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Acute lymphoblastic leukemia

Vaccination to improve the persistence of CD19CAR gene-modified T cells in relapsed pediatric acute lymphoblastic leukemia

Abstract

Trials with second generation CD19 chimeric antigen receptors (CAR) T-cells report unprecedented responses but are associated with risk of cytokine release syndrome (CRS). Instead, we studied the use of donor Epstein–Barr virus-specific T-cells (EBV CTL) transduced with a first generation CD19CAR, relying on the endogenous T-cell receptor for proliferation. We conducted a multi-center phase I/II study of donor CD19CAR transduced EBV CTL in pediatric acute lymphoblastic leukaemia (ALL). Patients were eligible pre-emptively if they developed molecular relapse (>5 × 10−4) post first stem cell transplant (SCT), or prophylactically post second SCT. An initial cohort showed poor expansion/persistence. We therefore investigated EBV-directed vaccination to enhance expansion/persistence. Eleven patients were treated. No CRS, neurotoxicity or graft versus host disease (GVHD) was observed. At 1 month, 5 patients were in CR (4 continuing, 1 de novo), 1 PR, 3 had stable disease and 3 no response. At a median follow-up of 12 months, 10 of 11 have relapsed, 2 are alive with disease and 1 alive in CR 3 years. Although CD19CAR CTL expansion was poor, persistence was enhanced by vaccination. Median persistence was 0 (range: 0–28) days without vaccination compared to 56 (range: 0–221) days with vaccination (P=0.06). This study demonstrates the feasibility of multi-center studies of CAR T cell therapy and the potential for enhancing persistence with vaccination.

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Acknowledgements

We thank Profs Rob Wynn, Wendy Qian and Malcolm Brenner for oversight of the trial as the IDMC. The study was supported by the European Commission Sixth Framework Program through the CHILDHOPE - Chimaeric T-cells for the treatment of paediatric cancers project (LSHC-CT-2006-037381, specific targeted research project - STREP), the UK Leukaemia and Lymphoma Research Fund (Bloodwise), Children with Cancer UK, UK Department of Health, JP Moulton Charitable Foundation (grants to PA), Deutsche Krebshilfe, Deutsche Kinderkrebsstiftung and Löwenkinder e.V (grants to CR) and the Italian AIRC (grants to EB). MP is supported by the University College London Hospital BRC and PJA is in receipt of an NIHR Research Professorship.

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Correspondence to P J Amrolia.

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MP has received research funding from Cellectis, honoraria from Amgen and Roche and owns stock/receives salary from Autolus Ltd. PJA has received research funding from Bluebird bio and honoraria from Novartis. RR is now an employee of Genentech Inc. All other authors declare no conflict of interest.

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Supplementary Information accompanies this paper on the Leukemia website

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Rossig, C., Pule, M., Altvater, B. et al. Vaccination to improve the persistence of CD19CAR gene-modified T cells in relapsed pediatric acute lymphoblastic leukemia. Leukemia 31, 1087–1095 (2017). https://doi.org/10.1038/leu.2017.39

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