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Safety and efficacy of a novel anti-CD19 chimeric antigen receptor T cell product targeting a membrane-proximal domain of CD19 with fast on- and off-rates against non-Hodgkin lymphoma: a first-in-human study

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Abstract
Background
Commercial anti-CD19 chimeric antigen receptor T-cell therapies (CART19) are efficacious against advanced B-cell non-Hodgkin lymphoma (NHL); however, most patients ultimately relapse. Several mechanisms contribute to this failure, including CD19-negative escape and CAR T dysfunction. All four commercial CART19 products utilize the FMC63 single-chain variable fragment (scFv) specific to a CD19 membrane-distal epitope and characterized by slow association (on) and dissociation (off) rates. We hypothesized that a novel anti-CD19 scFv that engages an alternative CD19 membrane-proximal epitope independent of FMC63 and that is characterized by faster on- and off-rates could mitigate CART19 failure and improve clinical efficacy.

Methods
We developed an autologous CART19 product with 4-1BB co-stimulation using a novel humanized chicken antibody (h1218). This antibody is specific to a membrane-proximal CD19 epitope and harbors faster on/off rates compared to FMC63. We tested h1218-CART19 in vitro and in vivo using FMC63-CART19-resistant models. We conducted a first-in-human multi-center phase I clinical trial to test AT101 (clinical-grade h1218-CART19) in patients with relapsed or refractory (r/r) NHL.

Results
Preclinically, h1218- but not FMC63-CART19 were able to effectively eradicate lymphomas expressing CD19 point mutations (L174V and R163L) or co-expressing FMC63-CAR19 as found in patients relapsing after FMC63-CART19. Furthermore, h1218-CART19 exhibited enhanced killing of B-cell malignancies in vitro and in vivo compared with FMC63-CART19. Mechanistically, we found that h1218-CART19 had reduced activation-induced cell death (AICD) and enhanced expansion compared to FMC63-CART19 owing to faster on- and off-rates. Based on these preclinical results, we performed a phase I dose-escalation trial, testing three dose levels (DL) of AT101 (the GMP version of h1218) using a 3 + 3 design. In 12 treated patients (7 DLBCL, 3 FL, 1 MCL, and 1 MZL), AT101 showed a promising safety profile with 8.3% grade 3 CRS (n = 1) and 8.3% grade 4 ICANS (n = 1). In the whole cohort, the overall response rate was 91.7%, with a complete response rate of 75.0%, which improved to 100% in DL-2 and -3. AT101 expansion correlates with CR and B-cell aplasia.

Conclusions
We developed a novel, safe, and potent CART19 product that recognizes a membrane-proximal domain of CD19 with fast on- and off-rates and showed significant efficacy and promising safety in patients with relapsed B-cell NHL.

Trial registration
NCT05338931; Date: 2022–04-01.
Author(s)
Yunlin ZhangRuchi P. PatelKi Hyun KimHyungwoo ChoJae-Cheol JoSeong Hyun JeongSung Yong OhYoon Seok ChoiSung Hyun KimJi Hyun LeeMathew AngelosPuneeth GuruprasadIvan CohenOsitadimma UgwuanyiYong Gu LeeRaymone PajarilloJong Hyun ChoAlberto CarturanLuca ParuzzoGuido GhilardiMichael WangSoohwan KimSung-Min KimHyun-Jong LeeJi-Ho ParkLeiguang CuiTae Bum LeeIn-Sik HwangYoung-Ha LeeYong-Jun LeePatrizia PorazziDongfang LiuYoon LeeJong-Hoon KimJong-Seo LeeDok Hyun YoonJunho ChungMarco Ruella
Issued Date
2023
Type
Article
Keyword
CAR T cellsCD19CD19 mutationsEpitope maskingFast on- and off-rateLeukemiaLow avidityLymphomaMembrane-proximal epitopeResistance
DOI
10.1186/s12943-023-01886-9
URI
https://oak.ulsan.ac.kr/handle/2021.oak/16615
Publisher
Molecular Cancer
Language
영어
ISSN
1476-4598
Citation Volume
22
Citation Number
1
Citation Start Page
1
Citation End Page
23
Appears in Collections:
Medicine > Nursing
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