Chimeric receptors containing CD137 signal transduction domains mediate enhanced survival of T cells and increased antileukemic efficacy in vivo.
Persistence of T cells engineered with chimeric antigen receptors (CARs) has been a major barrier to use of these cells for molecularly targeted adoptive immunotherapy. To address this issue, we created a series of CARs that contain the T cell receptor-zeta (TCR-zeta) signal transduction domain with the CD28 and/or CD137 (4-1BB) intracellular domains in tandem. After short-term expansion, primary human T cells were subjected to lentiviral gene transfer, resulting in large numbers of cells with >85% CAR expression. In an immunodeficient mouse xenograft model of primary human pre-B-cell acute lymphoblastic leukemia, human T cells expressing anti-CD19 CARs containing CD137 exhibited the greatest antileukemic efficacy and prolonged (>6 months) survival in vivo, and were significantly more effective than cells expressing CARs containing TCR-zeta alone or CD28-zeta signaling receptors. We uncovered a previously unrecognized, antigen-independent effect of CARs expressing the CD137 cytoplasmic domain that likely contributes to the enhanced antileukemic efficacy and survival in tumor bearing mice. Furthermore, our studies revealed significant discrepancies between in vitro and in vivo surrogate measures of CAR efficacy. Together these results suggest that incorporation of the CD137 signaling domain in CARs should improve the persistence of CARs in the hematologic malignancies and hence maximize their antitumor activity.
Milone
Michael C
MC
Department of Pathology and Laboratory Medicine, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104-5160, USA. milone@mail.med.upenn.edu
Fish
Jonathan D
JD
Carpenito
Carmine
C
Carroll
Richard G
RG
Binder
Gwendolyn K
GK
Teachey
David
D
Samanta
Minu
M
Lakhal
Mehdi
M
Gloss
Brian
B
Danet-Desnoyers
Gwenn
G
Campana
Dario
D
Riley
James L
JL
Grupp
Stephan A
SA
June
Carl H
CH
D000818:Animals; D018106:CD28 Antigens / Q000235:genetics / Q000276:immunology; D002470:Cell Survival; D002478:Cells, Cultured; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods; D016086:Lentivirus / Q000235:genetics; D007938:Leukemia / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D016133:Polymerase Chain Reaction; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000502:physiology*; D011994:Recombinant Proteins / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000235:genetics / Q000276:immunology*; D023041:Xenograft Model Antitumor Assays
D018106:CD28 Antigens; D011948:Receptors, Antigen, T-Cell; D011994:Recombinant Proteins; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9