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( )Tj
ET
EMC
/P <>BDC
BT
7.5 0 0 7.5 255.2051 528.4158 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7.5 0 0 7.5 259.5045 528.4158 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7.5 0 0 7.5 263.8041 528.4158 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7.5 0 0 7.5 268.1037 528.4158 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7.5 0 0 7.5 272.4033 528.4158 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7.5 0 0 7.5 276.7029 528.4158 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7.5 0 0 7.5 281.0025 528.4158 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7.5 0 0 7.5 285.3021 528.4158 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7.5 0 0 7.5 289.6017 528.4158 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7.5 0 0 7.5 21.2587 521.2158 Tm
-.0294 Tc
-.0356 Tw
[(impr)22(o)27(v)27(ed anti-tumor )]TJ
ET
EMC
/P <>BDC
BT
7.5 0 0 7.5 95.6965 521.2158 Tm
-.0694 Tc
[(activity of GPC3 CAR + GO)48(T2 \(BO)43(XR10)10(30\))]TJ
ET
EMC
/P <>BDC
BT
7.5 0 0 7.5 233.4059 521.2158 Tm
0 Tc
0 Tw
( )Tj
ET
EMC
/P <>BDC
BT
7.5 0 0 7.5 21.2587 514.0157 Tm
-.0674 Tc
-.0376 Tw
[(T c)15(ells c)15(ompar)22(ed)]TJ
ET
EMC
/P <>BDC
BT
7.5 0 0 7.5 76.0195 514.0157 Tm
-.0274 Tc
[( t)15(o)0( C)10(ontr)22(ol \()30(GPC3 CAR only\) T c)15(ells)]TJ
ET
EMC
/P <>BDC
BT
4.5 0 0 4.5 199.1459 516.4158 Tm
0 Tc
0 Tw
(3)Tj
ET
EMC
/P <>BDC
BT
7.5 0 0 7.5 201.6992 514.0157 Tm
-.0274 Tc
-.0376 Tw
(. A Phase)Tj
ET
EMC
/P <>BDC
BT
7.5 0 0 7.5 233.7063 514.0157 Tm
0 Tc
0 Tw
( )Tj
ET
EMC
/P <>BDC
BT
7.5 0 0 7.5 21.2587 506.8157 Tm
-.0201 Tc
.018 Tw
[(I/II trial is ongoing t)14.9(o)-.1( as)9.9(ses)9.9(s saf)9.9(ety and pr)21.9(eliminary ecacy)]TJ
ET
EMC
/P <>BDC
BT
7.5 0 0 7.5 233.7071 506.8157 Tm
0 Tc
0 Tw
( )Tj
ET
EMC
/P <>BDC
BT
7.5 0 0 7.5 21.2587 499.6157 Tm
-.02 Tc
[(of BO)43(XR10)10(30 in GPC3+ solid tumors \(NCT05120)10(2)12(7)-10(1\).)]TJ
ET
EMC
/P <>BDC
BT
7.5 0 0 7.5 210.2972 499.6157 Tm
0 Tc
()Tj
ET
EMC
/P <>BDC
BT
7.5 0 0 7.5 212.5472 499.6157 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7.5 0 0 7.5 21.2587 492.4157 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7.5 0 0 7.5 21.2587 485.2158 Tm
.01 Tc
.1847 Tw
[(In the curr)22(ent s)10(tudy)85(, w)22(e)0( ha)19(v)27(e)0( char)25(act)15(eriz)15(ed the T c)15(ell)]TJ
ET
EMC
/P <>BDC
BT
7.5 0 0 7.5 233.8571 485.2158 Tm
0 Tc
0 Tw
( )Tj
ET
EMC
/P <>BDC
BT
7.5 0 0 7.5 237.5672 485.2158 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7.5 0 0 7.5 241.2778 485.2158 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7.5 0 0 7.5 244.988 485.2158 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7.5 0 0 7.5 248.6982 485.2158 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7.5 0 0 7.5 252.4085 485.2158 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7.5 0 0 7.5 256.1189 485.2158 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7.5 0 0 7.5 259.8291 485.2158 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7.5 0 0 7.5 21.2587 478.0157 Tm
.01 Tc
.1449 Tw
[(phenotype)10(, e)10(ect)15(or functions and metabolic tnes)10(s of)]TJ
ET
EMC
/P <>BDC
BT
7.5 0 0 7.5 233.8568 478.0157 Tm
0 Tc
0 Tw
( )Tj
ET
EMC
/P <>BDC
BT
7.5 0 0 7.5 21.2587 470.8157 Tm
.0099 Tc
.0809 Tw
[(BO)42.9(XR10)9.9(30 T c)14.9(ells r)21.9(elativ)26.9(e t)14.9(o)-.1( C)9.9(ontr)21.9(ol GPC3 CAR T c)14.9(ells)]TJ
ET
EMC
/P <>BDC
BT
7.5 0 0 7.5 233.8568 470.8157 Tm
0 Tc
0 Tw
( )Tj
ET
EMC
/P <>BDC
BT
7.5 0 0 7.5 21.2587 463.6157 Tm
[(\(which lack e)26(x)30(ogenous GO)48(T2 c)15(o-e)26(xpr)22(es)10(sion\) )]TJ
ET
EMC
/P <>BDC
BT
/F4 1 Tf
7.5 0 0 7.5 189.1688 463.6157 Tm
-.0007 Tc
.0007 Tw
(in vitro)Tj
ET
EMC
/P <>BDC
BT
/F2 1 Tf
7.5 0 0 7.5 214.9915 463.6157 Tm
0 Tc
0 Tw
(. )Tj
ET
EMC
/P <>BDC
BT
/F3 1 Tf
7 0 0 7 245.1968 444.8683 Tm
-.015 Tc
.0369 Tw
[(Figur)15(e 1.)]TJ
ET
EMC
/P <>BDC
BT
/F2 1 Tf
7 0 0 7 274.4695 444.8683 Tm
[( BO)43(XR10)10(30 and C)10(ontr)22(ol \()30(GPC3 CAR only)85(, no GO)48(T2\) T c)15(ells )]TJ
28.5387 0 TD
[( w)22(e)0(r)22(e)0( manuf)15(actur)22(ed b)21(y)0( r)22(etr)22(o)27(vir)25(al tr)25(ansduction of PBMCs fr)22(om health)12(y donors.)]TJ
ET
EMC
/P <>BDC
BT
7 0 0 7 738.3209 444.8683 Tm
0 Tc
0 Tw
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 245.1968 437.6682 Tm
-.0152 Tc
-.0041 Tw
[(F)14.8(ollo)21.8(wing tha)16.8(w)69.8(,)-.2( c)14.8(ells w)21.8(e)-.2(r)21.8(e)-.2( analy)5.8(z)14.8(ed b)20.8(y)-.2( o)21.8(w cyt)14.8(ometry with a c)14.8(ock)8.8(tail of antibodies r)21.8(e)-.2(c)14.8(ognizing CD3, CD4, CD8, GPC3 CAR, CD45RA,)]TJ
64.2668 0 TD
-.0155 Tc
-.0038 Tw
[( C)19.5(CR7)99.5(, CD2)11.5(7)99.5(,)]TJ
ET
EMC
/P <>BDC
BT
7 0 0 7 738.3211 437.6682 Tm
0 Tc
0 Tw
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 245.1968 430.4683 Tm
-.0152 Tc
.0708 Tw
[(CD95 and Liv)26.8(e/Dead dy)26.8(e)9.8(.)-.2( )]TJ
ET
EMC
/P <>BDC
BT
/F3 1 Tf
7 0 0 7 335.9344 430.4683 Tm
-.015 Tc
0 Tw
(\(A\))Tj
ET
EMC
/P <>BDC
BT
/F2 1 Tf
7 0 0 7 347.2116 430.4683 Tm
.0706 Tw
[( Di)10(er)22(ent T c)15(ell subsets w)22(e)0(r)22(e)0( dened using the c)15(ell surf)15(ac)15(e phenotype)]TJ
ET
EMC
/P <>BDC
BT
4.2 0 0 4.2 589.2371 432.7183 Tm
-.025 Tc
0 Tw
(4,5)Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 595.3397 430.4683 Tm
-.0154 Tc
.071 Tw
[( illus)9.6(tr)24.6(at)14.6(ed in the table and r)21.6(epr)21.6(esentativ)26.6(e)]TJ
ET
EMC
/P <>BDC
BT
7 0 0 7 738.3207 430.4683 Tm
0 Tc
0 Tw
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 245.1968 423.2682 Tm
-.0246 Tc
-.0404 Tw
[(gating e)25.6(x)14.6(ample)9.6(. )]TJ
ET
EMC
/P <>BDC
BT
/F3 1 Tf
7 0 0 7 299.2488 423.2682 Tm
-.0242 Tc
0 Tw
(\(B\))Tj
ET
EMC
/P <>BDC
BT
/F2 1 Tf
7 0 0 7 310.0238 423.2682 Tm
-.0407 Tw
[( R)9.9(epr)21.9(esentativ)26.9(e o)21.9(w plots of the di)9.9(er)21.9(ent T c)14.9(ell subsets gat)14.9(ed on CD4 CAR+ and CD8 CAR+ populations in BO)42.9(XR10)9.9(30 and C)9.9(ontr)21.9(ol)]TJ
ET
EMC
/P <>BDC
BT
7 0 0 7 738.2881 423.2682 Tm
0 Tc
0 Tw
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 245.1968 416.0682 Tm
-.005 Tc
.1217 Tw
[(CAR T c)15(ells ar)22(e sho)22(wn and r)22(esults fr)22(om thr)22(ee donors ar)22(e summariz)15(ed in the s)10(tack)21(ed bar plots. )]TJ
ET
EMC
/P <>BDC
BT
/F3 1 Tf
7 0 0 7 583.8272 416.0682 Tm
0 Tw
[(\()30(C)10(-E\))]TJ
ET
EMC
/P <>BDC
BT
/F2 1 Tf
7 0 0 7 602.3147 416.0682 Tm
.1217 Tw
[( As)10(ses)10(sment of the degr)22(ee of t)15(erminal)]TJ
ET
EMC
/P <>BDC
BT
7 0 0 7 738.3211 416.0682 Tm
0 Tc
0 Tw
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 741.2384 416.0682 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 744.1556 416.0682 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 747.0729 416.0682 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 749.9899 416.0682 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 752.9072 416.0682 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 755.8245 416.0682 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 758.7413 416.0682 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 761.6586 416.0682 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 764.5758 416.0682 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 767.4929 416.0682 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 770.4101 416.0682 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 773.3274 416.0682 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 776.2444 416.0682 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 779.1614 416.0682 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 782.0787 416.0682 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 784.9957 416.0682 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 787.913 416.0682 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 790.8303 416.0682 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 793.7473 416.0682 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 796.6646 416.0682 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 799.5816 416.0682 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 802.4988 416.0682 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 805.4159 416.0682 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 245.1968 408.8683 Tm
-.0134 Tc
.0734 Tw
[(di)9.9(er)21.9(entiation or senesc)14.9(enc)14.9(e w)15.9(as perf)9.9(ormed b)20.9(y)-.1( e)23.9(v)20.9(aluating CD2)11.9(7 e)25.9(xpr)21.9(es)9.9(sion in BO)42.9(XR10)9.9(30 and C)9.9(ontr)21.9(ol CAR T c)14.9(ells within the Nav)26.9(e/T)]TJ
