Stem cell-derived allogeneic anti-CD19 CAR-iNKT cell therapy GT719 for relapsed/refractory B cell malignancies

Background: Adoptive cell therapy, particularly CAR-T therapy, has transformed the treatment of hematologic malignancies, but autologous products remain limited by high cost, long manufacturing, and insufficient functional T cells in heavily pretreated patients. These challenges underscore the need for off-the-shelf allogeneic approaches. Invariant natural killer T (iNKT) cells are an attractive cell platform because they recognize lipid antigens via the non-polymorphic CD1d molecule, avoiding graft-versus-host disease (GvHD). CAR-engineered iNKT cells also provide multimodal tumor killing, tumor microenvironment modulation, enhanced infiltration, and natural bone marrow homing. However, their scarcity in peripheral blood poses manufacturing challenges. To address this, we developed GT719, an allogeneic anti-CD19 CAR-iNKT therapy generated through in vitro differentiation of cord blood-derived CD34 + hematopoietic stem cells. Rational CAR design and optimized manufacturing enable scalable production capable of treating thousands of patients per batch. Extensive preclinical studies show that GT719 eliminates malignant B cells through coordinated CAR-, invariant TCR-, and NK receptor-mediated cytotoxicity and selectively depletes immunosuppressive macrophages and myeloid-derived suppressor cells. Study Design and Methods: Based on promising preclinical results, a first-in-human investigator-initiated clinical trial (NCT06948981) has been launched to evaluate the safety, toxicity, dose-limiting toxicities (DLTs), and recommended treatment dose of GT719 for patients with relapsed or refractory CD19-positive B cell malignancies, including both B cell non-Hodgkin lymphoma (B-NHL) and B cell acute lymphoblastic leukemia (B-ALL). This open-label Trial in Progress begins with two single-patient acceleration cohorts testing doses of 5× 10 7 and 1 × 10 8 cells per patient, followed by a classical 3+3 dose-escalation design testing doses of 5 × 10 8 and 1 × 10 9 cells per patient. Enrolled patients undergo a standard lymphodepletion regimen consisting of cyclophosphamide and fludarabine from Day -5 to Day -2, consistent with protocols used for autologous CAR-T therapies. GT719 is administered intravenously on Day 0, and the primary safety observation window for DLTs extends from Day 1 to Day 28. Adverse events are assessed for incidence and severity according to CTCAE version 5.0. Although the trial is ongoing, we anticipate presenting preliminary safety and efficacy data for GT719 at the meeting. Clinical trial registration number: NCT06948981