In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 8_Supplement ( 2023-04-14), p. CT130-CT130
Abstract:
Background and Preliminary Data: All the FDA-approved CD19 CAR-T cell therapies are based on an antigen-binding domain (scFv) based on the FMC63 antibody which binds to the membrane-distal region of CD19 to an epitope encoded by exons 3 and 4 (Klesmith JR, Biochemistry, 2019; Zhang Z, JITC, 2020). While these CART19 products are very effective in the clinic, the majority of patients still do not respond or eventually relapse due to several mechanisms of resistance, including T cell dysfunction and epitope CD19-negative escape. Novel strategies to enhance the activity of CART cells and reduce escape are critically needed. We recently demonstrated that modifications of the binding region of the CAR (scFv) (Singh N., Nat Med, 2021) can drastically change the interaction between the CAR T cell and the cancer cells, potentially improving the anti-tumor effect. To this goal, we developed a novel anti-CD19 antibody clone (1218) that binds to a membrane-proximal epitope of CD19 (exon 2 region K59-K63) thereby not competing with FMC63. We developed a novel CART19, called AT101, using a humanized 1218 scFv along with 4-1BB costimulatory and CD3zeta domain in a lentiviral backbone. In preclinical models, AT101 showed more potent in vitro cytotoxicity against CD19-positive B lymphoma cells in a long-term killing assay and in a B-ALL (NALM6) in vivo model as compared to the control of FMC63 based CAR-T cells. In addition, differently than FMC63-based CART, AT101 could target tumor cells expressing point mutations of CD19 that are associated with relapse post-CART19 (FMC63) (Zhang Z, JITC, 2020) and leukemic blasts aberrantly expressing FMC63 CAR19 on their surface (Ruella M, Nat Med, 2018). Based on the preclinical efficacy and safety, a phase 1 clinical trial testing autologous AT101 was started for patients with relapsed and refractory B-cell non-Hodgkin lymphoma. Trial Design and Methods: This open-label, multi-center, first-in-human Phase 1 study will assess the safety and feasibility of AT101 in patients with relapsed or refractory B cell non-Hodgkin lymphoma. Key eligibility criteria include patients aged ≥19 years of age with histologically confirmed relapsed or refractory aggressive B-cell non-Hodgkin lymphoma. In this phase 1 trial, patients (n=3 per dose level; up to n=18 in total) are treated with AT101 in 3 dose-escalation cohorts based on a standard 3 + 3 design. CART doses are 2.0 × 105, 1.0 × 106, or 5.0 × 106 CAR+T cells/kg. The primary objective is to determine the safety, the maximum tolerated dose (MTD), and the recommended phase 2 dose (RP2D) of AT101 in participants following lymphodepletion with cyclophosphamide and fludarabine (250 mg/m2 and 25 mg/m2). The secondary objective is to evaluate the preliminary efficacy assessments (overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), event-free survival (EFS), and pharmacokinetics of AT101. Exploratory objectives include assessment of CD19 expression and cytokines in the blood. Patients will be followed for safety for at least 60 months post AT101 infusion. Clinical trial registry number: NCT05338931. As of January 11, 2023, AT101 has been infused to six patients in cohort 1 and three patients in cohort 2. Detailed results will be presented at the meeting. Citation Format: Yunlin Zhang, Ki Hyun Kim, Dok Hyun Yoon, Ruchi P. Patel, Jae-Cheol Jo, Hyungwoo Cho, Jong-Ho Lee, Hyun-Jong Lee, Lei-Guang Cui, In-Sik Hwang, Young Ha Lee, Jong-Hoon Kim, Yong Gu Lee, Puneeth Guruprasad, Jong-Seo Lee, Junho Chung, Marco Ruella. An open label, dose escalation, phase 1 study of AT101, a novel CD19-directed CAR-T cell therapy targeting a membrane-proximal epitope of CD19, in patients with relapsed or refractory B cell non-Hodgkin lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT130.
Type of Medium:
Online Resource
ISSN:
1538-7445
DOI:
10.1158/1538-7445.AM2023-CT130
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2023
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2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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