Introduction: CD19 CAR T therapy has advanced treatment of relapsed/refractory (r/r) Acute Lymphoblastic Leukemia (B-ALL). However, several challenges remain including: (1) considerable toxicity of CD19 CAR therapy; (2) the need for long-term persistence to deliver sustained response; (3) requirement for robust, cost effective manufacture.
All current CD19 CARs for B-ALL use a high affinity CD19 binder, fmc63. We hypothesized that a CD19 binder with a lower affinity due to a fast binding off-rate, would result in more physiological T-cell activation, reduce toxicity and improve engraftment. Preliminary pediatric clinical data of a novel CD19 CAR (AUTO1) supports this assertion.
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. AUTO1 may be particularly well suited to this patient group. We describe preliminary data testing AUTO1 in adults with r/r B-ALL. Further, to address large-scale manufacture, we compare standard manufacturing with a closed semi-automated manufacture process.
Manufacturing: AUTO1 utilizes non-mobilized autologous leucapheresate. The first 6 trial products were generated using a standard dynal bead/WAVE Bioreactor process and subsequent products using a closed CliniMACS® Prodigy/ TransACTTM process.
Study design: ALLCAR19 (NCT02935257) is a phase I/II study recruiting subjects 16-65y with r/r B ALL. Lymphodepletion with fludarabine (30 mg/m2 x3) and cyclophosphamide (60mg/kg x1) is followed by split dose CAR T infusion (Day 0: if ≥20% BM blasts, infuse 10 x 106 CAR T; if <20% BM blasts, infuse 100 x 106 CAR T. Day +9: if no Grade 3-5 CRS/ CRES, infuse Dose 2, to a total dose of 410 x106 CAR T). Study endpoints include feasibility of manufacture, grade 3-5 toxicity and remission rates at 1 and 3 months.
Results: To date (data cut off Dec 13 2018), 13 patients of median age 51y (range 18 - 63) were leucapheresed and 12 products manufactured. 9 infused patients (5 with ≥ 70% BM blasts) showed excellent peak CAR T expansion (median 367 CAR/uL blood). 0/9 patients had CRS ≥ Grade 3 by Lee criteria and 1/9 had CRES Grade 3 that resolved with steroids. 1/9 died of sepsis within the first month. Two patients are pending infusion. 7/8 (88%) response evaluable patients achieved CR at 1 month and all 7 had ongoing CAR T persistence and B cell aplasia at last follow up (median follow-up 2.5 months (range 1-7.5)). 1/7 had a CD19 negative relapse, 1/7 in molecular CR died of sepsis but 5/7 remain on study and continue in flow/molecular MRD negative remission.
Conclusions: AUTO1 delivers excellent early remission rates and CAR expansion/ persistence. Despite high tumour burden, the safety profile compares favorably to other CD19 CARs, consistent with experience in the pediatric cohort. Updated results will be presented.
Citation Format: Claire Roddie, Maeve A. O'Reilly, Juliana Dias Alves Pinto, Ketki Vispute, Fahetullah Syed, Lauren Nickolay, Yashma Pathak, Alexia Gali, Helen Lowe, Kim Champion, Graham Wheeler, Jo Olejnik, Maria Marzolini, Martin A. Pule, Karl S. Peggs. AUTO1, a novel fast off CD19CAR delivers durable remissions and prolonged CAR T cell persistence with low CRS or neurotoxicity in adult ALL [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT105.