AUTO1, a Novel Fast Off CD19CAR Delivers Durable Remissions and Prolonged CAR T Cell Persistence with Low CRS or Neurotoxicity in Adult ALL

Introduction: In adults, prognosis for B-ALL is poor, patients are more vulnerable to CD19 CAR immunotoxicity and there is currently no CD19 CAR therapeutic with acceptable toxicity and durable efficacy. We have developed a novel second generation CD19CAR (CAT-41BBz CAR), with a faster off-rate but equivalent on rate than the FMC63-41BBz CAR (Kd 116 nM vs 0.9 nM, T1/2 9s vs 4.2 hours) designed to result in more physiological T-cell activation, reduce toxicity and improve engraftment. Preliminary paediatric clinical data of this novel CD19 CAR (AUTO1) supports this assertion. We here describe preliminary data from ALLCAR19 (NCT02935257), a multi-centre, Phase I clinical study of AUTO1 as therapy for r/r adult B-ALL. Methods: Manufacturing: AUTO1 utilises non-mobilised autologous leucapheresate. The first 6 trial products were generated using a standard dynal bead/WAVE Bioreactor process and subsequent products using a semi-automated closed process. Study design: ALLCAR19 is a phase I/II study recruiting subjects 16-65y with r/r B ALL. Lymphodepletion with fludarabine (30mg/m2 x3) and cyclophosphamide (60mg/kg x1) is followed by split dose CAR T cell infusion (Day 0: if ≥20% BM blasts, infuse 10 x 106 CAR T cells ; if 5% leukemic blasts of which 6/13 (46%) had ≥50% blast. 9/13 patients (69%) received the total target split dose of 410 x 106 CAR T cells while 1/13 patients (8%) received a reduced split total dose of 51.3 x 106 CAR T cells due to manufacturing constraints. 3/13 patients (23%) received only a first dose of 10 x 106 CAR T cells. The dose was administered safely to date: No patients experienced ≥Grade 3 CRS (using Lee criteria) and only 1/13 (8%) experienced Grade 3 neurotoxicity (dysphasia) that resolved swiftly with steroids. All patients had robust CAR expansion (media