65.7408 0 TD
.0733 Tw
[( s)10(t)15(em c)15(ell)]TJ
ET
EMC
/P <>BDC
BT
7 0 0 7 738.3214 408.8683 Tm
0 Tc
0 Tw
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 245.1968 401.6682 Tm
-.03 Tc
(memory)Tj
ET
EMC
/P <>BDC
BT
/F3 1 Tf
7 0 0 7 272.8608 401.6682 Tm
-.06 Tc
.0471 Tw
[( \(C)-30(\))]TJ
ET
EMC
/P <>BDC
BT
/F2 1 Tf
7 0 0 7 285.4263 401.6682 Tm
-.03 Tc
.0171 Tw
[(, T c)15(entr)25(al memory)]TJ
ET
EMC
/P <>BDC
BT
/F3 1 Tf
7 0 0 7 347.2104 401.6682 Tm
[( \(D)30(\))]TJ
ET
EMC
/P <>BDC
BT
/F2 1 Tf
7 0 0 7 360.0842 401.6682 Tm
[( and T e)10(ect)15(or memory )]TJ
ET
EMC
/P <>BDC
BT
/F3 1 Tf
7 0 0 7 440.4757 401.6682 Tm
0 Tw
(\(E\))Tj
ET
EMC
/P <>BDC
BT
/F2 1 Tf
7 0 0 7 450.7657 401.6682 Tm
.0172 Tw
[( c)14.9(ell subsets. L)9.9(o)-.1(s)9.9(s)-.1( of CD2)11.9(7 is as)9.9(sociat)14.9(ed with t)14.9(erminal di)9.9(er)21.9(entiation and pr)21.9(ogr)21.9(es)9.9(sion t)14.9(o)]TJ
ET
EMC
/P <>BDC
BT
7 0 0 7 738.2159 401.6682 Tm
0 Tc
0 Tw
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 245.1968 394.4683 Tm
-.0303 Tc
.034 Tw
[(r)21.7(eplicativ)26.7(e senesc)14.7(enc)14.7(e)]TJ
ET
EMC
/P <>BDC
BT
4.2 0 0 4.2 318.7507 396.7183 Tm
0 Tc
0 Tw
(6)Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 321.2581 394.4683 Tm
-.0301 Tc
.0338 Tw
[(. Samples w)21.9(e)-.1(r)21.9(e)-.1( analy)5.9(z)14.9(ed using an A)26.9(ttune Nxt o)21.9(w cyt)14.9(omet)14.9(er \(T)15.9(hermo Fisher Scientic)14.9(\). Data w)21.9(e)-.1(r)21.9(e)-.1( analy)5.9(z)14.9(ed using Flo)21.9(wJo v)84.9(.)49.9(10)]TJ
ET
EMC
/P <>BDC
BT
7 0 0 7 738.2161 394.4683 Tm
0 Tc
0 Tw
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 245.1968 387.2682 Tm
-.0301 Tc
.0001 Tw
[(and OMIQ. Statis)9.9(tical analy)16.9(sis w)15.9(as perf)9.9(ormed using Gr)24.9(aphP)9.9(ad Prism 9 with pair)21.9(ed t-t)14.9(es)9.9(t \(n=3 donors)19.9(\), ns, not signicant; *p<0)19.9(.)19.9(0)]TJ
59.607 0 TD
-.0303 Tc
.0003 Tw
[(5; **p<0)19.7(.)19.7(0)4.7(1; ***p<0)19.7(.)19.7(0)-.3(01.)]TJ
ET
EMC
/P <>BDC
BT
/F3 1 Tf
7 0 0 7 749.7635 444.8683 Tm
-.0112 Tc
-.0388 Tw
[(Figur)15(e 3.)]TJ
ET
EMC
/P <>BDC
BT
/F2 1 Tf
7 0 0 7 780.1376 444.8683 Tm
[( BO)43(XR10)10(30 and C)10(ontr)22(ol \()30(GPC3 CAR only)85.1(, no GO)48(T2\) T c)15(ells )]TJ
27.9859 0 TD
-.0114 Tc
-.0386 Tw
[( w)21.8(e)-.2(r)21.8(e)-.2( r)21.8(epeat)14.8(edly s)9.8(timulat)14.8(ed with plat)14.8(e-bound GPC3 CAR anti-idiotype antibody)84.8(. )]TJ
ET
EMC
/P <>BDC
BT
/F3 1 Tf
7 0 0 7 1248.0876 444.8683 Tm
-.0112 Tc
0 Tw
(\(A\))Tj
ET
EMC
/P <>BDC
BT
/F2 1 Tf
7 0 0 7 1259.4441 444.8683 Tm
-.0116 Tc
-.0384 Tw
[()38.4(Schematic r)21.6(epr)21.6(esentation of s)9.6(timulation)]TJ
ET
EMC
/P <>BDC
BT
7 0 0 7 1396.0271 444.8683 Tm
0 Tc
0 Tw
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 749.7635 437.6682 Tm
-.0004 Tc
-.0442 Tw
[(with anti-idiotype antibody c)14.6(o)-.4(at)14.6(ed plat)14.6(e)9.6(. )]TJ
ET
EMC
/P <>BDC
BT
/F3 1 Tf
7 0 0 7 892.0873 437.6682 Tm
0 Tc
0 Tw
(\(B\))Tj
ET
EMC
/P <>BDC
BT
/F2 1 Tf
7 0 0 7 903.3713 437.6682 Tm
-.0001 Tc
-.0445 Tw
[( Fr)21.9(equency of CD4+ and CD8+ populations w)21.9(e)-.1(r)21.9(e)-.1( as)9.9(ses)9.9(sed in CAR+ c)14.9(ells in BO)42.9(XR10)9.9(30 and C)9.9(ontr)21.9(ol CAR T c)14.9(ells f)9.9(ollo)21.9(wing 5 r)21.9(epeat)14.9(ed s)9.9(t)]TJ
65.2905 0 TD
-.0005 Tc
0 Tw
(imulations)Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 1396.0637 437.6682 Tm
0 Tc
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 749.7635 430.4683 Tm
-.0001 Tc
.015 Tw
[(o)26.9(v)26.9(er 15 da)16.9(y)16.9(s. R)9.9(epr)21.9(esentativ)26.9(e o)21.9(w plots of BO)42.9(XR10)9.9(30 and C)9.9(ontr)21.9(ol CAR T c)14.9(ells ar)21.9(e sho)21.9(wn.)]TJ
ET
EMC
/P <>BDC
BT
/F3 1 Tf
7 0 0 7 1058.5923 430.4683 Tm
-.03 Tc
.0449 Tw
[( \(C)-30(\))]TJ
ET
EMC
/P <>BDC
BT
/F2 1 Tf
7 0 0 7 1071.9823 430.4683 Tm
-.0001 Tc
.015 Tw
[( Expr)21.9(es)9.9(sion of CD2)11.9(7 and CD28 within the CD8+ CAR+ CD45RA+ population w)15.9(as e)23.9(v)20.9(aluat)14.9(ed in)]TJ
ET
EMC
/P <>BDC
BT
7 0 0 7 1396.0642 430.4683 Tm
0 Tc
0 Tw
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 749.7635 423.2682 Tm
-.0001 Tc
-.0268 Tw
[(BO)42.9(XR10)9.9(30 and C)9.9(ontr)21.9(ol CAR T c)14.9(ells f)9.9(ollo)21.9(wing 5 r)21.9(epeat)14.9(ed s)9.9(timulations o)26.9(v)26.9(er 15 da)16.9(y)16.9(s. T)15.9(he t-SNE plot sho)21.9(w)11.9(s)-.1( les)9.9(s di)9.9(er)21.9(entiat)14.9(e)-.1(d)]TJ
ET
EMC
/P <>BDC
BT
4.2 0 0 4.2 1173.5719 425.5182 Tm
0 Tc
0 Tw
(5)Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 1176.1421 423.2682 Tm
-.0001 Tc
-.0268 Tw
[( CD2)11.9(7+CD28+ \(blue)29.9(\) and t)14.9(erminally di)9.9(er)21.9(entiat)14.9(e)-.1(d)]TJ
ET
EMC
/P <>BDC
BT
4.2 0 0 4.2 1347.8401 425.5182 Tm
0 Tc
0 Tw
(8)Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 1350.4866 423.2682 Tm
-.0269 Tw
[( CD2)12(7)30(-CD28-)]TJ
ET
EMC
/P <>BDC
BT
7 0 0 7 1396.0637 423.2682 Tm
0 Tw
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 749.7635 416.0682 Tm
-.0258 Tw
[(populations \()30(o)0(r)25(ange)30(\) in BO)43(XR10)10(30 and C)10(ontr)22(ol CAR T c)15(ells and r)22(esults fr)22(om 3 donors ar)22(e summariz)15(ed in the s)10(tack)21(ed bar plots. )]TJ
ET
EMC
/P <>BDC
BT
/F3 1 Tf
7 0 0 7 1188.0619 416.0682 Tm
0 Tw
[(\(D)30(\))]TJ
ET
EMC
/P <>BDC
BT
/F2 1 Tf
7 0 0 7 1199.5557 416.0682 Tm
-.0001 Tc
-.0257 Tw
[( L)9.9(e)23.9(v)26.9(els of tr)24.9(anscription f)14.9(act)14.9(or T)47.9(CF1 \(which ar)21.9(e as)9.9(sociat)14.9(e)-.1(d)]TJ
ET
EMC
/P <>BDC
BT
7 0 0 7 1396.0637 416.0682 Tm
0 Tc
0 Tw
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 749.7635 408.8683 Tm
.0583 Tw
(with T)Tj
ET
EMC
/P <>BDC
BT
4.2 0 0 4.2 771.6896 408.8083 Tm
0 Tw
(SCM)Tj
ET
EMC
/P <>BDC
BT
4.2 0 0 4.2 781.1229 411.1183 Tm
(9)Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 783.8405 408.8683 Tm
-.0001 Tc
.0584 Tw
[(\) w)21.9(e)-.1(r)21.9(e)-.1( quantitat)14.9(ed in CD8+ CAR+ c)14.9(ells in BO)42.9(XR10)9.9(30 and C)9.9(ontr)21.9(ol CAR T c)14.9(ells f)9.9(ollo)21.9(wing 3 r)21.9(epeat)14.9(ed s)9.9(timulations o)26.9(v)26.9(er 9 da)16.9(y)16.9(s. R)9.9(epr)21.9(es)]TJ
66.0773 0 TD
-.0003 Tc
.0586 Tw
[(entativ)26.7(e o)21.7(w plots of T)47.7(CF1 gat)14.7(ed on CD8+)]TJ
ET
EMC
/P <>BDC
BT
7 0 0 7 1396.0642 408.8683 Tm
0 Tc
0 Tw
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 749.7635 401.6682 Tm
-.0021 Tc
-.0429 Tw
[(CAR+ populations in BO)43(XR10)10(30 and C)10(ontr)22(ol CAR T c)15(ells ar)22(e sho)22(wn and r)22(esults fr)22(om 2 donors ar)22(e summariz)15(ed in the gr)25(aph. )]TJ
ET
EMC
/P <>BDC
BT
/F3 1 Tf
7 0 0 7 1171.7405 401.6682 Tm
0 Tw
(\(E\))Tj
ET
EMC
/P <>BDC
BT
/F2 1 Tf
7 0 0 7 1182.6169 401.6682 Tm
-.0022 Tc
-.0428 Tw
[( Ki6)21.9(7 le)23.9(v)26.9(els w)21.9(e)-.1(r)21.9(e)-.1( quantitat)14.9(ed in CD8+ CAR+ c)14.9(e)-.1(lls in BO)42.9(XR10)9.9(30)]TJ
ET
EMC
/P <>BDC
BT
7 0 0 7 1396.0656 401.6682 Tm
0 Tc
0 Tw
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 749.7635 394.4683 Tm
-.0002 Tc
-.0247 Tw
[(and C)9.8(ontr)21.8(ol CAR T c)14.8(ells f)9.8(ollo)21.8(wing 3 r)21.8(epeat)14.8(ed s)9.8(timulations o)26.8(v)26.8(er 9 da)16.8(y)16.8(s. R)9.8(epr)21.8(esentativ)26.8(e o)21.8(w plots of Ki6)21.8(7 gat)14.8(ed on CD8+ CAR+ popu)]TJ
64.9718 0 TD
-.0001 Tc
[(lations in BO)42.9(XR10)9.9(30 and C)9.9(ontr)21.9(ol CAR T c)14.9(ells ar)21.9(e sho)21.9(wn)]TJ
ET
EMC
/P <>BDC
BT
7 0 0 7 1396.0637 394.4683 Tm
0 Tc
0 Tw
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 749.7635 387.2682 Tm
.0276 Tw
[(and r)22(esults fr)22(om 2 donors ar)22(e summariz)15(ed in the gr)25(aph. )]TJ
ET
EMC
/P <>BDC
BT
/F3 1 Tf
7 0 0 7 946.2054 387.2682 Tm
0 Tw
(\(F\))Tj
ET
EMC
/P <>BDC
BT
/F2 1 Tf
7 0 0 7 957.0275 387.2682 Tm
.0276 Tw
[( Mit)15(ochondrial morphology in BO)43(XR10)10(30 and C)10(ontr)22(ol CAR T c)15(ells w)16(as e)26(x)15(amined b)21(y)0( electr)22(on micr)22(osc)15(op)21(y f)10(ollo)22(wing 4 r)22(epeat)15(e)0(d)]TJ
ET
EMC
/P <>BDC
BT
7 0 0 7 1396.0637 387.2682 Tm
0 Tw
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 749.7635 380.0682 Tm
-.0001 Tc
-.0083 Tw
[(s)9.9(timulations o)26.9(v)26.9(er 12 da)16.9(y)16.9(s. Higher number of mit)14.9(ochondria with tubular appear)24.9(anc)14.9(e ar)21.9(e as)9.9(sociat)14.9(ed with memory T c)14.9(ells)]TJ
ET
EMC
/P <>BDC
BT
4.2 0 0 4.2 1159.17 382.3182 Tm
