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
- 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 Zhang; Ruchi P. Patel; Ki Hyun Kim; Hyungwoo Cho; Jae-Cheol Jo; Seong Hyun Jeong; Sung Yong Oh; Yoon Seok Choi; Sung Hyun Kim; Ji Hyun Lee; Mathew Angelos; Puneeth Guruprasad; Ivan Cohen; Ositadimma Ugwuanyi; Yong Gu Lee; Raymone Pajarillo; Jong Hyun Cho; Alberto Carturan; Luca Paruzzo; Guido Ghilardi; Michael Wang; Soohwan Kim; Sung-Min Kim; Hyun-Jong Lee; Ji-Ho Park; Leiguang Cui; Tae Bum Lee; In-Sik Hwang; Young-Ha Lee; Yong-Jun Lee; Patrizia Porazzi; Dongfang Liu; Yoon Lee; Jong-Hoon Kim; Jong-Seo Lee; Dok Hyun Yoon; Junho Chung; Marco Ruella
- Issued Date
- 2023
- Type
- Article
- Keyword
- CAR T cells; CD19; CD19 mutations; Epitope masking; Fast on- and off-rate; Leukemia; Low avidity; Lymphoma; Membrane-proximal epitope; Resistance
- 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
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- Medicine > Nursing
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