Abstract LB-138: Stimulation of natural killer cells with an anti-CD137 antibody enhances the efficacy trastuzumab, cetuximab, and rituximab in HER2-expressing breast cancer, EGFR+ head and neck cancer, and CD20+ lymphoma
Authors: Kohrt Holbrook , Houot Roch , Weiskopf Kipp , Goldstein Matthew , Lund Peder , Czerwinski Debra , Sunwoo John , Tedder Thomas , Chen Lieping , Levy Ronald 
Published: August 2012

Antibody-dependent cell-mediated cytotoxicity (ADCC), largely mediated by natural killer (NK) cells, is thought to play an important role in the efficacy of monoclonal antibodies (mAb)s including rituximab, an anti-CD20 mAb, trastuzumab, an anti-HER2 mAb, and cetuximab, an anti-EGFR mAb used to treat patients with B cell lymphomas, HER2-expressing breast cancer, and EGFR-expressing solid tumors. CD137 is a costimulatory molecule expressed on NK cells following activation. We hypothesize that as the antitumor efficacy of mAbs is due in part to ADCC, the anti-cancer activity of these mAbs can be enhanced with an anti-CD137 agonistic mAb. Induction of CD137 on NK cells was assessed using CD20+lymphoma, HER2+breast, and EGFR+head and neck cell lines and primary patient samples and respective mAbs. In-vitro NK cell degranulation, cytokine release and cytotoxicity were assessed by CD107a mobilization, IFN-γ secretion, and chromium release. A murine lymphoma tumor model was used to assess in-vivo synergy and mechanism was explored by T cell, NK cell, and macrophage depletion. Xenotransplanted models in nude or SCID mice with lymphoma, breast cancer, or head and neck cancer were used to demonstrate efficacy of anti-CD137 mAb and rituximab, trastuzumab or cetuximab, and sufficiency of an innate immune response. NK cells in human primary patient samples do not express CD137 at baseline, however these cells highly upregulate CD137 when encountering mAb-coated tumor cells. Monoclonal antibody-induced NK cell degranulation and cytotoxicity as measured by chromium release are enhanced by anti-CD137 agonistic mAb. In a murine lymphoma model, anti-CD137 mAb significantly enhances anti-tumor activity of anti-CD20 mAb leading to complete tumor resolution and prolonged survival. Sequential administration of anti-CD20 mAb followed by anti-CD137 mAb is required for the synergistic effect. NK cell depletion completely abrogates the therapeutic effect of anti-CD20 plus anti-CD137 mAb combination. In xenotransplant lymphoma, breast, and head and neck models, rituximab, trastuzumab or cetuximab plus anti-CD137 mAb provided superior reduction in tumor burden and prolonged overall survival. In a Phase 0 biomarker study, level of CD137 expression on circulating and intratumoral NK cells was influenced by circulating disease burden, extent of prior treatment, FcγRIII polymorphism, and time since mAb therapy. Our results demonstrate the synergy of anti-CD137 mAb and a tumor-targeting mAb (rituximab, trastuzumab, or cetuximab) by stimulation of mAb-activated NK cells with anti-CD137 mAb to enhance ADCC. These results support a novel, sequential antibody approach against CD20+B cell, HER2+breast, and EGFR+head and neck malignancies by targeting first the tumor and then the host immune system.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-138. doi:1538-7445.AM2012-LB-138