Antibody Tumor Targeting Is Enhanced by CD27 Agonists through Myeloid Recruitment

• Published in: Cancer cell Vol. 32; no. 6; pp. 777 - 791.e6
• Main Authors: Turaj, Anna H., Hussain, Khiyam, Cox, Kerry L., Rose-Zerilli, Matthew J.J., Testa, James, Dahal, Lekh N., Chan, H.T. Claude, James, Sonya, Field, Vikki L., Carter, Matthew J., Kim, Hyung J., West, Jonathan J., Thomas, Lawrence J., He, Li-Zhen, Keler, Tibor, Johnson, Peter W.M., Al-Shamkhani, Aymen, Thirdborough, Stephen M., Beers, Stephen A., Cragg, Mark S., Glennie, Martin J., Lim, Sean H.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 11-12-2017; Cell Press
• Subjects: Animals; Antibodies, Monoclonal - pharmacology; Antibodies, Monoclonal, Humanized; Antineoplastic Agents - pharmacology; cancer; CD20; CD27; Humans; Immunotherapy - methods; Lymphocyte Activation - drug effects; Lymphocyte Activation - immunology; Lymphoma - immunology; macrophage; Macrophage Activation - drug effects; Macrophage Activation - immunology; Mice; Mice, Transgenic; monoclonal antibody; NK cell; T cell; Tumor Necrosis Factor Receptor Superfamily, Member 7 - agonists; CD20; T cell; NK cell; CD27; macrophage; cancer; monoclonal antibody
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccell.2017.11.001

Monoclonal antibodies (mAbs) can destroy tumors by recruiting effectors such as myeloid cells, or targeting immunomodulatory receptors to promote cytotoxic T cell responses. Here, we examined the therapeutic potential of combining a direct tumor-targeting mAb, anti-CD20, with an extended panel of immunomodulatory mAbs. Only the anti-CD27/CD20 combination provided cures. This was apparent in multiple lymphoma models, including huCD27 transgenic mice using the anti-huCD27, varlilumab. Detailed mechanistic analysis using single-cell RNA sequencing demonstrated that anti-CD27 stimulated CD8+ T and natural killer cells to release myeloid chemo-attractants and interferon gamma, to elicit myeloid infiltration and macrophage activation. This study demonstrates the therapeutic advantage of using an immunomodulatory mAb to regulate lymphoid cells, which then recruit and activate myeloid cells for enhanced killing of mAb-opsonized tumors.
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•CD27 stimulation enhances anti-tumor efficacy of tumor-targeting mAbs•Stimulation of CD27 on T and NK cells increases chemokine and IFNγ release•Released IFNγ leads to myeloid cell activation and infiltration•Activated macrophages have enhanced anti-CD20 dependent phagocytic capability
Turaj et al. test anti-tumor efficacy of immunomodulatory antibodies combined with anti-CD20 and find that anti-CD27/CD20 has a strong benefit in several tumor models. Anti-CD27 induces IFNγ and chemokines in CD8+ T and NK cells, enhancing macrophage infiltration and activation to promote anti-CD20 activity.