0 Tc
0 Tw
(10)Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 1163.5365 380.0682 Tm
-.0001 Tc
-.0083 Tw
[(. R)9.9(epr)21.9(esentativ)26.9(e images ar)21.9(e sho)21.9(wn and mit)14.9(ochondrial numbers/)79.9(c)14.9(ell)]TJ
ET
EMC
/P <>BDC
BT
7 0 0 7 1396.0637 380.0682 Tm
0 Tc
0 Tw
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 749.7635 372.8683 Tm
-.0008 Tc
-.0442 Tw
[(and mit)15(ochondrial length da)5(ta fr)22(om 20 independent images \(n=1 donor\) ar)22(e summariz)14.9(ed in the gr)25(aph. Samples w)22(e)0(r)21.9(e)0( analy)6(z)15(ed using a)]TJ
65.2992 0 TD
-.0009 Tc
[(n A)26.9(t)-.2(tune Nxt o)21.9(w cyt)14.9(omet)14.9(e)-.2(r \(T)15.8(hermo Fisher Scientic)14.8(\))]TJ
ET
EMC
/P <>BDC
BT
7 0 0 7 1396.0603 372.8683 Tm
0 Tc
0 Tw
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 749.7635 365.6682 Tm
-.0034 Tc
-.0416 Tw
[(or tr)24.9(ansmis)9.9(sion electr)21.9(on micr)21.9(osc)14.8(ope)9.9(. Images/)69.9(data w)21.9(e)-.1(r)21.9(e)-.1( analy)5.9(z)14.8(ed using ImageJ)14.8(, Flo)21.9(wJo v)84.9(.)49.9(10 and OMIQ. Statis)9.9(tical analy)16.9(sis w)15.9(as per)]TJ
63.235 0 TD
[(f)9.9(ormed on mit)14.9(ochondrial data fr)21.9(om 20 independent images)]TJ
ET
EMC
/P <>BDC
BT
7 0 0 7 1396.0608 365.6682 Tm
0 Tc
0 Tw
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 749.7635 358.4683 Tm
-.0001 Tc
.0001 Tw
[(with unpair)21.9(ed non-par)24.9(ametric s)9.9(tudent t t)14.9(e)-.1(s)9.9(t; *p<0)19.9(.)19.9(05; ***p<0)19.9(.)19.9(0)-.1(01.)]TJ
ET
EMC
/P <>BDC
BT
/F3 1 Tf
7 0 0 7 749.7631 200.2361 Tm
-.005 Tc
.0602 Tw
[(Figur)15(e 4. )]TJ
ET
EMC
/P <>BDC
BT
/F2 1 Tf
7 0 0 7 784.1851 200.2361 Tm
[(E)10(ect)15(or function of BO)43(XR10)10(30 and C)10(ontr)22(ol \()30(GPC3 CAR only)85(, no GO)48(T2\) T c)15(ells )]TJ
39.0472 0 TD
-.0051 Tc
.0603 Tw
[( f)9.9(ollo)21.9(wing cultur)21.9(e in s)9.9(t)-.1(r)21.9(e)-.1(s)9.9(s)-.1( c)14.9(onditions such as r)21.9(epeat)14.9(ed s)9.9(timulation or lo)21.9(w gluc)14.9(ose w)15.9(as e)25.9(x)14.9(amined.)]TJ
ET
EMC
/P <>BDC
BT
7 0 0 7 1396.0286 200.2361 Tm
0 Tc
0 Tw
( )Tj
ET
EMC
/P <>BDC
BT
/F3 1 Tf
7 0 0 7 749.7631 193.0361 Tm
-.015 Tc
(\(A\))Tj
ET
EMC
/P <>BDC
BT
/F2 1 Tf
7 0 0 7 761.0403 193.0361 Tm
-.0133 Tw
[()13.3(C)10(yt)15(ot)15(o)30(xic gr)25(anules \(r)22(ed arr)22(o)22(w)12(s)20(\))0( pr)22(esent in individual T c)15(ells w)16(as quantied in BO)43(XR10)10(30 and C)10(ontr)22(ol CAR T c)15(ells b)21(y)0( electr)22(on mi)]TJ
61.439 0 TD
-.0153 Tc
-.013 Tw
[(cr)21.7(osc)14.7(op)20.7(y f)9.7(ollo)21.7(wing 4 r)21.7(epeat)14.7(ed s)9.7(timulations with plat)14.7(e-bound)]TJ
ET
EMC
/P <>BDC
BT
7 0 0 7 1395.9587 193.0361 Tm
0 Tc
0 Tw
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 749.7631 185.8362 Tm
-.0105 Tc
-.0395 Tw
[(GPC3 CAR anti-idiotype antibody o)27(v)27(er 12 da)17(y)17(s. R)10(epr)22(esentativ)27(e images ar)22(e sho)22(wn and gr)25(anule numbers/)80(c)15(ell fr)22(om 7 independent image)]TJ
64.6361 0 TD
[(s \(n=1 donor\) w)22(e)0(r)22(e)0( quantied b)21(y)0( ImageJ and summariz)15(ed)]TJ
ET
EMC
/P <>BDC
BT
7 0 0 7 1396.0294 185.8362 Tm
0 Tc
0 Tw
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 749.7631 178.6362 Tm
-.005 Tc
.0026 Tw
[(in the gr)25(aph. )]TJ
ET
EMC
/P <>BDC
BT
/F3 1 Tf
7 0 0 7 795.1003 178.6362 Tm
0 Tw
(\(B\))Tj
ET
EMC
/P <>BDC
BT
/F2 1 Tf
7 0 0 7 806.2795 178.6362 Tm
-.0051 Tc
.0027 Tw
[( Gr)24.9(anzyme B \()29.9(GNB\) le)23.9(v)26.9(els in supernatants of BO)42.9(XR10)9.9(30 and C)9.9(ontr)21.9(ol CAR T c)14.9(ells f)9.9(ollo)21.9(wing 5 r)21.9(epeat)14.9(ed s)9.9(timulations with plat)14.9(e-bound)]TJ
64.9248 0 TD
-.0049 Tc
.0025 Tw
[( GPC3 CAR anti-idiotype antibody o)27.1(v)27.1(e).1(r)]TJ
ET
EMC
/P <>BDC
BT
7 0 0 7 1396.0291 178.6362 Tm
0 Tc
0 Tw
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 749.7631 171.4361 Tm
-.0051 Tc
.0687 Tw
[(15 da)16.9(y)16.9(s)-.1( w)15.9(as det)14.9(ermined b)20.9(y)-.1( MSD \(Meso Scale Diagnos)9.9(tics)19.9(\) as)9.9(sa)16.9(y)84.9(.)-.1( Gr)24.9(aphs summariz)14.9(e data fr)21.9(om 2 donors. )]TJ
ET
EMC
/P <>BDC
BT
/F3 1 Tf
7 0 0 7 1116.4435 171.4361 Tm
-.005 Tc
0 Tw
[(\()30(C\) )]TJ
ET
EMC
/P <>BDC
BT
/F2 1 Tf
7 0 0 7 1130.0696 171.4361 Tm
-.0051 Tc
.0687 Tw
[(Schematic of GPC3+ Hep3B-NLR c)14.9(ell killing as)9.9(sa)16.9(y in lo)21.9(w gluc)14.9(ose c)14.9(onditions.)]TJ
ET
EMC
/P <>BDC
BT
7 0 0 7 1396.0291 171.4361 Tm
0 Tc
0 Tw
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 749.7631 164.2361 Tm
-.0251 Tc
-.0196 Tw
[(BO)42.9(XR10)9.9(30 and C)9.9(ontr)21.9(ol CAR T c)14.9(ells w)21.9(e)-.1(r)21.9(e)-.1( r)21.9(epeat)14.9(edly s)9.9(timulat)14.9(ed with plat)14.9(e-bound GPC3 CAR anti-idiotype antibody o)26.9(v)26.9(er 12 da)16.9(y)16.9(s)-.1( and t)]TJ
62.7781 0 TD
[(hen c)14.9(ocultur)21.9(ed at 1:1 e)9.9(ect)14.9(or:tar)20.9(get r)24.9(a)4.9(tio with Hep3B-NLR)]TJ
ET
EMC
/P <>BDC
BT
7 0 0 7 1379.0724 164.2361 Tm
-.005 Tc
[( c)15(ells)]TJ
ET
EMC
/P <>BDC
BT
7 0 0 7 1396.0286 164.2361 Tm
0 Tc
0 Tw
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 749.7631 157.0361 Tm
-.005 Tc
.0239 Tw
[(in normal gluc)15(ose \(3)24(7mM\) or lo)22(w gluc)15(ose \(1:25 dilut)15(ed = 1.48mM gluc)15(ose)30(\) media. C)10(ell killing w)16(as monit)15(or)22(ed e)24(v)27(ery six hours f)10(or 4)]TJ
63.1502 0 TD
[(.5 da)17(y)17(s)0( using a Sart)15(orius IncuC)10(yt)15(e)10(.)0( Fluor)22(esc)15(ent ar)22(ea of NLR)]TJ
ET
EMC
/P <>BDC
BT
7 0 0 7 1396.0286 157.0361 Tm
0 Tc
0 Tw
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 749.7631 149.8362 Tm
-.005 Tc
-.0141 Tw
[(pr)22(ot)15(ein r)22(e)0(s)10(trict)15(ed t)15(o)0( the nucleus of tar)21(get c)15(ells w)16(as quantied using IncuC)10(yt)15(e analy)17(sis softw)16(ar)22(e)10(.)0( )]TJ
ET
EMC
/P <>BDC
BT
/F3 1 Tf
7 0 0 7 1077.7407 149.8362 Tm
0 Tw
[(\(D)30(\))]TJ
ET
EMC
/P <>BDC
BT
/F2 1 Tf
7 0 0 7 1089.1296 149.8362 Tm
-.0141 Tw
[( Gr)22(o)22(wth of Hep3B-NLR c)15(ells cultur)22(ed without CAR T c)15(ells in normal or lo)22(w gluc)15(ose media.)]TJ
ET
EMC
/P <>BDC
BT
7 0 0 7 1396.0291 149.8362 Tm
0 Tc
0 Tw
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 749.7631 142.6361 Tm
-.005 Tc
-.0146 Tw
[(R)10(ed-uor)22(esc)15(ent ar)22(ea of Hep3B-NLR nuclei w)16(as normaliz)15(ed t)15(o)0( s)10(tart of c)15(ocultur)22(e)10(.)0( Per)22(c)15(ent incr)22(ease of r)22(ed uor)22(esc)15(ent ar)22(ea normaliz)15(e)]TJ
63.8098 0 TD
-.0051 Tc
-.0145 Tw
[(d t)14.9(o)-.1( the beginning of c)14.9(ocultur)21.9(e \(t=0h\) indicat)14.9(es c)14.9(ell pr)21.9(olif)]TJ
ET
EMC
/Span <>BDC
BT
7 0 0 7 1393.1724 142.6361 Tm
0 Tc
0 Tw
(-)Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 749.7631 135.4362 Tm
-.0056 Tc
[(er)24.4(ation. )]TJ
ET
EMC
/P <>BDC
BT
/F3 1 Tf
7 0 0 7 777.326 135.4362 Tm
-.005 Tc
(\(E-H\) )Tj
ET
EMC
/P <>BDC
BT
/F2 1 Tf
7 0 0 7 798.0499 135.4362 Tm
-.0374 Tw
[(Analy)17(sis of Hep3B killing b)21(y)0( BO)43(XR10)10(30 and C)10(ontr)22(ol CAR T c)15(ells in normal or lo)22(w gluc)15(ose media f)10(ollo)22(wing multiple s)10(timulations ac)]TJ
62.8628 0 TD
-.0051 Tc
[(c)14.9(o)-.1(r)20.9(ding t)14.9(o)-.1( the schematic \()29.9(C\).)37.4( R)9.9(ed-uor)21.9(esc)14.9(ent)]TJ
ET
EMC
/P <>BDC
BT
7 0 0 7 1396.0291 135.4362 Tm
0 Tc
0 Tw
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 749.7631 128.2361 Tm
-.0051 Tc
.0465 Tw
[(ar)21.9(ea of Hep3B-NLR nuclei w)15.9(as normaliz)14.9(ed t)14.9(o)-.1( s)9.9(tart of c)14.9(ocultur)21.9(e)9.9(.)-.1( Per)21.9(c)14.9(ent los)9.9(s of r)21.9(ed uor)21.9(esc)14.9(ent ar)21.9(ea r)21.9(elativ)26.9(e t)14.9(o)-.1( the beginning of)]TJ
63.1657 0 TD
[( c)14.8(ocultur)21.8(e \(t=0h\) indicat)14.8(es c)14.8(ell killing. R)9.8(epr)21.8(esentativ)26.8(e plots)]TJ
ET
EMC
/P <>BDC
BT
7 0 0 7 1396.0286 128.2361 Tm
0 Tc
0 Tw
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 749.7631 121.0361 Tm
-.005 Tc
.0534 Tw
[(fr)22(om one donor sho)22(wing Hep3B-NLR killing o)27(v)27(er time b)21(y)0( BO)43(XR10)10(30 and C)10(ontr)22(ol CAR T c)15(ells in normal and lo)22(w gluc)15(ose c)15(onditions ar)22(e)]TJ
66.9831 0 TD
[( sho)22(wn )]TJ
ET
EMC
/P <>BDC
BT
/F3 1 Tf
7 0 0 7 1245.8335 121.0361 Tm
(\(E, F\))Tj
ET
EMC
/P <>BDC
BT
/F2 1 Tf
7 0 0 7 1265.6115 121.0361 Tm
[( and gr)25(aphs summariz)15(e Hep3B tumor)]TJ
ET
EMC
/P <>BDC
BT
7 0 0 7 1396.0286 121.0361 Tm
0 Tc
0 Tw
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 749.7631 113.8363 Tm
-.0041 Tc
.0741 Tw
