Focusing and sustaining the antitumor CTL effector killer response by agonist anti-CD137 mAb

• Published in: Proceedings of the National Academy of Sciences - PNAS 2015-06, Vol.112 (24), p.7551-7556
• Main Authors: Weigelin, Bettina, Elixabet Bolaños, Alvaro Teijeira, Ivan Martinez-Forero, Sara Labiano, Arantza Azpilikueta, Aizea Morales-Kastresana, Josñé I. Quetglas, Esther Wagena, Alfonso Rodrñéíguez Sñéíánchez-Paulete, Lieping Chen, Peter Friedl, Ignacio Melero
• Format: Article
• Language: English
• Subjects: adoptive T-cell therapy; agonists; Animals; Antibodies, Monoclonal - administration & dosage; antigens; Apoptosis; Avian Proteins - genetics; Biological Sciences; CD137; Cell Line, Tumor; Cells; chimerism; clinical trials; Combined Modality Therapy; costimulation; Cytotoxic T lymphocyte; cytotoxic T-lymphocytes; immunity; Immunotherapy; Immunotherapy, Adoptive - methods; Lymphocytes; Lymphocytes, Tumor-Infiltrating - immunology; Male; Melanoma; Melanoma, Experimental - immunology; Melanoma, Experimental - pathology; Melanoma, Experimental - therapy; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; monoclonal antibodies; neoplasms; Ovalbumin - genetics; patients; receptors; Rodents; synergism; T-Box Domain Proteins - metabolism; T-Lymphocytes, Cytotoxic - immunology; Tumor Microenvironment - immunology; Tumor Necrosis Factor Receptor Superfamily, Member 9 - deficiency; Tumor Necrosis Factor Receptor Superfamily, Member 9 - genetics; Tumor Necrosis Factor Receptor Superfamily, Member 9 - immunology; Tumors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1506357112

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. Significance Immunotherapy of cancer with immunomodulatory agents is achieving significant efficacy in an important fraction of patients. The stimulatory inducible receptor of T and NK lymphocytes known as CD137 or 4-1BB is being stimulated with agonist antibodies to enhance antitumor immunity in clinical trials. In addition, the intracellular signaling domain of CD137 is crucial as a component of successful anti-leukemia therapies with chimeric antigen receptors transduced into adoptively transferred T lymphocytes. In this study the marked synergistic effects of adoptive T cell and agonist anti-CD137 mAb therapies are studied, providing in vivo evidence for improved, more sustained and focused tumoricidal functions of antitumor cytotoxic T lymphocytes when under the influence of CD137-targeted pharmacological stimulation with immunostimulatory monoclonal antibodies.