Reducing Ex Vivo Culture Improves the Antileukemic Activity of Chimeric Antigen Receptor (CAR) T Cells

Cancer Immunology Research - Tập 6 Số 9 - Trang 1100-1109 - 2018
Saba Ghassemi1,2, Selene Nuñez-Cruz1,2, Roddy S. O’Connor1,2,3, Joseph A. Fraietta1,2,3, Prachi Patel1,2, John Scholler1,2, David M. Barrett4, Stefan Lundh1, Megan M. Davis1,2, Felipe Bedoya1,2, Changfeng Zhang1, John Leferovich1,2, Simon F. Lacey1,2, Bruce L. Levine1,2, Stephan A. Grupp4, Carl H. June1,2,3, J. Joseph Melenhorst1,2, Michael C. Milone1,2
11Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
22Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
33Parker Institute for Cancer Immunotherapy, University of Pennsylvania, Philadelphia, Pennsylvania.
44Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.

Tóm tắt

Abstract The success of chimeric antigen receptor (CAR)–mediated immunotherapy in acute lymphoblastic leukemia (ALL) highlights the potential of T-cell therapies with directed cytotoxicity against specific tumor antigens. The efficacy of CAR T-cell therapy depends on the engraftment and persistence of T cells following adoptive transfer. Most protocols for T-cell engineering routinely expand T cells ex vivo for 9 to 14 days. Because the potential for engraftment and persistence is related to the state of T-cell differentiation, we hypothesized that reducing the duration of ex vivo culture would limit differentiation and enhance the efficacy of CAR T-cell therapy. We demonstrated that T cells with a CAR-targeting CD19 (CART19) exhibited less differentiation and enhanced effector function in vitro when harvested from cultures at earlier (day 3 or 5) compared with later (day 9) timepoints. We then compared the therapeutic potential of early versus late harvested CART19 in a murine xenograft model of ALL and showed that the antileukemic activity inversely correlated with ex vivo culture time: day 3 harvested cells showed robust tumor control despite using a 6-fold lower dose of CART19, whereas day 9 cells failed to control leukemia at limited cell doses. We also demonstrated the feasibility of an abbreviated culture in a large-scale current good manufacturing practice–compliant process. Limiting the interval between T-cell isolation and CAR treatment is critical for patients with rapidly progressing disease. Generating CAR T cells in less time also improves potency, which is central to the effectiveness of these therapies. Cancer Immunol Res; 6(9); 1100–9. ©2018 AACR.

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Cancer Immunology Research

Tập 6 Số 9

1100-1109

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