Abstract CT145: A Cancer Research UK phase I trial of anti-GD2 chimeric antigen receptor (CAR) transduced T-cells (1RG-CART) in patients with relapsed or refractory neuroblastoma

Background: Treatment of high risk neuroblastoma remains challenging; current multimodal treatment regimens achieve long term survival in Trial design: The therapeutic (1RG- CART) is autologous T-cells transduced with a gamma-retroviral vector encoding both an anti-GD2 CAR and the RQR8 suicide gene. The CAR comprises a humanized anti-GD2 single chain variable fragmentderived from the K666 antibody and CD28/CD3ζ signalling domains. Both lymphodepletion and CARTdose were escalated as follows: dose level (DL) 1 without lymphodepletion, DL2 with 1.2 g/m 2 cyclophosphamide and DL3 and beyond 1.2 g/m 2 cyclophosphamide and 125 mg/m 2 fludarabinefollowed by administration of a single intravenous dose of 1x10 7 /m 2 (DL1-3) or 1x10 8 /m 2 (DL4) 1RG- CART. Primary objectives are to assess safety and tolerability. Results: To date, 12 patients have been enrolled. All had relapsed/refractory neuroblastoma with measurable disease in bone (n=11), bone marrow (n=7) and/or soft tissue sites (n=9). Cell products were successfully manufactured for all patients. Median transduction efficiency was 34.5% (range 16-54%). Nine patients have been treated on DL1 (n=4), DL2 (n=1), DL3 (n=1) and DL4 (n=3) respectively. No dose limiting toxicity (DLT) was seen. For patients treated on DL1-3 (1x10 7 /m 2 ), 1RG- CARTcould not be detected in peripheral blood, and no clinical responses were seen. In contrast, expansion of 1RG- CARTcells as detected by flow cytometry and qPCR was seen in the 3 patients treated on DL4 (1x10 8 /m 2 ). In two DL4 patients, 1RG- CARTexpansion was still limited and transient (marking levels 40,000 copies/μg DNA were achieved. This patient developed Grade 2 cytokine release syndrome(Day +5) and biochemical evidence of tumour lysis (Day +21). Disease reassessment on Day +28 showed response in many sites of bone/marrow disease as measured by mIBG scintigraphy, and near complete tumour clearance in bone marrow which at baseline was heavily infiltrated with neuroblastoma. Disease progression occurred on Day +45 at which time 1RG- CARTwere no longer detectable. In the absence of DLT this prompted us to continue with DL5 (1x10 9 /m 2 ). Conclusions: These preliminary results are the first to demonstrate on-target activity in bone and bone marrow of GD2- CARTin this childhood solid tumour. Further 1RG- CARTdose escalation is warranted, and under way. Citation Format: Karin Straathof, Barry Flutter, Rebecca Wallace, Simon Thomas, Gordon Cheung, Angela Collura, Talia Gileadi, Jack Barton, Gary Wright, Sarah Inglott, David Edwards, Claire Barton, Karen Dyer, Nigel Westwood, ThaliaLoka, Sarita Depani, Karen Howe, Giuseppe Barone, Martin Pule, John Anderson. A Cancer Research UK phase I trial of anti-GD2 chimeric antigen receptor(CAR) transduced T-cells (1RG- CART) in patients with relapsed or refractory neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT145.