Structural Design of Engineered Costimulation Determines Tumor Rejection Kinetics and Persistence of CAR T Cells

Zeguo Zhao; Maud Condomines; Sjoukje J C van der Stegen; Fabiana Perna; Christopher C Kloss; Gertrude Gunset; Jason Plotkin; Michel Sadelain

doi:10.1016/j.ccell.2015.09.004

Structural Design of Engineered Costimulation Determines Tumor Rejection Kinetics and Persistence of CAR T Cells

Cancer Cell. 2015 Oct 12;28(4):415-428. doi: 10.1016/j.ccell.2015.09.004.

Authors

Zeguo Zhao¹, Maud Condomines¹, Sjoukje J C van der Stegen¹, Fabiana Perna¹, Christopher C Kloss¹, Gertrude Gunset¹, Jason Plotkin¹, Michel Sadelain²

Affiliations

¹ Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Immunology Program, Sloan Kettering Institute, New York, NY 10065, USA.
² Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Immunology Program, Sloan Kettering Institute, New York, NY 10065, USA. Electronic address: m-sadelain@ski.mskcc.org.

Abstract

T cell engineering is a powerful means to rapidly generate anti-tumor T cells. The costimulatory properties of second-generation chimeric antigen receptors (CARs) determine the overall potency of adoptively transferred T cells. Using an in vivo "stress test" to challenge CD19-targeted T cells, we studied the functionality and persistence imparted by seven different CAR structures providing CD28 and/or 4-1BB costimulation. One configuration, which uses two signaling domains (CD28 and CD3ζ) and the 4-1BB ligand, provided the highest therapeutic efficacy, showing balanced tumoricidal function and increased T cell persistence accompanied by an elevated CD8/CD4 ratio and decreased exhaustion. Remarkably, induction of the IRF7/IFNβ pathway was required for optimal anti-tumor activity. Thus, 1928z-41BBL T cells possess strikingly potent intrinsic and immunomodulatory qualities.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Antigens, CD19 / immunology
Antigens, CD19 / metabolism
CD28 Antigens / biosynthesis
CD28 Antigens / genetics
CD28 Antigens / immunology*
Hematologic Neoplasms / immunology*
Hematologic Neoplasms / pathology
Hematologic Neoplasms / therapy
Humans
Immunotherapy, Adoptive
Interferon Regulatory Factor-7 / metabolism
Interferon-gamma / metabolism
Kinetics
Lymphocyte Activation / immunology
Receptors, Antigen / genetics
Receptors, Antigen / immunology*
Recombinant Proteins / genetics
Recombinant Proteins / immunology
Signal Transduction
T-Lymphocytes / immunology*
T-Lymphocytes / pathology
Tumor Necrosis Factor Receptor Superfamily, Member 9 / biosynthesis
Tumor Necrosis Factor Receptor Superfamily, Member 9 / genetics
Tumor Necrosis Factor Receptor Superfamily, Member 9 / immunology*

Substances

Antigens, CD19
CD28 Antigens
Interferon Regulatory Factor-7
Receptors, Antigen
Recombinant Proteins
Tumor Necrosis Factor Receptor Superfamily, Member 9
Interferon-gamma

Grants and funding

P30 CA008748/CA/NCI NIH HHS/United States