[(killing endpoint data f)9.8(or BO)42.8(XR10)9.8(30 and C)9.8(ontr)21.7(ol CAR T c)14.8(e)-.3(lls in lo)21.7(w and normal gluc)14.8(ose c)14.7(o)-.3(nditions \(mean+/-SEM f)9.8(o)-.2(r 3 donors)19.8(\))-.2(. Stat)]TJ
65.9663 0 TD
-.0039 Tc
.0739 Tw
[(is)10(tical analy)17(sis w)16(a)-.1(s perf)10(ormed on killing curv)27(es using)]TJ
ET
EMC
/P <>BDC
BT
7 0 0 7 1396.0276 113.8363 Tm
0 Tc
0 Tw
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 1398.6174 113.8363 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 1401.2078 113.8363 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 1403.7976 113.8363 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 1406.3875 113.8363 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 1408.9778 113.8363 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 1411.5676 113.8363 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 1414.158 113.8363 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 1416.7478 113.8363 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 749.7631 106.6363 Tm
-.0052 Tc
.0002 Tw
[(2-)9.8(w)15.8(a)16.8(y R)9.8(epeat)14.8(ed Measur)21.8(es ANO)35.8(V)91.8(A)-.2( )]TJ
ET
EMC
/P <>BDC
BT
/F3 1 Tf
7 0 0 7 870.6396 106.6363 Tm
-.005 Tc
0 Tw
(\(E,F\))Tj
ET
EMC
/P <>BDC
BT
/F2 1 Tf
7 0 0 7 887.9787 106.6363 Tm
-.0051 Tc
.0001 Tw
[(, or endpoint summary data using s)9.9(tudent's t-t)14.9(es)9.9(t)]TJ
ET
EMC
/P <>BDC
BT
/F3 1 Tf
7 0 0 7 1058.0303 106.6363 Tm
-.005 Tc
0 Tw
[(\()30(G, H\))]TJ
ET
EMC
/P <>BDC
BT
/F2 1 Tf
7 0 0 7 1080.8154 106.6363 Tm
-.0051 Tc
.0001 Tw
[(, ns, not signicant, *p<0)19.9(.)19.9(05, **p<0)19.9(.)19.9(0)4.9(1, ***p<0)19.9(.)19.9(0)-.1(01.)]TJ
ET
EMC
/Artifact <>BDC
.83 .01 0 0 k
21.261 62.472 212.598 17.008 re
f
EMC
/P <>BDC
BT
/F3 1 Tf
9.999 0 0 10 99.342 67.9763 Tm
1 g
0 Tc
0 Tw
[(R)10(e)0(f)10(e)0(r)15(enc)15(es)]TJ
ET
EMC
/P <>BDC
BT
/F2 1 Tf
6 0 0 6 21.2597 54.8377 Tm
1 .89 0 0 k
(1.)Tj
ET
EMC
/P <>BDC
BT
6 0 0 6 29.7635 54.8377 Tm
[(F)15(onk)21(oua )]TJ
ET
EMC
/P <>BDC
BT
/F4 1 Tf
6 0 0 6 57.3094 54.8377 Tm
(et al.)Tj
ET
EMC
/P <>BDC
BT
/F2 1 Tf
6 0 0 6 71.6196 54.8377 Tm
(, Molecular )Tj
ET
EMC
/P <>BDC
BT
6 0 0 6 105.5074 54.8377 Tm
( )Tj
ET
EMC
/P <>BDC
BT
6 0 0 6 29.7635 48.2377 Tm
[(T)16(her)25(ap)21(y 20)10(22)]TJ
ET
EMC
/P <>BDC
BT
6 0 0 6 70.7496 48.2377 Tm
( )Tj
ET
EMC
/P <>BDC
BT
6 0 0 6 21.2597 41.6378 Tm
(2.)Tj
ET
EMC
/P <>BDC
BT
6 0 0 6 29.7635 41.6378 Tm
[(Y)91(ang )]TJ
ET
EMC
/P <>BDC
BT
/F4 1 Tf
6 0 0 6 46.4196 41.6378 Tm
(et al.)Tj
ET
EMC
/P <>BDC
BT
/F2 1 Tf
6 0 0 6 60.7296 41.6378 Tm
-.0004 Tc
.0004 Tw
[(, C)9.6(ell Death )]TJ
ET
EMC
/P <>BDC
BT
6 0 0 6 96.4835 41.6378 Tm
0 Tc
0 Tw
( )Tj
ET
EMC
/P <>BDC
BT
6 0 0 6 29.7635 35.0378 Tm
-.0003 Tc
.0003 Tw
(and Disease 2018)Tj
ET
EMC
/P <>BDC
BT
6 0 0 6 81.1235 35.0378 Tm
0 Tc
0 Tw
( )Tj
ET
EMC
/P <>BDC
BT
6 0 0 6 21.2597 28.4377 Tm
(3.)Tj
ET
EMC
/P <>BDC
BT
6 0 0 6 29.7635 28.4377 Tm
(Hickman )Tj
ET
EMC
/P <>BDC
BT
/F4 1 Tf
6 0 0 6 57.4116 28.4377 Tm
(et al.)Tj
ET
EMC
/P <>BDC
BT
/F2 1 Tf
6 0 0 6 71.7216 28.4377 Tm
[(, PL)10(oS One 20)10(22)]TJ
ET
EMC
/P <>BDC
BT
6 0 0 6 121.3296 28.4377 Tm
( )Tj
ET
EMC
/P <>BDC
BT
6 0 0 6 21.2597 21.8377 Tm
(4.)Tj
ET
EMC
/P <>BDC
BT
6 0 0 6 29.7635 21.8377 Tm
[(Kisht)15(on )]TJ
ET
EMC
/P <>BDC
BT
/F4 1 Tf
6 0 0 6 54.0155 21.8377 Tm
(et al.)Tj
ET
EMC
/P <>BDC
BT
/F2 1 Tf
6 0 0 6 68.3257 21.8377 Tm
-.0003 Tc
.0003 Tw
[(, C)9.7(ell Metab 2017)]TJ
ET
EMC
/P <>BDC
BT
6 0 0 6 118.4916 21.8377 Tm
0 Tc
0 Tw
( )Tj
ET
EMC
/P <>BDC
BT
6 0 0 6 21.2597 15.2377 Tm
-.03 Tc
(5.)Tj
ET
EMC
/P <>BDC
BT
6 0 0 6 29.7635 15.2377 Tm
[(Mahnk)21(e )]TJ
ET
EMC
/P <>BDC
BT
/F4 1 Tf
6 0 0 6 52.9659 15.2377 Tm
-.0409 Tw
(et al)Tj
ET
EMC
/P <>BDC
BT
/F2 1 Tf
6 0 0 6 64.6008 15.2377 Tm
-.0302 Tc
-.0407 Tw
(., Eur J Immunol 2013)Tj
ET
EMC
/P <>BDC
BT
6 0 0 6 123.1268 15.2377 Tm
0 Tc
0 Tw
( )Tj
ET
EMC
/Artifact <>BDC
.83 .01 0 0 k
245.198 33.472 334.488 17.008 re
f
EMC
/P <>BDC
BT
/F3 1 Tf
9.999 0 0 10 362.2249 38.9763 Tm
1 g
[(A)10(ckno)13(wledgements)]TJ
ET
EMC
/P <>BDC
BT
/F2 1 Tf
6 0 0 6 245.1968 25.8377 Tm
1 .89 0 0 k
[(HMS Electr)22(on Micr)22(osc)15(op)21(y F)25(acility who perf)10(ormed electr)22(on micr)22(osc)15(op)21(yimaging)]TJ
ET
EMC
/P <>BDC
BT
6 0 0 6 480.6486 25.8377 Tm
( )Tj
ET
EMC
/P <>BDC
BT
6 0 0 6 245.1968 21.8377 Tm
( )Tj
ET
EMC
/P <>BDC
BT
6 0 0 6 245.1968 15.2377 Tm
[(All those within SO)48(TIO who c)15(ontribut)15(ed t)15(o)0( this s)10(tudy and participat)15(ed in the as)10(sembly and r)22(e)24(vie)22(w of this pos)10(t)15(e)0(r)]TJ
ET
EMC
/P <>BDC
BT
6 0 0 6 576.9609 15.2377 Tm
( )Tj
ET
EMC
/Artifact <>BDC
.83 .01 0 0 k
591.024 33.472 147.401 17.008 re
f
EMC
/P <>BDC
BT
/F3 1 Tf
9.999 0 0 10 635.761 38.9763 Tm
1 g
[(Disclosur)15(es)]TJ
ET
EMC
/P <>BDC
BT
/F2 1 Tf
6 0 0 6 591.0234 22.3551 Tm
1 .89 0 0 k
.01 Tc
.4276 Tw
[(All authors ar)22(e curr)22(ent emplo)26(y)27(ees of SO)48(TIO)]TJ
ET
EMC
/P <>BDC
BT
6 0 0 6 738.4252 22.3551 Tm
0 Tc
0 Tw
( )Tj
ET
EMC
/P <>BDC
BT
6 0 0 6 742.8509 22.3551 Tm
( )Tj
ET
EMC
/P <>BDC
BT
6 0 0 6 747.2769 22.3551 Tm
( )Tj
ET
EMC
/P <>BDC
BT
6 0 0 6 751.7028 22.3551 Tm
( )Tj
ET
EMC
/P <>BDC
BT
6 0 0 6 756.1285 22.3551 Tm
( )Tj
ET
EMC
/P <>BDC
BT
6 0 0 6 760.5544 22.3551 Tm
( )Tj
ET
EMC
/P <>BDC
BT
6 0 0 6 591.0234 15.7549 Tm
[(Biot)15(ech Inc. )]TJ
ET
EMC
/P <>BDC
BT
6 0 0 6 131.025 54.8377 Tm
(6.)Tj
ET
EMC
/P <>BDC
BT
6 0 0 6 139.5291 54.8377 Tm
(Zhang )Tj
ET
EMC
/P <>BDC
BT
/F4 1 Tf
6 0 0 6 160.3369 54.8377 Tm
(et al.)Tj
ET
EMC
/P <>BDC
BT
/F2 1 Tf
6 0 0 6 174.6469 54.8377 Tm
(, )Tj
ET
EMC
/P <>BDC
BT
6 0 0 6 177.9169 54.8377 Tm
( )Tj
ET
EMC
/P <>BDC
BT
6 0 0 6 139.5291 48.2377 Tm
[(EBioMedicine 20)10(21)]TJ
ET
EMC
/P <>BDC
BT
6 0 0 6 195.275 48.2377 Tm
( )Tj
ET
EMC
/P <>BDC
BT
6 0 0 6 131.025 41.6378 Tm
-.1 Tc
(7.)Tj
ET
EMC
/P <>BDC
BT
6 0 0 6 139.5291 41.6378 Tm
0 Tc
(Callender )Tj
ET
EMC
/P <>BDC
BT
/F4 1 Tf
6 0 0 6 169.601 41.6378 Tm
(et al.)Tj
ET
EMC
/P <>BDC
BT
/F2 1 Tf
6 0 0 6 183.9108 41.6378 Tm
(, )Tj
ET
EMC
/P <>BDC
BT
6 0 0 6 187.1808 41.6378 Tm
( )Tj
ET
EMC
/P <>BDC
BT
6 0 0 6 139.5291 35.0378 Tm
[(Fr)22(ont A)21(ging 20)10(21)]TJ
ET
EMC
/P <>BDC
BT
6 0 0 6 190.7447 35.0378 Tm
( )Tj
ET
EMC
/P <>BDC
BT
6 0 0 6 131.025 28.4377 Tm
(8.)Tj
ET
EMC
/P <>BDC
BT
6 0 0 6 139.5291 28.4377 Tm
-.0002 Tc
.0002 Tw
[(X)16.8(u)-.2( and Larbi, Int J Mol Sc 2017)]TJ
ET
EMC
/P <>BDC
BT
6 0 0 6 230.531 28.4377 Tm
0 Tc
0 Tw
( )Tj
ET
EMC
/P <>BDC
BT
6 0 0 6 131.025 21.8377 Tm
-.01 Tc
(9.)Tj
ET
EMC
/P <>BDC
BT
6 0 0 6 139.5291 21.8377 Tm
0 Tc
[(G)-10(a)5(ttinoni )]TJ
ET
EMC
/P <>BDC
BT
/F4 1 Tf
6 0 0 6 168.8091 21.8377 Tm
(et al.)Tj
ET
EMC
/P <>BDC
BT
/F2 1 Tf
6 0 0 6 183.1188 21.8377 Tm
-.0004 Tc
.0004 Tw
(, Nat Med 2009)Tj
ET
EMC
/P <>BDC
BT
6 0 0 6 229.3969 21.8377 Tm
0 Tc
0 Tw
( )Tj
ET
EMC
/P <>BDC
BT
6 0 0 6 131.025 15.2377 Tm
[(10)20(.)]TJ
ET
EMC
/P <>BDC
BT
6 0 0 6 139.5291 15.2377 Tm
(Buck )Tj
ET
EMC
/P <>BDC
BT
/F4 1 Tf
6 0 0 6 156.1908 15.2377 Tm
(et al.)Tj
ET
EMC
/P <>BDC
BT
/F2 1 Tf
6 0 0 6 170.5008 15.2377 Tm
-.0005 Tc
.0005 Tw
[(, C)9.5(ell 2016)]TJ
ET
EMC
/Artifact <>BDC
1 G
0 J 0 j 3 w 10 M [] 0 d
35.516 761.728 121.724 -53.693 re
200.531 15.238 m
S
EMC
/P <>BDC
BT
/F3 1 Tf
17 0 0 17 68.7525 739.2819 Tm
1 g
-.001 Tc
0 Tw
[(Pos)9(t)14(er )]TJ
ET
EMC
/P <>BDC
BT
17 0 0 17 129.1027 739.2819 Tm
0 Tc
( )Tj
ET
EMC
/P <>BDC
BT
17 0 0 17 67.384 720.2819 Tm
[(nr)90(. 238)]TJ
ET
EMC
/P <>BDC
BT
20 0 0 20 186.2689 744.3937 Tm
-.005 Tc
[(Ex)15(ogenous GO)30(T2 in CAR T c)15(ells impr)15(o)18(v)18(es metabolic function and pr)15(eserv)18(es early memory T c)15(ell subsets)]TJ
ET
EMC
/Artifact <>BDC
.83 .01 0 0 k
21.26 436.732 212.598 17.008 re
f
EMC
/P <>BDC
BT
9.999 0 0 10 38.4621 442.2361 Tm
1 g
-.0003 Tc
.0003 Tw
[(The BO)24.7(XR Platf)9.7(orm and BO)24.7(XR10)9.7(30)]TJ
ET
EMC
/Figure <>BDC
Q
q
1 i
18.937 160.556 219.082 -75.912 re
W n
21.38 156.779 215.433 -70.866 re
216.424 442.236 m
W* n
0 797.244 1417.323 -797.244 re
708.66 398.64 m
W n
0 797.25 1417.32 -797.25 re
W n
/GS1 gs
q
219.182 0 0 75.912 18.937 84.644 cm
/Im2 Do
Q
EMC
/Figure <>BDC
Q
q
1 i
17.082 274.608 220.953 -91.593 re
W n
21.26 274.583 212.598 -85.04 re
216.424 442.236 m
W* n
0 797.244 1417.323 -797.244 re
708.66 398.64 m
W n
0 797.25 1417.32 -797.25 re
W n
/GS1 gs
q
213.274 0 0 85.276 20.98 189.331 cm
/Im3 Do
Q
EMC
/Figure <>BDC
Q
q
1 i
16.008 417.707 220.249 -112.14 re
