First-in-human trial of GT719, a novel stem cell-derived allogeneic anti-CD19 CAR-iNKT cell therapy for relapsed/refractory B cell malignancies
Year: 2025
Type: conference-abstract
Abstract: Background and Significance:Adoptive cell therapy, particularly CAR-T therapy, has transformed cancer treatment, showing remarkable efficacy in hematologic malignancies. FDA-approved CAR-T products targeting CD19 and BCMA offer hope not only to cancer patients but also those with autoimmune diseases and viral infections. However, autologous CAR-T approaches are limited by high cost, lengthy manufacturing, and inadequate T cells in heavily pretreated patients, spurring interest in off-the-shelf allogeneic CAR-T therapies with broader accessibility and lower cost. Invariant natural killer T (iNKT) cells are promising candidates for allogeneic cell therapy due to their unique biology. They recognize lipid antigens via CD1d, a non-polymorphic MHC I-like molecule, enabling them to avoid inducing graft-versus-host disease (GvHD). CAR-engineered iNKT cells offer several advantages over conventional CAR-T cells: multi-modal tumor killing, modulation of the tumor microenvironment, improved infiltration, and bone marrow homing. However, their rarity in peripheral blood (0.001%–1%) presents a major obstacle for clinical use. To overcome this, we developed GT719, a novel anti-CD19 CAR-iNKT cell therapy derived from in vitro differentiation of cord blood CD34+ hematopoietic stem cells. Rational CAR design and optimized manufacturing enable large-scale production, potentially treating thousands of patients per batch. Preclinical studies demonstrate GT719 targets malignant B cells via multiple mechanisms: CAR-driven cytotoxicity, invariant TCR activity, NK receptor signaling, and selective depletion of tumor-associated macrophages and myeloid-derived suppressor cells. These findings support clinical evaluation of GT719. Study Design and Methods:This is a single-center, single-arm, open-label pilot trial conducted at the Chinese Academy of Medical Sciences Hematology Hospital in Tianjin, China (ClinicalTrials.gov: NCT06948981). The study population includes adults (≥18 years) with relapsed/refractory CD19-positive B cell malignancies, including B cell non-Hodgkin lymphoma (B-NHL) and B cell acute lymphoblastic leukemia (B-ALL). Key Inclusion Criteria: Relapsed/refractory CD19+ B-ALL (≥5% marrow blasts), Ph+ ALL resistant/intolerant to ≥2 TKIs (excluding T315I mutation), or B-NHL (aggressive/indolent) unresponsive to prior therapies. Key Exclusion Criteria: History or active CNS/testicular leukemia/lymphoma, recent HSCT, prior CD19 CAR-T/NK therapy. Treatment: This is a classical 3+3 dose-escalation design evaluating doses of 5 × 10⁸ and 1 × 10⁹ cells per patient. Lymphodepletion with cyclophosphamide and fludarabine is administered from Day –5 to Day –2. GT719 is infused on Day 0. The DLT evaluation window is from Day 1 to Day 28. AEs are graded using CTCAE v5.0. Endpoints: 1) Primary: Incidence and severity of DLTs and AEs within 28 days post-infusion; 2) Secondary: 3-month ORR, best overall response (BOR), progression-free survival (PFS), overall survival (OS), time to peak expansion, peak level AUC, and GT719 persistence; 3) Exploratory: Changes in peripheral immune cell populations and cytokine profiles over time. Statistics: Up to 24 patients will be enrolled. DLTs and ORR will be summarized with 95% confidence intervals (CI) via the Clopper-Pearson method. Duration of response (DOR), PFS, and OS will be analyzed using the Kaplan-Meier method. Summary: This first-in-human investigator-initiated trial evaluates the safety, DLTs, and recommended dose of GT719 for patients with CD19+ B cell malignancies. Preliminary safety data will be presented at the meeting.
Source: Blood
Authors: Dehui Zou, Wei LIU, Yan Xu, Huimin Liu, Yi Wang, Sisi Feng, Xiaona Xu, He Zhang, Ershao Zhang, Jiang Li, Jingman Wang, Jing Hao, Ning Wang, Huiping Zheng, Yin Cheng, Jun Cui, Jingwei Sun, Yarong Liu
Language: English
Topic: CAR-T cell therapy research
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4417010091
Cites:
Cited by:
Related to: