Abstract
T cells expressing chimeric antigen receptors (CARs) recognizing CD19 epitopes have produced remarkable anti-tumor effects in patients with B-cell malignancies. However, cancer cells lacking recognized epitopes can emerge, leading to relapse and death. Thus, CAR T cells targeting different epitopes on different antigens could improve immunotherapy. The Lym-1 antibody targets a conformational epitope of Human Leukocyte Antigen-antigen D Related (HLA-DR) on the surface of human B-cell lymphomas. Lym-1 CAR T cells were thus generated for evaluation of cytotoxic activity towards lymphoma cells in vitro and in vivo. Human T cells from healthy donors were transduced to express a Lym-1 CAR, and assessed for epitope-driven function in culture and towards Raji xenografts in NOD-scidIL2Rgammanull (NSG) mice. Lym-1 CAR T cells exhibited epitope-driven activation and lytic function against human B-cell lymphoma cell lines in culture and mediated complete regression of Raji/Luciferase-Green fluorescent protein (Raji/Luc-GFP) in NSG mice with similar or better reactivity than CD19 CAR T cells. Lym-1 CAR transduction of T cells is a promising immunotherapy for patients with Lym-1 epitope positive B-cell malignancies.
Highlights
B-cell non-Hodgkin lymphomas (B-NHL) encompass a heterogeneous group of cancers with increasing incidence [1,2]
Equal tumor eradication was achieved in the Cluster of Differentiation 19 (CD19) Chimeric antigen receptors (CARs) T cell group, except that one mouse relapsed 30 days after treatment and died on day 53 (Figure 8C)
When the Lym-1 antibody binds to a Lym-1 epitope, it can induce target cell apoptosis or autopLhyamgy-1inisaadmdiotiuosne tIogGA2DaCanCtiobrodCyDdCeveeffleocptesd[2i1n,2th2]e. eTaorlyde1t9e8r0ms i[n1e5]i.fCthliinsiceaflfescttudofieLsycmon-1firwmaesd siutsffiscaifeenttytaonedrapdoicteantetiRalajbiecneellfsitininththiseintrevaivtmo emnot doeflB, a-cgelrlomupaloigf nmaincecireesc[e2i4v]e.dIn10a0dμdgitihounm, wanhecnhibmoeurnicd Lym-1 on days 7, 9, and 11
Summary
B-cell non-Hodgkin lymphomas (B-NHL) encompass a heterogeneous group of cancers with increasing incidence [1,2]. CD19 CAR T cell treatment of R/R B-NHL has been less successful, it has improved objective response rates (ORR) from 20–30% [10] to 79%, with complete remission rates of 30–50% [11,12,13,14] which is 7-fold higher than historical results [10,11]. ETpCiteolplse-Driven Upregulation of CD107a and Epitope-Dependent Cytotoxicity of Lym-1 and CD19 CAR T Cells. When the Lym-1 antibody binds to a Lym-1 epitope, it can induce target cell apoptosis or autophagy in addition to ADCC or CDC effects [21,22] To determine if this effect of Lym-1 was the antitumor effect was durable throughout the 60 day experiment (Figure 8A–C). LLuucicfieferarassee bbioiolulumminineesscceennccee wwaass mmeeaassuurreedd aattddaayy66totoasasesssesspsrep-rter-etartematemntentut mtuomr bour rbduernd. eOnn. dOayn 7d,a1y077m, o10ck mtroacnks-dtruacnesddTucceedllsT, CcDel1ls, CCADR19T CceAllRs, oTrcLeyllms,-1orCLAyRmT-1ceCllAs iRn T10c0eμllLs pinho1s0p0hμaLte pbhuoffseprehdatsealbinueff(ePreBdS) swalienree (iPnBjeSc)tewderinetirnajvecetneoduisnltyra(vne=no5u).sFlyo(rnth=e5c).hFLoyrmth-1e achnLtiybmod-1yagnrtoibuopd, y10g0roμugp,ch10L0yμmg-1chwLaysmi-n1jewctaesd ininjetcrtaevdeninoturasvlyeninou10sl0yμilnP1B0S0 oμnl PdBaSyso7n, d9a, yans d7,191,.a(nBd) Q11u.a(nBt)ifQicuaatinotnifiocfabtiioonluomf binioelsucmenicneesscheonwcensihno“wAn.” in(C(A) K).a(pCl)anK–aMpleaine–rMpleoiterofpsloutrvoifvsaulrovfivmailcoef. m* =icpe.
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