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

  • Mol Cancer. 2023 Dec 9;22(1):200. doi: 10.1186/s12943-023-01886-9.
Yunlin Zhang  #  1  2 ,  Ruchi P Patel  #  1  2 ,  Ki Hyun Kim  #  3 ,  Hyungwoo Cho  #  4 ,  Jae-Cheol Jo  5 ,  Seong Hyun Jeong  6 ,  Sung Yong Oh  7 ,  Yoon Seok Choi  6 ,  Sung Hyun Kim  7 ,  Ji Hyun Lee  7 ,  Mathew Angelos  1  2 ,  Puneeth Guruprasad  1  2 ,  Ivan Cohen  1  2 ,  Ositadimma Ugwuanyi  1  2 ,  Yong Gu Lee  1  2  8 ,  Raymone Pajarillo  1  2 ,  Jong Hyun Cho  9 ,  Alberto Carturan  1  2 ,  Luca Paruzzo  1  2 ,  Guido Ghilardi  1  2 ,  Michael Wang  1  2 ,  Soohwan Kim  3 ,  Sung-Min Kim  3 ,  Hyun-Jong Lee  3 ,  Ji-Ho Park  3 ,  Leiguang Cui  3 ,  Tae Bum Lee  3 ,  In-Sik Hwang  3 ,  Young-Ha Lee  3 ,  Yong-Jun Lee  3 ,  Patrizia Porazzi  1  2 ,  Dongfang Liu  9 ,  Yoon Lee  3 ,  Jong-Hoon Kim  3 ,  Jong-Seo Lee  10 ,  Dok Hyun Yoon  11 ,  Junho Chung  12 ,  Marco Ruella  13  14  15
Affiliations
  • 1. Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, 3400 Civic Center Boulevard, Perelman Center for Advanced Medicine, SPE 8-112, Philadelphia, PA, 19104, USA.
  • 2. Division of Hematology-Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.
  • 3. Biopharmaceutical Research Center, AbClon Inc., #1401, Ace Twin Tower1, 285 Digital-Ro, Guro-Gu, Seoul, Korea.
  • 4. Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-Ro 43-Gil, Songpa-Gu, Seoul, Korea.
  • 5. Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea.
  • 6. Ajou University Hospital, Suwon, Korea.
  • 7. Division of Hematology-Oncology, Department of Internal Medicine, Dong-A University College of Medicine, Busan, Korea.
  • 8. College of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Korea.
  • 9. Department of Pathology, Immunology and Laboratory Medicine, Rutgers New Jersey Medical School, Newark, NJ, USA.
  • 10. Biopharmaceutical Research Center, AbClon Inc., #1401, Ace Twin Tower1, 285 Digital-Ro, Guro-Gu, Seoul, Korea. [email protected].
  • 11. Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-Ro 43-Gil, Songpa-Gu, Seoul, Korea. [email protected].
  • 12. Cancer Research Institute, Seoul National University College of Medicine, Suite 510, Samsung Cancer Research Building, 103 Daehak-Ro, Jongno-Gu, Seoul, Korea. [email protected].
  • 13. Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, 3400 Civic Center Boulevard, Perelman Center for Advanced Medicine, SPE 8-112, Philadelphia, PA, 19104, USA. [email protected].
  • 14. Division of Hematology-Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA, USA. [email protected].
  • 15. Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA. [email protected].
  • # Contributed equally.
PMID: 38066564 DOI: 10.1186/s12943-023-01886-9
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.

Keywords
CAR T cells; CD19; CD19 mutations; Epitope masking; Fast on- and off-rate; Leukemia; Low avidity; Lymphoma; Membrane-proximal epitope; Resistance.
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