At the In­flec­tion Point for the Next Gen­er­a­tion of Can­cer Im­munother­a­py

While on­col­o­gy re­searchers have long pur­sued the po­ten­tial of cel­lu­lar im­munother­a­pies for the treat­ment of can­cer, it was un­clear whether these ther­a­pies would ever reach pa­tients due to the com­plex­i­ty of man­u­fac­tur­ing and costs of de­vel­op­ment. For­tu­nate­ly, the re­cent suc­cess­ful de­vel­op­ment and reg­u­la­to­ry ap­proval of chimeric anti­gen re­cep­tor-en­gi­neered T (CAR-T) cells have demon­strat­ed the sig­nif­i­cant ben­e­fit of these ther­a­pies to pa­tients.

Now, the on­col­o­gy com­mu­ni­ty is fo­cused on nat­ur­al killer (NK) cells as an im­munother­a­peu­tic mech­a­nism with the po­ten­tial to of­fer ben­e­fits to can­cer pa­tients in need of new treat­ment op­tions. At Nek­tar Ther­a­peu­tics (Nek­tar), we be­lieve that NK cell ther­a­pies or cy­tokine ther­a­pies that stim­u­late pro­duc­tion of NK cells have the po­ten­tial to be­come the next gen­er­a­tion of can­cer im­munother­a­pies.

NK cells di­rect­ly rec­og­nize and kill ab­nor­mal cells, in­clud­ing can­cer cells, and they mod­u­late the body’s adap­tive (T cell) im­mune re­sponse against these cells. NK cells have the po­ten­tial to tar­get al­tered cells in the body with­out pri­or sen­si­ti­za­tion to spe­cif­ic tu­mor anti­gens. How­ev­er, NK cells can­not sur­vive for long with­out sig­nal­ing from IL-15, a cy­tokine that pro­motes the pro­duc­tion, func­tion and sur­vival of NK cells in the body.

Nek­tar has en­gi­neered a new IL-15 ag­o­nist, NK­TR-2551, de­signed to stim­u­late and ex­pand NK cells as well as CD8+ ef­fec­tor and mem­o­ry T cells, all crit­i­cal cells in the an­ti-can­cer im­mune re­sponse. NK­TR-255’s phar­ma­co­ki­net­ic and phar­ma­co­dy­nam­ic pro­file was in­ten­tion­al­ly de­signed to over­come the chal­lenges of re­com­bi­nant hu­man (rhIL-15), which has to be giv­en to pa­tients fre­quent­ly and in high dos­es due to its rapid clear­ance from the body. NK­TR-255 has the po­ten­tial to be more eas­i­ly ad­min­is­tered with an an­ti­body-like dos­ing sched­ule, with­out trig­ger­ing high tox­i­c­i­ty or over­stim­u­lat­ing the NK cells.

NK cells can be par­tic­u­lar­ly ef­fec­tive against liq­uid, or hema­to­log­i­cal tu­mors, pos­si­bly be­cause they are in close con­tact with these can­cer cells in the blood­stream and lym­phoid or­gans. How­ev­er, we have al­so ob­served en­cour­ag­ing ac­ti­va­tion of NK cells by NK­TR-255, as well as an­ti-tu­mor ac­tiv­i­ty, in lab­o­ra­to­ry re­sults of NK­TR-255 in sol­id tu­mor mod­els. Based on these re­sults, we are in­ves­ti­gat­ing NK­TR-255 in clin­i­cal tri­als in mul­ti­ple myelo­ma (MM), non-Hodgkin’s lym­phoma (NHL), head and neck squa­mous cell car­ci­no­ma (HN­SCC), col­orec­tal can­cer (CRC), and lo­cal­ly ad­vanced or metasta­t­ic urothe­lial car­ci­no­ma (UC).

With an NK cell ther­a­py, we may al­so have the abil­i­ty to im­prove up­on ex­ist­ing CAR-T cell ther­a­pies for hema­to­log­i­cal ma­lig­nan­cies. A chal­lenge with avail­able CAR-T ther­a­pies is that many pa­tients even­tu­al­ly re­lapse, and thus strate­gies are need­ed to fur­ther ex­tend the ben­e­fit of CAR-T cell re­spons­es for a pa­tient. Pre­clin­i­cal da­ta in B-cell lym­phoma xenograft mod­els have shown that NK­TR-255 en­hanced ex­pan­sion, sur­vival, and an­ti-tu­mor ac­tiv­i­ty of hu­man CD19 CAR-T cells.

NK cells are al­so ef­fec­tive at rec­og­niz­ing tu­mor cells coat­ed in tu­mor-bind­ing an­ti­bod­ies. This ca­pa­bil­i­ty is why we are in­ves­ti­gat­ing NK­TR-255 with mech­a­nisms that use an­ti­body-de­pen­dent cel­lu­lar cy­to­tox­i­c­i­ty (AD­CC). Cur­rent­ly, we are study­ing NK­TR-255 in com­bi­na­tion with lead­ing ap­proved an­ti­bod­ies that use the mech­a­nism of AD­CC to kill can­cer cells by func­tion­al NK cells. Re­search has shown that long-term ex­pan­sion of NK cells through ac­ti­va­tion of the IL-15 path­way can en­hance the ac­tiv­i­ty of these AD­CC agents.

At the So­ci­ety for Im­munother­a­py of Can­cer (SITC) 2021 An­nu­al Meet­ing, Dr. Mehmet Al­tan, As­sis­tant Pro­fes­sor, De­part­ment of Tho­racic/Head and Neck Med­ical On­col­o­gy, Di­vi­sion of Can­cer Med­i­cine at The Uni­ver­si­ty of Texas MD An­der­son Can­cer Cen­ter, pre­sent­ed da­ta from an on­go­ing Phase 1b/2 study eval­u­at­ing NK­TR-255 plus ce­tux­imab in re­lapsed or re­frac­to­ry, ad­vanced HN­SCC, or CRC that sup­port­ed the mech­a­nism of ac­tion of the com­bi­na­tion. Ear­ly ev­i­dence of on-tar­get bi­o­log­i­cal ac­tiv­i­ty was ob­served with NK­TR-255 treat­ment re­sult­ing in ex­pan­sion and pro­lif­er­a­tion of NK cells and CD8+T cells. Clin­i­cal ac­tiv­i­ty was al­so ob­served in this heav­i­ly pre-treat­ed and high­ly re­frac­to­ry pa­tient pop­u­la­tion, and a cor­re­la­tion was ob­served with in­creased NK cell lev­els in the blood and in tu­mor tis­sue.

As clin­i­cal re­search is be­gin­ning to show, ther­a­pies that stim­u­late the pro­duc­tion of NK cells have the po­ten­tial to make a sig­nif­i­cant im­pact on the way we treat can­cer. We are ex­cit­ed to har­ness the full po­ten­tial of this ground­break­ing im­munother­a­peu­tic ap­proach from the on­go­ing re­search of lead­ers across the on­col­o­gy com­mu­ni­ty. To learn more about the con­tin­ued clin­i­cal de­vel­op­ment of the IL-15 ag­o­nist, NK­TR-255, vis­it our web­site.


Ref­er­ences:

1NK­TR-255 is in ear­ly-stage clin­i­cal de­vel­op­ment and has not been ap­proved by FDA or any oth­er reg­u­la­to­ry agency for any in­di­ca­tion.

AUTHOR

Willem Overwijk, Ph.D.

Vice President, Oncology Research, Nektar Therapeutics