Generation of human islet-specific regulatory T cells by TCR gene transfer

Abstract

! 1! Generation) of) human) islet0specific) regulatory) T) cells) by) TCR) gene) transfer.) )Caroline)M.)Hull 1,5) *,)Lauren)E.)Nickolay 1,5 ,)Megan)Estorninho 1,5 ,)Max)W.) Richardson 2 ,)James)L.)Riley 2 ,)Mark)Peakman 1,3,4,5 ,)John)Maher 5,6,7 ,)Timothy) I.M.)Tree 1,5) *) ) 1 Department)of)Immunobiology,)Faculty)of)Life)Sciences)&)Medicine,)King's) College)London,)London)SE1)9RT,)UK) ) 2 Department)of)Microbiology,)University)of)Pennsylvania)School)of)Medicine,) Philadelphia,)Pennsylvania,)USA) ) 3 Peak)Therapeutics,)London)SE24)9LG,)UK ) 4 Division)of)Diabetes)and)Nutrition,)King's)College)London)SE1)1UL,)UK) ) 5 NIHR)Biomedical)Research)Centre,)Guy's)and)St)Thomas')NHS)Foundation) Trust)and)King's)College)London,)London)SE1)9RT,)UK) ) 6) CAR)Mechanics)Group,)Division)of)Cancer)Studies,)Guy's)Hospital)Campus,) King's)College)London)School)of)Medicine,)London)SE1)1UL,)UK) ) 7 Department)of)Allergy)and)Immunology,)King's)College)Hospital)National) Health)Service)Foundation)Trust,)London)SE5)9RS,)UK) ) ) Short)Running)Title:)Generation)of)human)islet[specific)Tregs.) ) ) ) *Corresponding)authors) ) caroline.hull@kcl.ac.uk) timothy.tree@kcl.ac.uk) ) ! 2! Abstract) )Based)on)the)success)in)animal)models)of)type)1)diabetes)(T1D),)clinical)trials) of) adoptive) regulatory) T) cell) (Treg)) therapy) are) underway) using) ex# vivo) expanded)polyclonal)Tregs.)However,)pre[clinical)data)also)demonstrate)that)islet[specific) Tregs) are) more) potent) than) polyclonal) Tregs) at) reversing) T1D.)Translation) of) this) approach) into) man) will) require) methods) to) generate) large) populations) of) islet[specific) Tregs) which,) to) date,) has) proved) to) be) a) major)hurdle.)Here)we)demonstrate)the)feasibility)of)lentiviral[mediated)T)cell)receptor) (TCR))gene)transfer)to)confer)antigen)specificity)on)polyclonal)human)Tregs.)Targeting) has) been) achieved) using) TCRs) isolated) from) human) islet [specific) and) viral[specific) CD4+) T) cell) clones.) Engineered) T) cells) demonstrated) expression)of)ectopically[delivered)TCRs,)resulting)in)endowment)of)cognate)antigen[specific) responses.) This) enabled) antigen[specific) suppression) at) increased)potency)compared)to)polyclonal)Tregs.)However,)cells)transduced) with) islet[specific) TCRs) were) less) responsive) to) cognate) antigen) than) viral[ specific) TCRs,) and) in) some) cases,) required) additional) methods) to) isolate) functional)antigen[specific)Tregs.)This)study)demonstrates)the)potential)of)TCR) gene)transfer)to)develop)islet[specific)Treg)therapies)for)effective)treatment)of) T1D,)but)also)highlights)that)additional)optimisation)may)be)required)to)achieve)Populations) of) Tregs) found) in) the) periphery,) including) those) expressing) the)with)T1D.)This)abnormality)is)evident)before)clinical)diagnosis,)at)the)time)of) diagnosis) and) many) years) following) onset) of) T1D [4[7].) Since) defective) Treg) function) appears) to) be) central) to) the) pathogenesis) of) T1D,) it) is) logical) to) hypothesise) that) correction) of) this) imbalance) may...

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