W n
21.26 414.055 212.477 -112.884 re
216.424 442.236 m
W* n
0 797.244 1417.323 -797.244 re
708.66 398.64 m
W n
0 797.25 1417.32 -797.25 re
W n
/GS1 gs
q
220.249 0 0 112.14 16.008 305.567 cm
/Im4 Do
Q
EMC
/Artifact <>BDC
Q
q
1 i
0 797.244 1417.323 -797.244 re
708.66 398.64 m
W n
0 797.25 1417.32 -797.25 re
W n
.249 .003 0 0 k
/GS1 gs
21.26 414.055 212.477 19.843 re
f
EMC
/P <>BDC
BT
/F1 1 Tf
7 0 0 7 53.6606 425.7346 Tm
1 .89 0 0 k
0 Tc
0 Tw
[(BO)33(XR10)10(30 T c)15(ells c)15(o-e)20(xpr)18(es)10(s a glypican-)10(3 )]TJ
ET
EMC
/P <>BDC
BT
7 0 0 7 203.6777 425.7346 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 47.0316 417.3346 Tm
[(\()30(GPC3\)-tar)15(geting CAR and the enzyme GO)38(T2. )]TJ
ET
EMC
/Artifact <>BDC
.249 .003 0 0 k
245.197 652.677 493.228 11.339 re
f
EMC
/P <>BDC
BT
7 0 0 7 303.1013 655.9047 Tm
1 .89 0 0 k
[(Figur)18(e 1: BO)33(XR10)10(30 T c)15(ells e)20(xhibit a les)10(sdi)10(er)18(entiat)15(ed phenotype than C)10(ontr)18(ol CAR T c)15(ells in drug pr)18(oduct)]TJ
ET
EMC
/Artifact <>BDC
.166 .002 0 0 k
245.197 632.835 212.598 17.007 re
f
EMC
/P <>BDC
BT
/F2 1 Tf
7 0 0 7 255.4453 642.3967 Tm
1 .89 0 0 k
-.0001 Tc
.0001 Tw
[(C)9.9(ell surf)14.9(ac)14.9(e mark)20.9(ers and gating s)9.9(t)-.1(r)24.9(a)4.9(t)14.9(egy used t)14.9(o)-.1( dene )]TJ
ET
EMC
/P <>BDC
BT
7 0 0 7 449.6464 642.3967 Tm
0 Tc
0 Tw
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 307.137 635.3967 Tm
-.0006 Tc
.0006 Tw
[(T c)14.4(ell di)9.4(er)21.4(entiation s)9.4(t)-.6(at)14.4(e )]TJ
ET
EMC
/Artifact <>BDC
.166 .002 0 0 k
245.197 524.126 212.598 17.008 re
f
EMC
/Figure <>BDC
Q
/GS1 gs
q
212.826 0 0 66.715 245.197 455.216 cm
/Im5 Do
Q
EMC
/Figure <>BDC
q
1 i
269.296 586.835 162.857 -42.47 re
W n
0 797.244 1417.323 -797.244 re
708.66 398.64 m
W n
0 797.25 1417.32 -797.25 re
W n
q
162.918 0 0 42.47 269.296 544.365 cm
/Im6 Do
Q
EMC
/Figure <>BDC
Q
q
1 i
278.277 629.405 173.297 -40.894 re
W n
0 797.244 1417.323 -797.244 re
708.66 398.64 m
W n
0 797.25 1417.32 -797.25 re
W n
q
173.513 0 0 40.894 278.277 588.511 cm
/Im7 Do
Q
EMC
/P <>BDC
Q
q
1 i
0 797.244 1417.323 -797.244 re
708.66 398.64 m
W n
0 797.25 1417.32 -797.25 re
W n
BT
/F2 1 Tf
7 0 0 7 255.0797 533.688 Tm
1 .89 0 0 k
0 Tc
0 Tw
(T)Tj
ET
EMC
/P <>BDC
BT
4.2 0 0 4.2 259.6158 533.6281 Tm
(N)Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 262.9338 533.688 Tm
(/T)Tj
ET
EMC
/P <>BDC
BT
4.2 0 0 4.2 270.9209 533.6281 Tm
(SCM)Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 280.3542 533.688 Tm
( and T)Tj
ET
EMC
/P <>BDC
BT
4.2 0 0 4.2 302.1033 533.6281 Tm
(EM)Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 308.5627 533.688 Tm
-.0001 Tc
.0001 Tw
[( populations ar)21.9(e incr)21.9(eased in BO)42.9(XR10)9.9(30)]TJ
ET
EMC
/P <>BDC
BT
7 0 0 7 447.9117 533.688 Tm
0 Tc
0 Tw
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 276.2316 526.688 Tm
-.0001 Tc
.0001 Tw
[(CAR+ T c)14.9(ells r)21.9(elativ)26.9(e t)14.9(o)-.1( C)9.9(ontr)21.9(ol CAR T c)14.9(ells)]TJ
ET
EMC
/Artifact <>BDC
.166 .002 0 0 k
469.134 632.835 269.291 17.007 re
f
EMC
/Figure <>BDC
Q
q
1 i
469.814 629.238 270.792 -179.359 re
W n
469.134 630.238 269.291 -178.746 re
W* n
0 797.244 1417.323 -797.244 re
708.66 398.64 m
W n
0 797.25 1417.32 -797.25 re
W n
q
270.842 0 0 179.359 469.814 449.879 cm
/Im8 Do
Q
EMC
/P <>BDC
Q
q
1 i
0 797.244 1417.323 -797.244 re
708.66 398.64 m
W n
0 797.25 1417.32 -797.25 re
W n
BT
/F2 1 Tf
7 0 0 7 471.6956 642.3967 Tm
1 .89 0 0 k
-.0451 Tc
.0001 Tw
[(W)14.9(ithin all memory T c)14.9(ell subsets, BO)42.9(XR10)9.9(30 CAR+ T c)14.9(ells e)25.9(xhibit les)9.9(s di)9.9(er)21.9(entiat)14.9(e)-.1(d)]TJ
ET
EMC
/P <>BDC
BT
7 0 0 7 735.548 642.3967 Tm
0 Tc
0 Tw
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 495.462 635.3967 Tm
-.02 Tc
[(phenotype \()30(CD2)12(7)]TJ
ET
EMC
/P <>BDC
BT
4.2 0 0 4.2 554.8784 635.3367 Tm
-.0333 Tc
(HI)Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 559.0125 635.3967 Tm
-.02 Tc
[( \) c)15(onsis)10(t)15(ent with incr)22(eased surviv)21(al capability)]TJ
ET
EMC
/Artifact <>BDC
.249 .003 0 0 k
749.764 652.677 646.299 11.339 re
f
EMC
/P <>BDC
BT
/F1 1 Tf
7 0 0 7 787.1414 655.9047 Tm
1 .89 0 0 k
-.0001 Tc
.0001 Tw
[(Figur)17.9(e 3: T s)9.9(t)14.9(em-lik)14.9(e/)49.9(memory populations with superior capacity f)9.9(or persis)9.9(t)14.9(enc)14.9(e and pr)17.9(olif)9.9(er)24.9(ation ar)17.9(e pr)17.9(eserv)21.9(ed in BO)32.9(XR10)9.9(30 T c)]TJ
65.087 0 TD
-.0002 Tc
.0002 Tw
[(ells f)9.8(ollo)16.8(wing chr)17.8(onic s)9.8(timulation)]TJ
ET
EMC
/Artifact <>BDC
.166 .002 0 0 k
749.764 632.835 184.252 17.007 re
f
EMC
/Figure <>BDC
Q
q
1 i
749.764 631.727 184.255 -60.903 re
W n
749.764 630 184.252 -69.449 re
W* n
0 797.244 1417.323 -797.244 re
708.66 398.64 m
W n
0 797.25 1417.32 -797.25 re
W n
q
184.44 0 0 60.903 749.764 570.824 cm
/Im9 Do
Q
EMC
/P <>BDC
Q
q
1 i
0 797.244 1417.323 -797.244 re
708.66 398.64 m
W n
0 797.25 1417.32 -797.25 re
W n
BT
/F2 1 Tf
7 0 0 7 805.276 642.3967 Tm
1 .89 0 0 k
-.0002 Tc
.0002 Tw
[(Schematic of chr)21.8(onic )]TJ
ET
EMC
/P <>BDC
BT
7 0 0 7 880.6029 642.3967 Tm
0 Tc
0 Tw
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 801.9474 635.3967 Tm
-.0003 Tc
.0003 Tw
[(s)9.7(timulation e)25.7(xperiment)]TJ
ET
EMC
/Artifact <>BDC
.166 .002 0 0 k
1111.181 632.835 284.881 17.007 re
f
EMC
/Figure <>BDC
Q
q
1 i
1111.181 634.723 154.174 -68.543 re
W n
1111.181 630 184.252 -69.449 re
W* n
0 797.244 1417.323 -797.244 re
708.66 398.64 m
W n
0 797.25 1417.32 -797.25 re
W n
q
154.318 0 0 68.543 1111.181 566.18 cm
/Im10 Do
Q
EMC
/Figure <>BDC
Q
q
1 i
1292.676 626.773 99.285 -59.806 re
W n
1293.478 630 102.584 -69.449 re
W* n
0 797.244 1417.323 -797.244 re
708.66 398.64 m
W n
0 797.25 1417.32 -797.25 re
W n
q
99.341 0 0 59.806 1292.676 566.967 cm
/Im11 Do
Q
EMC
/P <>BDC
Q
q
1 i
0 797.244 1417.323 -797.244 re
708.66 398.64 m
W n
0 797.25 1417.32 -797.25 re
W n
BT
/F2 1 Tf
7 0 0 7 1113.6052 642.3967 Tm
1 .89 0 0 k
-.0301 Tc
.0001 Tw
[(BO)42.9(XR10)9.9(30 T c)14.9(ells e)25.9(xhibit higher T)47.9(CF1 e)25.9(xpr)21.9(es)9.9(sion \(as)9.9(sociat)14.9(ed with T)]TJ
ET
EMC
/P <>BDC
BT
4.2 0 0 4.2 1334.2178 642.3367 Tm
-.05 Tc
0 Tw
(SCM)Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 1343.0212 642.3967 Tm
-.03 Tc
[(\) and incr)22(eased)]TJ
ET
EMC
/P <>BDC
BT
7 0 0 7 1393.4283 642.3967 Tm
0 Tc
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 1115.5013 635.3967 Tm
-.0001 Tc
.0001 Tw
[(pr)21.9(olif)9.9(er)24.9(ativ)26.9(e capacity c)14.9(ompar)21.9(ed t)14.9(o)-.1( C)9.9(ontr)21.9(ol CAR T c)14.9(ells aft)14.9(er chr)21.9(onic s)9.9(timulation)]TJ
ET
EMC
/Figure <>BDC
Q
q
1 i
1110.497 527.972 158.629 -64.857 re
W n
1111.181 543.092 167.244 -85.791 re
1391.742 635.397 m
W* n
0 797.244 1417.323 -797.244 re
708.66 398.64 m
W n
0 797.25 1417.32 -797.25 re
W n
q
158.639 0 0 64.857 1110.497 463.115 cm
/Im12 Do
Q
EMC
/Figure <>BDC
Q
q
1 i
1278.039 530.392 137.673 -72.07 re
W n
1241.574 543.092 156.419 -83.171 re
1391.742 635.397 m
W* n
0 797.244 1417.323 -797.244 re
708.66 398.64 m
W n
0 797.25 1417.32 -797.25 re
W n
q
120.377 0 0 70.882 1278.039 459.51 cm
/Im13 Do
Q
EMC
/Artifact <>BDC
Q
q
1 i
0 797.244 1417.323 -797.244 re
708.66 398.64 m
W n
0 797.25 1417.32 -797.25 re
W n
.166 .002 0 0 k
749.764 547.166 184.252 17.008 re
f
EMC
/Figure <>BDC
Q
q
1 i
795.881 544.331 171.241 -88.864 re
W n
749.764 544.331 184.252 -88.863 re
W* n
0 797.244 1417.323 -797.244 re
708.66 398.64 m
W n
0 797.25 1417.32 -797.25 re
W n
q
138.436 0 0 88.864 795.881 455.467 cm
/Im14 Do
Q
EMC
/P <>BDC
Q
q
1 i
0 797.244 1417.323 -797.244 re
708.66 398.64 m
W n
0 797.25 1417.32 -797.25 re
W n
BT
/F2 1 Tf
7 0 0 7 753.8796 556.7278 Tm
1 .89 0 0 k
-.0301 Tc
.0001 Tw
[(Higher fr)21.9(equency of CD4 and CD8)]TJ
ET
EMC
/P <>BDC
BT
4.2 0 0 4.2 866.3489 556.6678 Tm
-.05 Tc
0 Tw
(HI)Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 870.3431 556.7278 Tm
-.03 Tc
[( subsets observ)27(ed)]TJ
ET
EMC
/P <>BDC
BT
7 0 0 7 929.6895 556.7278 Tm
0 Tc
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 931.7895 556.7278 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 766.9929 549.7278 Tm
-.0001 Tc
.0001 Tw
[(in BO)42.9(XR10)9.9(30 c)14.9(ells aft)14.9(er chr)21.9(onic s)9.9(timulation)]TJ
ET
EMC
/Artifact <>BDC
.166 .002 0 0 k
945.354 610.157 155.906 39.685 re
f
EMC
/Figure <>BDC
Q
q
1 i
950.983 608.11 144.647 -150.595 re
W n
