Focusing and sustaining the antitumor CTL effector killer response by agonist anti-CD137 mAb
Weigelin B(1), Bolaños E(2), Teijeira A(2), Martinez-Forero I(2), Labiano S(2), Azpilikueta A(2), Morales-Kastresana A(2), Quetglas JI(2), Wagena E(1), Sánchez-Paulete AR(2), Chen L(3), Friedl P(1), Melero I(4) [SP].
(1) Department of Cell Biology, Radboud University Nijmegen Medical Center, 6525 GA Nijmegen, The Netherlands;
(2) Centro de Investigación Médica Aplicada (CIMA) and Clinica Universidad de Navarra, University of Navarra, 31008 Pamplona, Spain;
(3) Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06511;
(4) Centro de Investigación Médica Aplicada (CIMA) and Clinica Universidad de Navarra, University of Navarra, 31008 Pamplona, Spain.
Magazine: Proceedings of the National Academy of Sciences of the United States of America
Date: Jun 16, 2015Medical Oncology
Cancer immunotherapy is undergoing significant progress due to recent clinical successes by refined adoptive T-cell transfer and immunostimulatory monoclonal Ab (mAbs). B16F10-derived OVA-expressing mouse melanomas resist curative immunotherapy with either adoptive transfer of activated anti-OVA OT1 CTLs or agonist anti-CD137 (4-1BB) mAb.
However, when acting in synergistic combination, these treatments consistently achieve tumor eradication. Tumor-infiltrating lymphocytes that accomplish tumor rejection exhibit enhanced effector functions in both transferred OT-1 and endogenous cytotoxic T lymphocytes (CTLs). This is consistent with higher levels of expression of eomesodermin in transferred and endogenous CTLs and with intravital live-cell two-photon microscopy evidence for more efficacious CTL-mediated tumor cell killing.
Anti-CD137 mAb treatment resulted in prolonged intratumor persistence of the OT1 CTL-effector cells and improved function with focused and confined interaction kinetics of OT-1 CTL with target cells and increased apoptosis induction lasting up to six days postadoptive transfer. The synergy of adoptive T-cell therapy and agonist anti-CD137 mAb thus results from in vivo enhancement and sustainment of effector functions.
CITATION Proc Natl Acad Sci U S A. 2015 Jun 16;112(24):7551-6. doi: 10.1073/pnas.1506357112.
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