Clinical Evaluation of Fast-in-Time (FIT) Anti-CD19 CAR T-a Non-Viral, 2-Day Rapid Manufacture CAR T-Cell Therapy for B-Cell Malignancies

Chimeric antigen receptor (CAR) T-cell therapy has shown promise in the treatment of hematologic malignancies, but access barriers exist globally. FIT™, a non-viral, 2-day rapid manufacture autologous CAR T platform, aims to address limitations associated with current CAR T-cell therapies. Here we performed initial clinical evaluation of FIT-CD19-CAR-T, a 2nd generation CD28-CD3ζ CAR T utilizing a humanized anti-CD19 binder. This investigator-initiated trial evaluated the safety, pharmacokinetics (PK), and preliminary efficacy of FIT-CD19-CAR-T cells in 4 patients (pts) with relapsed or refractory B-cell malignancies, including a B-ALL patient (pt) with 9 prior lines of therapy (LOT) and 50% bone marrow (BM) blasts, a B-ALL pt with 2 LOT and 0.5% BM blasts, an FL pt with 4 LOT and moderate tumor burden (sum of product of diameters [SPD] 3440 mm2) and an FL pt with 2 LOT and 36% BM tumor cells. CAR T-cells were prepared within 3 days post apheresis. Three pts received 2-3 days of LD chemotherapy (cyclophosphamide 250 mg/m2/day and fludarabine 25 mg/m2/day) begun within 1 day of apheresis at the investigator's discretion and received fresh (non-frozen) FIT-CD19-CAR T-cells with a 5-day vein-to-vein time, while 1 FL is planned to receive cryopreserved CAR T-cells as per his willingness. Two ALL pts received 70k and 100k CAR-T cells/kg, while the FL pt received 600k CAR T-cells/kg. Peak CAR T-cell copy numbers were comparable to approved CD19 CAR T-cell products with Cmax occurring on days 13-14 after CAR T treatment. Overall, the treatment exhibited an acceptable safety profile with manageable cytokine release syndrome (CRS; G3 and G2 in ALL pts; no CRS in FL pt) and immune effector cell-associated neurotoxicity syndrome (ICANS; 1 case of G3 in ALL patient). All three evaluable pts have achieved complete remission as their best objective response, with ongoing MRD-negative CR for over 4 months and 6 months in the two ALL pts. One FL pt experienced disease progression at the 6-month assessment due to newly developed cervical lesions, while the original lesions continued to show ongoing metabolic remission. In conclusion, FIT-CD19-CAR-T demonstrates a favorable safety profile and encouraging initial efficacy and PK at relative low doses in pts with heavily pretreated B-cell malignancies, which may be attributable to enhanced expression of naïve and stem cell memory markers on rapidly manufactured FIT-CD19-CAR-T cells that were not expanded or activated ex vivo. Phase 1 studies are planned for continued investigation.