0 797.244 1417.323 -797.244 re
708.66 398.64 m
W n
0 797.25 1417.32 -797.25 re
W n
q
144.661 0 0 150.595 950.983 457.516 cm
/Im15 Do
Q
EMC
/P <>BDC
Q
q
1 i
0 797.244 1417.323 -797.244 re
708.66 398.64 m
W n
0 797.25 1417.32 -797.25 re
W n
BT
/F2 1 Tf
7 0 0 7 964.1218 641.6155 Tm
1 .89 0 0 k
-.0003 Tc
.0003 Tw
[(Dr)24.7(amatically incr)21.7(eased population )]TJ
ET
EMC
/P <>BDC
BT
7 0 0 7 1084.5919 641.6155 Tm
0 Tc
0 Tw
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 962.3578 634.6154 Tm
[(of CD2)12(7+CD28+ T c)15(ells is observ)27(ed )]TJ
ET
EMC
/P <>BDC
BT
7 0 0 7 1086.3558 634.6154 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 963.8349 627.6155 Tm
[(within CD45RA+ CD8+ BO)43(XR10)10(30 )]TJ
ET
EMC
/P <>BDC
BT
7 0 0 7 1084.8788 627.6155 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 957.0833 620.6155 Tm
-.0001 Tc
.0001 Tw
[(CAR+ T c)14.9(ells aft)14.9(er chr)21.9(onic s)9.9(timulation, )]TJ
ET
EMC
/P <>BDC
BT
7 0 0 7 1091.6302 620.6155 Tm
0 Tc
0 Tw
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 969.2473 613.6154 Tm
[(c)15(onsis)10(t)15(ent with T)]TJ
ET
EMC
/P <>BDC
BT
4.2 0 0 4.2 1028.3412 613.5554 Tm
(SCM)Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 1037.7745 613.6154 Tm
-.0005 Tc
.0005 Tw
( population)Tj
ET
EMC
/Artifact <>BDC
.249 .003 0 0 k
245.197 369.709 493.228 11.338 re
f
EMC
/P <>BDC
BT
/F1 1 Tf
7 0 0 7 250.4473 372.9362 Tm
1 .89 0 0 k
-.0001 Tc
.0001 Tw
[(Figur)17.9(e 2: BO)32.9(XR10)9.9(30 T c)14.9(ells demons)9.9(tr)24.9(at)14.9(e impr)17.9(o)21.9(v)21.9(ed metabolic health and surviv)14.9(al in lo)16.9(w gluc)14.9(ose c)14.9(onditions r)17.9(elativ)21.9(e t)14.9(o)-.1( C)9.9(ontr)17.9(ol CAR)]TJ
65.48 0 TD
0 Tc
0 Tw
[( T c)15(ells)]TJ
ET
EMC
/Artifact <>BDC
.166 .002 0 0 k
245.197 349.866 212.598 17.008 re
f
EMC
/Figure <>BDC
Q
q
1 i
478.293 345.986 156.858 -62.539 re
W n
0 797.244 1417.323 -797.244 re
708.66 398.64 m
W n
0 797.25 1417.32 -797.25 re
W n
q
156.897 0 0 62.539 478.293 283.447 cm
/Im16 Do
Q
EMC
/Figure <>BDC
Q
q
1 i
660.866 347.005 78.599 -55.997 re
W n
0 797.244 1417.323 -797.244 re
708.66 398.64 m
W n
0 797.25 1417.32 -797.25 re
W n
q
78.689 0 0 55.996 660.866 291.008 cm
/Im17 Do
Q
EMC
/P <>BDC
Q
q
1 i
0 797.244 1417.323 -797.244 re
708.66 398.64 m
W n
0 797.25 1417.32 -797.25 re
W n
BT
/F2 1 Tf
7 0 0 7 272.0984 359.4283 Tm
1 .89 0 0 k
0 Tc
0 Tw
[(En)17(vir)22(onmental and metabolic s)10(t)0(r)22(e)0(s)10(sors impair )]TJ
ET
EMC
/P <>BDC
BT
7 0 0 7 432.9933 359.4283 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 295.951 352.4282 Tm
[(mit)15(ochondrial function in T c)15(ells)]TJ
ET
EMC
/Artifact <>BDC
.166 .002 0 0 k
469.134 349.866 269.291 17.008 re
f
EMC
/P <>BDC
BT
7 0 0 7 476.9766 359.4283 Tm
1 .89 0 0 k
-.0101 Tc
.0001 Tw
[(L)9.9(o)21.9(w)21.9(er fr)21.9(equency of non-functional mit)14.9(ochondria is observ)26.9(ed in BO)42.9(XR10)9.9(30)]TJ
ET
EMC
/P <>BDC
BT
7 0 0 7 730.5122 359.4283 Tm
0 Tc
0 Tw
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 521.3534 352.4282 Tm
-.0102 Tc
.0002 Tw
[(CAR+ T c)14.8(ells activ)20.8(at)14.8(ed in lo)21.8(w gluc)14.8(ose c)14.8(onditions)]TJ
ET
EMC
/Artifact <>BDC
.166 .002 0 0 k
245.367 266.343 212.598 17.007 re
f
EMC
/Figure <>BDC
Q
q
1 i
273.259 263.481 208.742 -79.371 re
W n
245.367 263.481 212.598 -79.37 re
W* n
0 797.244 1417.323 -797.244 re
708.66 398.64 m
W n
0 797.25 1417.32 -797.25 re
W n
q
185.157 0 0 79.371 273.259 184.11 cm
/Im18 Do
Q
EMC
/Figure <>BDC
Q
q
1 i
472.934 259.208 134.639 -70.175 re
W n
0 797.244 1417.323 -797.244 re
708.66 398.64 m
W n
0 797.25 1417.32 -797.25 re
W n
q
134.825 0 0 70.175 472.934 189.033 cm
/Im19 Do
Q
EMC
/Figure <>BDC
Q
q
1 i
615.286 257.68 123.634 -66.363 re
W n
0 797.244 1417.323 -797.244 re
708.66 398.64 m
W n
0 797.25 1417.32 -797.25 re
W n
q
123.79 0 0 66.363 615.286 191.317 cm
/Im20 Do
Q
EMC
/P <>BDC
Q
q
1 i
0 797.244 1417.323 -797.244 re
708.66 398.64 m
W n
0 797.25 1417.32 -797.25 re
W n
BT
/F2 1 Tf
7 0 0 7 259.9203 275.9048 Tm
1 .89 0 0 k
-.0001 Tc
.0001 Tw
[(Decr)21.9(eased ROS le)23.9(v)26.9(els ar)21.9(e seen in BO)42.9(XR10)9.9(30 CAR+ T )]TJ
ET
EMC
/P <>BDC
BT
7 0 0 7 445.5115 275.9048 Tm
0 Tc
0 Tw
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 282.0089 268.9047 Tm
-.0003 Tc
.0003 Tw
[(c)14.7(ells activ)20.7(at)14.7(ed in lo)21.7(w gluc)14.7(ose c)14.7(onditions)]TJ
ET
EMC
/Artifact <>BDC
.166 .002 0 0 k
469.304 266.343 269.291 17.007 re
f
EMC
/P <>BDC
BT
7 0 0 7 488.1401 275.9048 Tm
1 .89 0 0 k
-.0101 Tc
.0001 Tw
[(Higher fr)21.9(equency of liv)26.9(e)9.9(,)-.1( pr)21.9(olif)9.9(er)24.9(ating c)14.9(ells is observ)26.9(ed in BO)42.9(XR10)9.9(30 )]TJ
ET
EMC
/P <>BDC
BT
7 0 0 7 721.7189 275.9048 Tm
0 Tc
0 Tw
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 521.5233 268.9047 Tm
-.0102 Tc
.0002 Tw
[(CAR+ T c)14.8(ells activ)20.8(at)14.8(ed in lo)21.8(w gluc)14.8(ose c)14.8(onditions)]TJ
ET
EMC
/Artifact <>BDC
.249 .003 0 0 k
21.26 276 212.477 19.842 re
f
EMC
/P <>BDC
BT
/F1 1 Tf
7 0 0 7 30.3717 287.6795 Tm
1 .89 0 0 k
0 Tc
0 Tw
[(GO)38(T2 pla)13(y)13(s)0( an important r)18(ole in mit)15(ochondrial function )]TJ
ET
EMC
/P <>BDC
BT
7 0 0 7 226.9666 287.6795 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 57.7802 279.2795 Tm
[(and maint)15(enanc)15(e of r)18(edo)21(x homeos)10(tasis. )]TJ
ET
EMC
/Artifact <>BDC
.249 .003 0 0 k
21.26 159.781 212.477 19.843 re
f
EMC
/P <>BDC
BT
7 0 0 7 23.2659 171.2608 Tm
1 .89 0 0 k
-.0353 Tc
.0003 Tw
[(BO)32.7(XR10)9.7(30 T c)14.7(ells demons)9.7(tr)24.7(at)14.7(e superior )]TJ
ET
EMC
/P <>BDC
BT
/F5 1 Tf
7 0 0 7 156.3928 171.2608 Tm
-.035 Tc
0 Tw
[(in viv)20(o)]TJ
ET
EMC
/P <>BDC
BT
/F1 1 Tf
7 0 0 7 177.6309 171.2608 Tm
-.0355 Tc
.0005 Tw
[( ecacy r)17.5(elativ)21.5(e)]TJ
ET
EMC
/P <>BDC
BT
7 0 0 7 231.7275 171.2608 Tm
0 Tc
0 Tw
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 26.0037 163.2608 Tm
-.015 Tc
[(t)15(o)0( C)10(ontr)18(ol CAR T c)15(ells in multiple GPC3+ x)21(enogr)25(aft models. )]TJ
ET
EMC
/P <>BDC
BT
/F3 1 Tf
6 0 0 6 467.7162 620.4282 Tm
0 Tc
(C)Tj
ET
EMC
/P <>BDC
BT
6 0 0 6 245.1968 515.2501 Tm
(B)Tj
ET
EMC
/P <>BDC
BT
6 0 0 6 245.1968 340.0638 Tm
(A)Tj
ET
EMC
/P <>BDC
BT
6 0 0 6 469.1337 340.0638 Tm
(B)Tj
ET
EMC
/P <>BDC
BT
6 0 0 6 650.041 340.0638 Tm
(C)Tj
ET
EMC
/P <>BDC
BT
6 0 0 6 245.1968 252.3631 Tm
(D)Tj
ET
EMC
/P <>BDC
BT
6 0 0 6 469.1337 252.3631 Tm
(E)Tj
ET
EMC
/P <>BDC
BT
6 0 0 6 617.1971 252.3631 Tm
(F)Tj
ET
EMC
/P <>BDC
BT
6 0 0 6 245.1968 624.5828 Tm
(A)Tj
ET
EMC
/P <>BDC
BT
6 0 0 6 749.7635 622.3654 Tm
(A)Tj
ET
EMC
/P <>BDC
BT
6 0 0 6 749.7635 537.8387 Tm
(B)Tj
ET
EMC
/P <>BDC
BT
6 0 0 6 945.3542 597.162 Tm
(C)Tj
ET
EMC
/P <>BDC
BT
6 0 0 6 1111.1808 622.3654 Tm
(D)Tj
ET
EMC
/P <>BDC
BT
6 0 0 6 1285.5112 622.3654 Tm
(E)Tj
ET
EMC
/P <>BDC
BT
6 0 0 6 1111.1808 530.3259 Tm
(F)Tj
ET
EMC
/P <>BDC
BT
6 0 0 6 1274.1727 530.3259 Tm
(G)Tj
ET
EMC
/P <>BDC
BT
6 0 0 6 1331.0869 530.3259 Tm
(H)Tj
ET
EMC
/P <>BDC
BT
6 0 0 6 564.8348 620.4282 Tm
(D)Tj
ET
EMC
/P <>BDC
BT
6 0 0 6 656.0032 620.4282 Tm
(E)Tj
ET
EMC
/Artifact <>BDC
.83 .01 0 0 K
0 J 0 j .5 w 10 M [] 0 d
q 1 0 0 1 556.764 625.42 cm 0 0 m
0 -169.952 l
S
Q
EMC
/Artifact <>BDC
q 1 0 0 1 650.764 625.42 cm 0 0 m
0 -169.952 l
S
Q
EMC
/P <>BDC
BT
7 0 0 7 245.1964 173.3686 Tm
-.03 Tc
-.0376 Tw
[(Figur)15(e 2.)]TJ
ET
EMC
/P <>BDC
BT
/F2 1 Tf
7 0 0 7 274.4105 173.3686 Tm
[( BO)43(XR10)10(30 and C)10(ontr)22(ol \()30(GPC3 CAR only)85(, no GO)48(T2\) T c)15(ells )]TJ
26.9843 0 TD
-.0302 Tc
-.0374 Tw
[( w)21.8(e)-.2(r)21.8(e)-.2( activ)20.8(at)14.8(ed in normal \(3)23.8(7mM gluc)14.8(ose)29.8(\) or lo)21.8(w gluc)14.8(ose c)14.8(onditions. )]TJ
ET
EMC
/P <>BDC
BT
/F3 1 Tf
7 0 0 7 686.6899 173.3686 Tm
-.03 Tc
0 Tw
(\(A\))Tj
ET
EMC
/P <>BDC
BT
/F2 1 Tf
7 0 0 7 697.6522 173.3686 Tm
-.0376 Tw
[()37.6(Model high)]TJ
ET
EMC
/Span <>BDC
BT
7 0 0 7 735.36 173.3686 Tm
0 Tc
0 Tw
(-)Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 245.1964 166.1687 Tm
-.03 Tc
.0221 Tw
[(lighting v)21(arious s)10(t)0(r)22(e)0(s)10(sors r)22(esulting in Non-functional Mit)15(ochondria \(NFM\))]TJ
ET
EMC
/P <>BDC
BT
4.2 0 0 4.2 483.7353 168.4186 Tm
0 Tc
0 Tw
(7)Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 485.3283 166.1687 Tm
-.03 Tc
(. )Tj
ET
EMC
/P <>BDC
BT
/F3 1 Tf
7 0 0 7 488.8784 166.1687 Tm
[(\(B-D)30(\))]TJ
ET
EMC
/P <>BDC
BT
/F2 1 Tf
7 0 0 7 507.2323 166.1687 Tm
.0222 Tw
