title: A Multifunctional Role for Adjuvant Anti-4-1BB Therapy in Augmenting Antitumor Response by Chimeric Antigen Receptor T Cells.
abstract: Adoptive immunotherapy utilizing chimeric antigen receptor (CAR) T cells has demonstrated high success rates in hematologic cancers, but results against solid malignancies have been limited to date, due in part to the immunosuppressive tumor microenvironment. Activation of the 4-1BB (CD137) pathway using an agonistic α-4-1BB antibody is known to provide strong costimulatory signals for augmenting and diversifying T-cell responses. We therefore hypothesized that a combination of α-4-1BB and CAR T-cell therapy would result in improved antitumor responses. Using a human-Her2 self-antigen mouse model, we report here that α-4-1BB significantly enhanced CAR T-cell efficacy directed against the Her2 antigen in two different established solid tumor settings. Treatment also increased the expression of IFNγ and the proliferation marker Ki67 in tumor-infiltrating CAR T cells when combined with α-4-1BB. Strikingly, α-4-1BB significantly reduced host immunosuppressive cells at the tumor site, including regulatory T cells and myeloid-derived suppressor cells, correlating with an increased therapeutic response. We conclude that α-4-1BB has a multifunctional role for enhancing CAR T-cell responses and that this combination therapy has high translational potential, given current phase I/II clinical trials with α-4-1BB against various types of cancer.Cancer Res; 77(6); 1296-309. ©2017 AACR.
authors.affiliation: Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Australia.|Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia.
authors.forename: Sherly
authors.initials: S
authors.lastname: Mardiana
authors.affiliation: Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Australia.|Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia.
authors.forename: Liza B
authors.initials: LB
authors.lastname: John
authors.affiliation: Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Australia.|Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Henderson
authors.affiliation: Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Australia.|Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia.
authors.forename: Clare Y
authors.initials: CY
authors.lastname: Slaney
authors.affiliation: Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Australia.|Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia.
authors.forename: Bianca
authors.initials: B
authors.lastname: von Scheidt
authors.affiliation: Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Australia.|Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia.
authors.forename: Lauren
authors.initials: L
authors.lastname: Giuffrida
authors.affiliation: Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Australia.|Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Davenport
authors.affiliation: Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Australia.|Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Trapani
authors.affiliation: Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Australia.|Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Neeson
authors.affiliation: Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Australia.|Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia.
authors.forename: Sherene
authors.initials: S
authors.lastname: Loi
authors.affiliation: Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia.|Cancer Therapeutics Program, Peter MacCallum Cancer Centre, Melbourne, Australia.
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Haynes
authors.affiliation: Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Australia.|Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia.|Department of Pathology, The University of Melbourne, Melbourne, Australia.|Department of Immunology, Monash University, Melbourne, Australia.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Kershaw
authors.affiliation: Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Australia. phil.darcy@petermac.org paula.beavis@petermac.org.|Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Beavis
authors.affiliation: Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Australia. phil.darcy@petermac.org paula.beavis@petermac.org.|Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia.|Department of Pathology, The University of Melbourne, Melbourne, Australia.|Department of Immunology, Monash University, Melbourne, Australia.
authors.forename: Phillip K
authors.initials: PK
authors.lastname: Darcy
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003110:Colonic Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D005260:Female; D006801:Humans; D016219:Immunotherapy, Adoptive; D008213:Lymphocyte Activation; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D012513:Sarcoma, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment / Q000276:immunology; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D018719:Erb-b2 Receptor Tyrosine Kinases; D011948:Receptors, Antigen, T-Cell; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; C508053:ERBB2 protein, human