther­a­peu­tic can­di­dates’ be­hav­ior, ef­fi­ca­cy, and chal­lenges be stud­ied in a con­text that is as close to hu­man as pos­si­ble.

For­tu­nate­ly, Or­gan-on-a-Chip tech­nol­o­gy can of­fer a path for­ward. Or­gan-Chips are mi­cro­engi­neered de­vices that em­u­late the ar­chi­tec­ture, func­tion­al­i­ty, and phys­i­o­log­i­cal re­spons­es of vas­cu­lar­ized hu­man or­gans. They pro­vide a dy­nam­ic plat­form that close­ly repli­cates hu­man tis­sue-tis­sue in­ter­faces, flu­id flow, and me­chan­i­cal forces, cre­at­ing an en­vi­ron­ment where CAR T cells can be stud­ied in a set­ting that more ac­cu­rate­ly mir­rors the hu­man body.

 

Re­cent­ly, this tech­nol­o­gy has been used to study the ef­fi­ca­cy of CAR T-cell ther­a­py in a mod­el of non-small cell lung car­ci­no­ma (NSCLC). By co-cul­tur­ing an NSCLC cell line and lung-spe­cif­ic vas­cu­lar cells, re­searchers were able to mod­el the jour­ney that CAR T cells un­der­go in vi­vo. Af­ter ad­min­is­ter­ing the im­munother­a­py in the chip vas­cu­la­ture—just like its in­tra­venous ad­min­is­tra­tion in the body—re­searchers saw how the CAR T cells at­tached to the vas­cu­la­ture, mi­grat­ed to the tu­mor cell-con­tain­ing chan­nel, and sub­se­quent­ly ex­hib­it­ed anti­gen-de­pen­dent killing of can­cer cells. Through imag­ing and ef­flu­ent analy­sis, they could even quan­ti­fy the amount of mi­gra­tion and killing as well as the lev­els of ex­haus­tion mark­ers for CAR T cells. A com­mon treat­ment ap­proach of ad­min­is­ter­ing a co-ther­a­peu­tic along­side CAR T cells was even mod­eled on-chip, where it demon­strat­ed im­proved CAR T-cell mi­gra­tion to the site of the sol­id tu­mor cell line. As this tech­nol­o­gy be­comes more wide­spread, it may en­able im­munother­a­py com­pa­nies to ac­cel­er­ate the suc­cess­ful de­vel­op­ment of the first sol­id tu­mor CAR T-cell ther­a­py.

Con­clu­sion

Sol­id tu­mors con­tin­ue to present nu­mer­ous chal­lenges for CAR T-cell ther­a­py re­searchers, in­clud­ing ef­fi­cient CAR T cell traf­fick­ing, mi­gra­tion, and in­fil­tra­tion, as well as over­com­ing the hos­tile tu­mor mi­croen­vi­ron­ment.

As re­searchers look to sur­mount these ob­sta­cles, ad­vanced cell cul­ture tech­nolo­gies like Or­gan-Chips may pro­vide a more hu­man-rel­e­vant and pre­dic­tive as­sess­ment of CAR T cell ef­fi­ca­cy, im­prov­ing trans­la­tion from pre-clin­i­cal test­ing to clin­i­cal suc­cess. With a num­ber of CAR T-cell ther­a­pies in de­vel­op­ment around the world, the hori­zon seems promis­ing, pro­vid­ing hope that re­searchers may be able to widen the reach of CAR T cells be­yond blood can­cer and in­to the more for­mi­da­ble realm of sol­id tu­mors.