Improving Immunotherapy Against B-Cell Malignancies Using γδ T-Cell-specific Stimulation and Therapeutic Monoclonal Antibodies.

Abstract

Tumor antigen-targeting monoclonal antibodies (mAbs) are an important element of current cancer therapies. Some of these therapeutic mAbs enable antibody-dependent cell mediated cytotoxicity (ADCC) against tumor cells. However, cancer-related functional impairment of immune effector cells may limit the clinical efficacy of antibody treatments. We reckoned that combining mAbs with cell-based immunotherapies would provide a clinically relevant synergism and benefit for cancer patients. Here, we focus on γδ T cells, as earlier studies demonstrated that γδ T-cell-based therapies are safe and promising for several types of malignancies. Similar to natural killer cells, their antitumor effects can be enhanced using antibodies, and they could, therefore, become a versatile effector cell platform for use with a variety of licensed therapeutic mAbs against cancer. In this study, we explore the potential of a combination therapy of activated γδ T cells with rituximab and the more recently developed mAbs (obinutuzumab and daratumumab) in different B-cell malignancies in vitro. Obinutuzumab outperformed the other mAbs with regard to direct target cell lysis and ADCC by γδ T cells in several CD20 cell lines and primary lymphoma specimens. We demonstrate that comparatively few CD16 γδ T cells are sufficient to mediate a strong ADCC. Using Fc-receptor-positive B-cell lymphomas as target cells, ADCC cannot be blocked by high concentrations of immunoglobulins or anti-CD16 antibodies, but both substances can promote cell mediated target cell lysis. This study expands on earlier reports on the therapeutic potential of distinctive tumor antigen-targeting mAbs and facilitates the understanding of the mechanism and potential of ADCC by γδ T-cell subsets.

• Authors: Timm Hoeres, Dominik Pretscher, Elisabeth Holzmann, Manfred Smetak, Josef Birkmann, Jakob Triebel, Thomas Bertsch, Martin Wilhelm
• Journal: Journal of immunotherapy (Hagerstown, Md. : 1997) (J Immunother) 2019 Nov/Dec Vol. 42 Issue 9 Pg. 331-344 ISSN: 1537-4513 [Electronic] United States
• PMID: 31318724 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents, Immunological
• Rituximab
• daratumumab
• obinutuzumab

Topics

• Antibodies, Monoclonal (pharmacology)
• Antibodies, Monoclonal, Humanized (pharmacology)
• Antineoplastic Agents, Immunological (pharmacology)
• Female
• Humans
• Immunotherapy
• Intraepithelial Lymphocytes (drug effects, immunology)
• Killer Cells, Natural (drug effects, immunology)
• Lymphoma, B-Cell (immunology, therapy)
• Male
• Rituximab (pharmacology)