[( NFM w)21.9(e)-.1(r)21.9(e)-.1( quantitat)14.9(ed in CAR+ c)14.9(ells in BO)42.9(XR10)9.9(30 and C)9.9(ontr)21.9(ol CAR T)]TJ
ET
EMC
/P <>BDC
BT
7 0 0 7 738.2155 166.1687 Tm
0 Tc
0 Tw
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 245.1964 158.9686 Tm
-.0276 Tc
.0726 Tw
[(C)10(ells using Mit)15(oT)89(r)25(ack)21(er Gr)22(een and Mit)15(oT)89(r)25(ack)21(er R)10(ed dy)27(es f)10(or mit)15(ochondrial mas)10(s and mit)15(ochondrial membr)25(ane pot)15(ential, r)22(espectiv)27(el)]TJ
62.679 0 TD
-.1126 Tc
0 Tw
[(y.)-85( )]TJ
ET
EMC
/P <>BDC
BT
/F3 1 Tf
7 0 0 7 691.2092 158.9686 Tm
-.0276 Tc
(\(B\))Tj
ET
EMC
/P <>BDC
BT
/F2 1 Tf
7 0 0 7 701.9128 158.9686 Tm
.0726 Tw
[( C)10(ells w)22(e)0(r)22(e)]TJ
ET
EMC
/P <>BDC
BT
7 0 0 7 738.214 158.9686 Tm
0 Tc
0 Tw
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 740.6288 158.9686 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 245.1964 151.7685 Tm
-.0301 Tc
-.0067 Tw
[(s)9.9(timulat)14.9(ed with plat)14.9(e-bound GPC3 CAR anti-idiotype antibody f)9.9(or 48 hours in lo)21.9(w gluc)14.9(ose \(0)19.9(.3)23.9(7mM\) media and as)9.9(ses)9.9(sed f)9.9(or NFM. R)9.9(e)]TJ
62.3661 0 TD
-.0303 Tc
-.0065 Tw
[(pr)21.7(esentativ)26.7(e o)21.7(w)]TJ
ET
EMC
/P <>BDC
BT
7 0 0 7 738.2159 151.7685 Tm
0 Tc
0 Tw
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 245.1964 144.5686 Tm
-.0301 Tc
-.0049 Tw
[(plots f)9.9(or NFM gat)14.9(ed on CAR+ populations in BO)42.9(XR10)9.9(30 and C)9.9(ontr)21.9(ol CAR T c)14.9(ells ar)21.9(e sho)21.9(wn and r)21.9(esults fr)21.9(om 3 donors ar)21.9(e summariz)14.9(ed )]TJ
62.8193 0 TD
[(in the gr)25(aph. )]TJ
ET
EMC
/P <>BDC
BT
/F3 1 Tf
7 0 0 7 727.6597 144.5686 Tm
-.06 Tc
0 Tw
[(\(C)-30(\))]TJ
ET
EMC
/P <>BDC
BT
/F2 1 Tf
7 0 0 7 738.2155 144.5686 Tm
0 Tc
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 245.1964 137.3686 Tm
-.0326 Tc
-.0424 Tw
[(C)9.9(ells w)21.9(e)-.1(r)21.9(e)-.1( activ)20.9(at)14.9(ed with GPC3+ Hep3B tumor c)14.9(ell spher)21.9(oids in normal gluc)14.9(ose \(3)23.9(7mM\) or lo)21.9(w gluc)14.9(ose \(1:5 dilut)14.9(ed = 7)99.9(.4mM gluc)14.9(ose)]TJ
60.278 0 TD
-.0325 Tc
-.0425 Tw
[(, 1:25 dilut)15(ed = 1.48mM)]TJ
ET
EMC
/P <>BDC
BT
7 0 0 7 738.2159 137.3686 Tm
0 Tc
0 Tw
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 245.1964 130.1687 Tm
-.0301 Tc
-.0397 Tw
[(gluc)14.9(ose)29.9(\) c)14.9(onditions f)9.9(or 7 da)16.9(y)16.9(s. A)20.9(ctiv)20.9(at)14.9(ed \()29.9(CD13)23.9(7+\) CAR+ c)14.9(ells w)21.9(e)-.1(r)21.9(e)-.1( as)9.9(ses)9.9(sed f)9.9(or NFM. )]TJ
39.9071 0 TD
0 Tc
0 Tw
( )Tj
T*
-.03 Tc
-.0398 Tw
[( R)10(esults fr)22(om 2 donors ar)22(e summariz)15(ed in the gr)25(aph. )]TJ
ET
EMC
/P <>BDC
BT
/F3 1 Tf
7 0 0 7 694.6508 130.1687 Tm
0 Tw
[(\(D)30(\))]TJ
ET
EMC
/P <>BDC
BT
/F2 1 Tf
7 0 0 7 705.5147 130.1687 Tm
-.0698 Tc
[(R)-39.8(O)-34.8(S)-39.8( l)-39.8(e)-15.8(v)-12.8(e)-39.8(l)]TJ
ET
EMC
/P <>BDC
BT
7 0 0 7 738.2155 130.1687 Tm
0 Tc
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 245.1964 122.9686 Tm
-.0201 Tc
.0964 Tw
[(w)21.9(e)-.1(r)21.9(e)-.1( as)9.9(ses)9.9(sed in CAR+ c)14.9(ells in BO)42.9(XR10)9.9(30 and C)9.9(ontr)21.9(ol CAR T c)14.9(ells using C)9.9(ellRO)42.9(X Gr)21.9(een dy)26.9(e f)9.9(ollo)21.9(wing s)9.9(timulation with plat)14.9(e-bound)]TJ
64.7804 0 TD
.0963 Tw
[( GPC3 CAR)]TJ
ET
EMC
/P <>BDC
BT
7 0 0 7 738.2169 122.9686 Tm
0 Tc
0 Tw
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 740.8505 122.9686 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 743.4846 122.9686 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 746.1185 122.9686 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 748.7527 122.9686 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 751.3864 122.9686 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 754.0205 122.9686 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 756.6544 122.9686 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 759.2886 122.9686 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 761.9222 122.9686 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 764.5564 122.9686 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 767.1902 122.9686 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 769.8244 122.9686 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 772.4581 122.9686 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 775.0922 122.9686 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 777.7261 122.9686 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 780.3603 122.9686 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 782.9942 122.9686 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 785.6281 122.9686 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 788.2622 122.9686 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 245.1964 115.7685 Tm
-.0302 Tc
.0234 Tw
[(anti-idiotype antibody f)9.8(or 48 hours in lo)21.8(w gluc)14.8(ose \(0)19.8(.3)23.8(7mM\) media. R)9.8(epr)21.8(esentativ)26.8(e o)21.8(w plots of ROS le)23.8(v)26.8(els gat)14.8(ed on CAR+ populat)]TJ
62.001 0 TD
-.03 Tc
.0232 Tw
[(ions in BO)43(XR10)10(30)]TJ
ET
EMC
/P <>BDC
BT
7 0 0 7 738.2159 115.7685 Tm
0 Tc
0 Tw
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 245.1964 108.5686 Tm
-.03 Tc
.0143 Tw
[(and C)10(ontr)22(ol CAR T c)15(ells ar)22(e sho)22(wn and r)22(esults fr)22(om 3 donors ar)22(e summariz)15(ed in the gr)25(aph. )]TJ
ET
EMC
/P <>BDC
BT
/F3 1 Tf
7 0 0 7 545.145 108.5686 Tm
0 Tw
(\(E\))Tj
ET
EMC
/P <>BDC
BT
/F2 1 Tf
7 0 0 7 555.4351 108.5686 Tm
.0144 Tw
[( Fr)21.9(equency of Liv)26.9(e)9.9(,)-.1( Early apopt)14.9(otic and Dead c)14.9(ells w)21.9(e)-.1(r)21.9(e)]TJ
ET
EMC
/P <>BDC
BT
7 0 0 7 738.2156 108.5686 Tm
0 Tc
0 Tw
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 245.1964 101.3686 Tm
-.0201 Tc
.1491 Tw
[(quantied in CAR+ c)14.9(ells in BO)42.9(XR10)9.9(30 and C)9.9(ontr)21.9(ol CAR T c)14.9(ells using Apotr)24.9(ack)20.9(er Gr)21.9(een dy)26.9(e f)9.9(ollo)21.9(wing s)9.9(timulation with plat)14.9(e-bound G)]TJ
65.8678 0 TD
.149 Tw
(PC3 CAR)Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 738.2166 101.3686 Tm
0 Tc
0 Tw
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 741.2197 101.3686 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 744.2231 101.3686 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 747.2262 101.3686 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 750.2297 101.3686 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 753.2328 101.3686 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 756.2363 101.3686 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 759.2396 101.3686 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 762.2429 101.3686 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 765.2463 101.3686 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 768.2494 101.3686 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 771.2529 101.3686 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 774.256 101.3686 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 777.2595 101.3686 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 780.2628 101.3686 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 783.2661 101.3686 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 786.2696 101.3686 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 789.2726 101.3686 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 792.2761 101.3686 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 795.2792 101.3686 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 798.2827 101.3686 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 801.2858 101.3686 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 245.1964 94.1687 Tm
-.0301 Tc
.0386 Tw
[(anti-idiotype antibody f)9.9(or 48 hours in lo)21.9(w gluc)14.9(ose \(0)19.9(.3)23.9(7mM\) media. R)9.9(epr)21.9(esentativ)26.9(e o)21.9(w plots sho)21.9(wing the 3 populations gat)14.9(ed on )]TJ
61.8486 0 TD
-.0303 Tc
.0389 Tw
(CAR+ populations)Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 738.2156 94.1687 Tm
0 Tc
0 Tw
