First-in-human trial of GT719, a novel stem cell-derived allogeneic anti-CD19 CAR-iNKT cell therapy for relapsed/refractory B cell malignancies

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.