RENIER(BRENTJENS((NEW(YORK)(
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A!patients!own!T!cells!may!be!genetically!modified!to!recognize!tumor!associated!antigens!
(TAA)!through!the!introduction!of!a!gene!encoding!a!chimeric!antigen!receptor!(CAR)!specific!
to! the! TAA.! ! CAR! T! cells! targeted! to! the! B! cell! specific! CD19! antigen! have! demonstrated!
remarkable!clinical!efficacy!in!patients!with!relapsed!and!refractory!(R/R)!B!cell!malignancies!
and!to!date!has!obtained!FDA!approval!for!the!patients!with!R/R!DLBCL!and!B!cell!ALL.!!!CAR!
T!cells!can!be!viewed!as!a!living!drug!and!following!infusion!and!upon!encounter!with!target!
antigen,! these! T! cells! undergo! marked! proliferation! and! secretion! of! pro>inflammatory!
cytokines.!!The!marked!elevation!of!cytokines!can!manifest!in!patients!with!varying!degrees!
of! fever,! hypotension,! and! hypoxia! which! is! collectively! termed! as! cytokine! release!
syndrome! (CRS).! ! Patients! may! further! experience! confusion,! word! finding! difficulties,!
obtundation,! and! even! frank! seizures,! collectively! termed! immune! effector! cell! associated!
neurotoxicity! syndrome! or! ICANS.! ! A! majority! of! R/R! DLBCL! patients! treated! with! CD>19!
targeted!CAR!T!cells!will!achieve!an!objective!response!to!therapy.!!While!those!patients!who!
achieve! a! complete! response! tend! to! have! a! durable! remission,! nonetheless,! a! significant!
number! of! patients! who! achieve! a! CR! and! most! of! those! who! only! achieve! a! PR! will!
experience!disease!relapse.!!Etiologies!of!treatment!failures!are!likely!multiple!and!include!
tumor!loss!of!target!antigen!expression!(antigen!escape),!lack!of!CAR!T!cell!persistence,!CAR!
T! cell! exhaustion,! and! the! immune! suppressive! tumor! microenvironment! (TME).! ! For! this!
reason! there! is! a! need! to! address! these! limitations! in! part! through! improving! CAR! T! cell!
function.!!Approaches!to!improve!function!include!further!modification!of!the!CAR.!!Further,!
T! cells! may! be! additionally! modified! to! improve! CAR! T! cell! function.! ! These! further!
engineered! CAR! T! cells,! termed! “armored! CAR”! T! cells,! include! T! cells! modified! to! secrete!
pro>inflammatory! cytokines,! express! co>stimulatory! ligands,! and! secrete! single! fragment!
length!antibodies!which!may!mediate!immune!checkpoint!inhibition.!
! !