A Multifunctional Role for Adjuvant Anti-4-1BB Therapy in Augmenting Antitumor Response by Chimeric Antigen Receptor T Cells

• Published in: Cancer research (Chicago, Ill.) Ill.), 2017-03, Vol.77 (6), p.1296-1309
• Main Authors: Mardiana, Sherly, John, Liza B, Henderson, Melissa A, Slaney, Clare Y, von Scheidt, Bianca, Giuffrida, Lauren, Davenport, Alexander J, Trapani, Joseph A, Neeson, Paul J, Loi, Sherene, Haynes, Nicole M, Kershaw, Michael H, Beavis, Paul A, Darcy, Phillip K
• Format: Article
• Language: English
• Subjects: Adoptive immunotherapy; Animals; Antibodies, Monoclonal - pharmacology; Antigens; Antitumor activity; Autoantigens; Cancer; CD137 antigen; CD8-Positive T-Lymphocytes - immunology; Cell proliferation; Chimeric antigen receptors; Clinical trials; Colonic Neoplasms - immunology; Colonic Neoplasms - pathology; Colonic Neoplasms - therapy; Cytotoxicity, Immunologic - immunology; ErbB-2 protein; Female; Human behavior; Humans; Immunoregulation; Immunosuppression; Immunotherapy; Immunotherapy, Adoptive; Lymphocyte Activation; Lymphocytes; Lymphocytes T; Mammary Neoplasms, Experimental - drug therapy; Mammary Neoplasms, Experimental - immunology; Mammary Neoplasms, Experimental - pathology; Mice; Mice, Inbred C57BL; Mice, Transgenic; Receptor, ErbB-2 - immunology; Receptor, ErbB-2 - metabolism; Receptors, Antigen, T-Cell - immunology; Sarcoma, Experimental - drug therapy; Sarcoma, Experimental - immunology; Sarcoma, Experimental - pathology; Solid tumors; Suppressor cells; T cell receptors; Tumor Cells, Cultured; Tumor Microenvironment - immunology; Tumor Necrosis Factor Receptor Superfamily, Member 9 - immunology; γ-Interferon
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-16-1831

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. .