TY - JOUR
T1 - Sleeping Beauty–engineered CAR T cells achieve antileukemic activity without severe toxicities
AU - Magnani, Chiara F.
AU - Gaipa, Giuseppe
AU - Lussana, Federico
AU - Belotti, Daniela
AU - Gritti, Giuseppe
AU - Napolitano, Sara
AU - Matera, Giada
AU - Cabiati, Benedetta
AU - Buracchi, Chiara
AU - Borleri, Gianmaria
AU - Fazio, Grazia
AU - Zaninelli, Silvia
AU - Tettamanti, Sarah
AU - Cesana, Stefania
AU - Colombo, Valentina
AU - Quaroni, Michele
AU - Cazzaniga, Giovanni
AU - Rovelli, Attilio
AU - Biagi, Ettore
AU - Galimberti, Stefania
AU - Calabria, Andrea
AU - Benedicenti, Fabrizio
AU - Montini, Eugenio
AU - Ferrari, Silvia
AU - Introna, Martino
AU - Balduzzi, Adriana
AU - Valsecchi, Maria Grazia
AU - Dastoli, Giuseppe
AU - Rambaldi, Alessandro
AU - Biondi, Andrea
N1 - Funding Information:
Authorship note: CFM and G Gaipa share first authorship. A Rambaldi and A Biondi are co–senior authors. Conflict of interest: The Tettamanti Foundation has filed a patent application for the technology used in this report (European patent application 15801344.1; PCT/ EPO2015/075980), and CFM, ST, EB, and A Biondi are inventors. The technology was licensed to Formula Pharmaceuticals for further development. Formula Pharmaceuticals provided a research grant to support the current academic study. Copyright: © 2020, American Society for Clinical Investigation. Submitted: April 6, 2020; Accepted: July 29, 2020; Published: October 12, 2020. Reference information: J Clin Invest. 2020;130(11):6021–6033. https://doi.org/10.1172/JCI138473.
Funding Information:
FUNDING. This study was supported by grants from the Fondazione AIRC per la Ricerca sul Cancro (AIRC); Cancer Research UK (CRUK); the Fundación Científica de la Asociación Española Contra el Cáncer (FC AECC); Ministero Della Salute; Fondazione Regionale per la Ricerca Biomedica (FRRB).
Publisher Copyright:
Copyright: © 2020, American Society for Clinical Investigation.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/11/2
Y1 - 2020/11/2
N2 - BACKGROUND. Chimeric antigen receptor (CAR) T cell immunotherapy has resulted in complete remission (CR) and durable response in highly refractory patients. However, logistical complexity and high costs of manufacturing autologous viral products limit CAR T cell availability. METHODS. We report the early results of a phase I/II trial in B cell acute lymphoblastic leukemia (B-ALL) patients relapsed after allogeneic hematopoietic stem cell transplantation (HSCT) using donor-derived CD19 CAR T cells generated with the Sleeping Beauty (SB) transposon and differentiated into cytokine-induced killer (CIK) cells. RESULTS. The cellular product was produced successfully for all patients from the donor peripheral blood (PB) and consisted mostly of CD3+ lymphocytes with 43% CAR expression. Four pediatric and 9 adult patients were infused with a single dose of CAR T cells. Toxicities reported were 2 grade I and 1 grade II cytokine-release syndrome (CRS) cases at the highest dose in the absence of graft-versus-host disease (GVHD), neurotoxicity, or dose-limiting toxicities. Six out of 7 patients receiving the highest doses achieved CR and CR with incomplete blood count recovery (CRi) at day 28. Five out of 6 patients in CR were also minimal residual disease negative (MRD–). Robust expansion was achieved in the majority of the patients. CAR T cells were measurable by transgene copy PCR up to 10 months. Integration site analysis showed a positive safety profile and highly polyclonal repertoire in vitro and at early time points after infusion. CONCLUSION. SB-engineered CAR T cells expand and persist in pediatric and adult B-ALL patients relapsed after HSCT. Antileukemic activity was achieved without severe toxicities.
AB - BACKGROUND. Chimeric antigen receptor (CAR) T cell immunotherapy has resulted in complete remission (CR) and durable response in highly refractory patients. However, logistical complexity and high costs of manufacturing autologous viral products limit CAR T cell availability. METHODS. We report the early results of a phase I/II trial in B cell acute lymphoblastic leukemia (B-ALL) patients relapsed after allogeneic hematopoietic stem cell transplantation (HSCT) using donor-derived CD19 CAR T cells generated with the Sleeping Beauty (SB) transposon and differentiated into cytokine-induced killer (CIK) cells. RESULTS. The cellular product was produced successfully for all patients from the donor peripheral blood (PB) and consisted mostly of CD3+ lymphocytes with 43% CAR expression. Four pediatric and 9 adult patients were infused with a single dose of CAR T cells. Toxicities reported were 2 grade I and 1 grade II cytokine-release syndrome (CRS) cases at the highest dose in the absence of graft-versus-host disease (GVHD), neurotoxicity, or dose-limiting toxicities. Six out of 7 patients receiving the highest doses achieved CR and CR with incomplete blood count recovery (CRi) at day 28. Five out of 6 patients in CR were also minimal residual disease negative (MRD–). Robust expansion was achieved in the majority of the patients. CAR T cells were measurable by transgene copy PCR up to 10 months. Integration site analysis showed a positive safety profile and highly polyclonal repertoire in vitro and at early time points after infusion. CONCLUSION. SB-engineered CAR T cells expand and persist in pediatric and adult B-ALL patients relapsed after HSCT. Antileukemic activity was achieved without severe toxicities.
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U2 - 10.1172/JCI138473
DO - 10.1172/JCI138473
M3 - Article
C2 - 32780725
AN - SCOPUS:85095461188
VL - 130
SP - 6021
EP - 6033
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 11
ER -