A PHASE I TRIAL OF 19‐28Z CAR‐T CELLS POST‐HIGH DOSE THERAPY AND AUTOLOGOUS TRANSPLANTATION (HDT‐ASCT) FOR RELAPSED AND REFRACTORY (R/R) B‐CELL NON‐HODGKIN LYMPHOMA (B‐NHL)

Abstract

Introduction: HDT-ASCT is the standard of care for patients with rel/ ref diffuse large B-cell lymphoma (DLBCL). Herein, we report safety and efficacy data on 15 patients of our phase I clinical trial of 19-28z CAR-T post HDT-ASCT for poor-risk r/r aggressive B-NHL (NCT01840566). Methods: Eligibility for this study includes poor-risk r/r aggressive histology B-NHL chemosensitive to salvage therapy with either: 1) FDG- (Table Presented) PET (+) following 2 cycles of salvage therapy or 2) bone marrow involvement of B-NHL at time of r/r disease. T cells were retroviral transduced with anti-CD19 scFV linked to CD28 and CD3η signaling domains. Patients underwent BEAM conditioned HDT-ASCT and 19-28z CAR-T were administered on days +2 and +3. Results: Fifteen patients with a median age of 61 years (range: 34-75 years) were treated on study, n = 14 at dose level (DL) #1 (5 x106 19-28z CAR-T/kg) and n = 1 at DL #2 (1 x107 CAR-T/kg). See table for full characteristics and status following study treatment. One dose limiting toxicity was observed at both DL #1 and DL #2. Ten of 15 patients experienced toxicity with either grade 2-4 neurotoxicity and/or cytokine-release syndrome (CRS). All study related toxicities were fully reversible with tocilizumab +/- corticosteroids. One death on study was secondary to pulmonary mucormycosis and not attributable to 19-28z CAR-T. Toxicity events were associated with longer persistence of 19-28z CAR-T at a median of 11 days compared to a median 4 days in patients without toxicity (p = 0.05). Peak 19-28z CAR-T expansion did not correlate to toxicity. Comprehensive serial serum cytokine analysis revealed upregulation of IFNgamma (p < 0.001) and a trend toward upregulation of IL-10 (p = 0.07) were associated with toxicity following 19-28z CAR-T infusion. At a median follow-up for survivors of 31 months, the 2 year progression-free survival (PFS) is 30% (95% CI: 20-70%, Figure 1). There was no observable associated between 19-28z CAR-T peak expansion, persistence in days or cytokine changes and PFS. Two of the 10 patients with progression of disease (POD) were CD19 (-) on re-biopsy. Conclusions: This study established safety of 19-28z CAR-T at 5 x106 19-28z CAR-T/kg following consolidative HDT-ASCT for poor-risk rel/ ref aggressive B-NHL. Persistence of 19-28z CAR-T was associated with toxicity, though not efficacy as measured in PFS. Strategies to enhance durability of response to CAR-T in this setting are in development.