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 740.3757 94.1687 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 742.5356 94.1687 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 744.6954 94.1687 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 746.8554 94.1687 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 749.0152 94.1687 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 751.1752 94.1687 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 753.3352 94.1687 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 755.4949 94.1687 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 245.1964 86.9686 Tm
-.03 Tc
.0024 Tw
[(in BO)43(XR10)10(30 and C)10(ontr)22(ol CAR T c)15(ells ar)22(e sho)22(wn and r)22(esults fr)22(om 2 donors ar)22(e summariz)15(ed in the gr)25(aph. )]TJ
ET
EMC
/P <>BDC
BT
/F3 1 Tf
7 0 0 7 589.0383 86.9686 Tm
0 Tw
(\(F\))Tj
ET
EMC
/P <>BDC
BT
/F2 1 Tf
7 0 0 7 599.2301 86.9686 Tm
.0024 Tw
[( Ki6)22(7 le)24(v)27(els w)22(e)0(r)22(e)0( quantitat)15(ed in CAR+ c)15(ells)]TJ
ET
EMC
/P <>BDC
BT
7 0 0 7 738.2155 86.9686 Tm
0 Tc
0 Tw
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 245.1964 79.7685 Tm
-.0301 Tc
.0337 Tw
[(in BO)42.9(XR10)9.9(30 and C)9.9(ontr)21.9(ol CAR T c)14.9(ells f)9.9(ollo)21.9(wing s)9.9(timulation with plat)14.9(e-bound GPC3 CAR anti-idiotype antibody f)9.9(or 48 hours in lo)21.9(w )]TJ
61.9305 0 TD
.0336 Tw
[(gluc)15(ose \(0)20(.3)24(7mM\))]TJ
ET
EMC
/P <>BDC
BT
7 0 0 7 738.2156 79.7685 Tm
0 Tc
0 Tw
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 245.1964 72.5686 Tm
-.0301 Tc
.0106 Tw
[(media. R)9.9(epr)21.9(esentativ)26.9(e o)21.9(w plots of Ki6)21.9(7 le)23.9(v)26.9(els gat)14.9(ed on CAR+ populations in BO)42.9(XR10)9.9(30 and C)9.9(ontr)21.9(ol CAR T c)14.9(ells ar)21.9(e sho)21.9(wn and r)21.9(esu)]TJ
62.4234 0 TD
[(lts fr)22(om 2 donors)]TJ
ET
EMC
/P <>BDC
BT
7 0 0 7 738.2156 72.5686 Tm
0 Tc
0 Tw
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 245.1964 65.3686 Tm
-.0301 Tc
-.0003 Tw
[(ar)21.9(e summariz)14.9(ed in the gr)24.9(aph. Samples w)21.9(e)-.1(r)21.9(e)-.1( analy)5.9(z)14.9(ed using an A)26.9(ttune Nxt o)21.9(w cyt)14.9(omet)14.9(er \(T)15.9(hermo Fisher Scientic)14.9(\). Data w)21.9(e)-.1(r)21.9(e)-.1( analy)]TJ
62.2581 0 TD
[(z)15(ed using Flo)22(wJo)]TJ
ET
EMC
/P <>BDC
BT
7 0 0 7 738.2159 65.3686 Tm
0 Tc
0 Tw
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 245.1964 58.1687 Tm
-.0301 Tc
.0001 Tw
[(v)84.9(.)49.9(10 and OMIQ. Statis)9.9(tical analy)16.9(sis w)15.9(as perf)9.9(ormed on gr)24.9(aphs with n=3 donors with pair)21.9(ed t-t)14.9(es)9.9(t, *p<0)19.9(.)19.9(05 )]TJ
48.364 0 TD
0 Tc
0 Tw
( )Tj
T*
(.)Tj
ET
EMC
/Artifact <>BDC
.166 .002 0 0 k
1111.181 541.927 284.881 17.008 re
f
EMC
/P <>BDC
BT
7 0 0 7 1116.9877 551.4891 Tm
1 .89 0 0 k
-.0201 Tc
.0001 Tw
[(Higher number of mit)14.9(ochondria per c)14.9(ell and mor)21.9(e tubular appear)24.9(anc)14.9(e \(as)9.9(sociat)14.9(ed )]TJ
ET
EMC
/P <>BDC
BT
7 0 0 7 1392.0754 551.4891 Tm
0 Tc
0 Tw
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 1119.6901 544.4891 Tm
-.0201 Tc
.0001 Tw
[(with memory T c)14.9(ells)19.9(\) ar)21.9(e observ)26.9(ed in BO)42.9(XR10)9.9(30 T c)14.9(ells aft)14.9(er chr)21.9(onic s)9.9(timulation)]TJ
ET
EMC
/Artifact <>BDC
.83 .01 0 0 k
749.764 82.913 566.93 17.008 re
f
EMC
/P <>BDC
BT
/F3 1 Tf
9.999 0 0 10 1002.5614 88.4172 Tm
1 g
0 Tc
0 Tw
[(C)10(onclusions)]TJ
ET
EMC
/P <>BDC
BT
/F1 1 Tf
7 0 0 7 749.7635 74.4787 Tm
1 .89 0 0 k
()Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 755.4329 74.4787 Tm
.0027 Tc
.0723 Tw
[(F)14.9(ollo)16.9(wing manuf)14.9(actur)17.9(e)9.9(,)-.1( BO)32.9(XR10)9.9(30 T c)14.9(ells ha)16.9(v)21.9(e)-.1( a higher fr)17.9(equency of les)9.9(s di)9.9(e)-.1(r)17.9(e)-.1(ntiat)14.9(ed T)]TJ
ET
EMC
/P <>BDC
BT
4.2 0 0 4.2 1078.6327 74.4187 Tm
.0047 Tc
0 Tw
(SCM)Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 1088.1254 74.4787 Tm
.0027 Tc
.0723 Tw
[( population and mor)17.9(e CD2)7.9(7+ c)14.9(ells in all memory T c)14.9(ells subsets)]TJ
ET
EMC
/P <>BDC
BT
7 0 0 7 1317.2256 74.4787 Tm
0 Tc
0 Tw
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 1319.8506 74.4787 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 1322.4756 74.4787 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 1325.1006 74.4787 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 1327.7256 74.4787 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 1330.3506 74.4787 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 1332.9756 74.4787 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 1335.6006 74.4787 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 1338.2256 74.4787 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 1340.8506 74.4787 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 1343.4756 74.4787 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 1346.1006 74.4787 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 755.4329 67.1786 Tm
-.0001 Tc
.0001 Tw
[(\(indicating f)9.9(e)17.9(w)16.9(er t)14.9(erminally di)9.9(er)17.9(entiat)14.9(ed c)14.9(ells)19.9(\) c)14.9(ompar)17.9(ed t)14.9(o)-.1( C)9.9(ontr)17.9(ol CAR T c)14.9(ells lacking the GO)37.9(T2 tr)24.9(ansgene)9.9(.)]TJ
ET
EMC
/P <>BDC
BT
7 0 0 7 1145.0673 67.1786 Tm
0 Tc
0 Tw
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 749.7635 59.8786 Tm
()Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 755.4329 59.8786 Tm
.0517 Tw
[(W)10(hen e)20(xposed t)15(o)0( s)10(t)0(r)18(e)0(s)10(sful c)15(onditions such as lo)17(w gluc)15(ose and chr)18(onic s)10(timulation, BO)33(XR10)10(30 T c)15(ells e)20(xhibit \(i\) impr)18(o)22(v)22(ed metabol)]TJ
66.4088 0 TD
[(ic tnes)10(s, \(ii\) incr)18(eased c)15(ell)]TJ
ET
EMC
/P <>BDC
BT
7 0 0 7 1317.2222 59.8786 Tm
0 Tw
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 755.4329 52.5788 Tm
.0041 Tc
.0709 Tw
[(surviv)14.9(al and pr)17.9(olif)9.9(er)24.9(ativ)21.9(e capacity)84.9(, \(iii\) multiple char)24.9(act)14.9(eris)9.9(tics of les)9.9(s)-.1( di)9.9(er)17.9(entiat)14.9(ed/)79.9(early memory T c)14.9(ell populations and \()]TJ
63.0456 0 TD
.0708 Tw
[(iv\) r)17.9(e)0(t)15(ention of e)10(ect)14.9(or functions)]TJ
ET
EMC
/P <>BDC
BT
7 0 0 7 1317.2251 52.5788 Tm
0 Tc
0 Tw
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 755.4329 45.2787 Tm
-.0002 Tc
.0002 Tw
[(r)17.8(elativ)21.8(e t)14.8(o)-.2( C)9.8(ontr)17.8(ol CAR T c)14.8(ells.)]TJ
ET
EMC
/P <>BDC
BT
7 0 0 7 863.3939 45.2787 Tm
0 Tc
0 Tw
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 749.7635 37.9787 Tm
()Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 755.4329 37.9787 Tm
.0334 Tw
[(T)10(he enrichment of early memory T c)15(ell subsets and r)18(esis)10(tanc)15(e t)15(o)0( t)15(erminal di)10(er)18(entiation in BO)33(XR10)10(30 ar)18(e lik)15(ely the r)18(esult of r)18(e)]TJ
64.4102 0 TD
[(inf)10(or)18(c)15(ed metabolic tnes)10(s fr)18(om)]TJ
ET
EMC
/P <>BDC
BT
7 0 0 7 1317.2222 37.9787 Tm
0 Tw
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 755.4329 30.6786 Tm
-.0001 Tc
.0001 Tw
[(e)19.9(x)20.9(ogenous GO)37.9(T2 and sugges)9.9(ts that BO)32.9(XR10)9.9(30 T c)14.9(ells will e)19.9(xhibit superior persis)9.9(t)14.9(enc)14.9(e and dur)24.9(able function in the tr)17.9(eatment of so)]TJ
65.343 0 TD
0 Tc
0 Tw
(lid tumors.)Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 1252.4822 30.6786 Tm
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 749.7635 23.3786 Tm
()Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 755.4329 23.3786 Tm
.0298 Tw
[(T)10(hese r)18(esults support the ongoing Ph1/)20(2 BO)33(XR10)10(30 clinical s)10(tudy and w)10(arr)25(ant futur)18(e in)13(v)22(e)0(s)10(tigation of GO)38(T2 and other tr)25(ansgenes t)]TJ
66.0861 0 TD
[(o enhanc)15(e metabolic tnes)10(s)]TJ
ET
EMC
/P <>BDC
BT
7 0 0 7 1317.2222 23.3786 Tm
0 Tw
( )Tj
ET
EMC
/P <>BDC
BT
7 0 0 7 755.4329 16.0786 Tm
[(of c)15(ellular ther)25(apies.)]TJ
ET
EMC
/P <>BDC
BT
/F5 1 Tf
7 0 0 7 827.7465 16.0786 Tm
( )Tj
ET
EMC
/P <>BDC
BT
/F4 1 Tf
7 0 0 7 1002.0471 16.0786 Tm
-.0001 Tc
.0001 Tw
[(F)21.9(or more inf)9.9(orma)9.9(tion, please c)10.9(ontact r)14.9(anger@sotio)19.9(.)60.9(c)10.9(om)]TJ
ET
EMC
/Artifact <>BDC
.249 .003 0 0 k
749.763 341.43 646.299 11.339 re
f
EMC
/P <>BDC
BT
/F1 1 Tf
7 0 0 7 859.9971 344.6576 Tm
1 .89 0 0 k
0 Tc
0 Tw
[(Figur)18(e 4: BO)33(XR10)10(30 T c)15(ells e)20(xhibit superior e)10(ect)15(or function under s)10(t)0(r)18(e)0(s)10(s)0( c)15(onditions as c)15(ompar)18(ed t)15(o)0( C)10(ontr)18(ol CAR T c)15(ells)]TJ
ET
EMC
/Artifact <>BDC
.166 .002 0 0 k
749.764 309.433 155.905 28.346 re
f
EMC
/Figure <>BDC
Q
q
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