T Lymphocytes Expressing a CD16 Signaling Receptor Exert Antibody-Dependent Cancer Cell Killing
- 1 January 2014
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 74 (1), 93-103
- https://doi.org/10.1158/0008-5472.can-13-1365
Abstract
To expand applications for T-cell–based immunotherapy in cancer, we designed a receptor that binds the Fc portion of human immunoglobulins and delivers activation signals. The construct included the high-affinity CD16 (FCGR3A) V158 variant, CD8α hinge, and transmembrane domains, along with signaling domains from CD3ζ and 4-1BB (TNFRSF9), forming a chimeric receptor termed CD16V-BB-ζ. After retrovirus-mediated expression in human T cells, CD16V-BB-ζ bound humanized antibodies with higher affinity than a control receptor containing the more common F158 variant. Engagement of CD16V-BB-ζ provoked T-cell activation, exocytosis of lytic granules, and sustained proliferation, with a mean cell recovery after 4-week coculture with Daudi lymphoma cells and rituximab of nearly 70-fold relative to input cells. In contrast, unbound antibody alone produced no effect. CD16V-BB-ζ T cells specifically killed lymphoma cells and primary chronic lymphocytic leukemia cells in combination with rituximab at a low effector:target ratio, even when assayed on mesenchymal cells. Trastuzumab triggered CD16V-BB-ζ–mediated killing of HER2 (ERBB2)+ breast and gastric cancer cells; similar results were obtained with an anti-GD2 antibody in neuroblastoma and osteosarcoma cells. Furthermore, coadministration of CD16V-BB-ζ T cells with immunotherapeutic antibodies exerted considerable antitumor activity in vivo. Signaling mediated by 4-1BB-CD3ζ induced higher T-cell activation, proliferation, and cytotoxicity than CD3ζ or FcεRIγ, and the receptor was expressed effectively after mRNA electroporation without viral vectors, facilitating clinical translation. Our results offer preclinical proof of concept for CD16V-BB-ζ as a universal, next-generation chimeric receptor with the potential to augment the efficacy of antibody therapies for cancer. Cancer Res; 74(1); 93–103. ©2013 AACR.Keywords
Other Versions
This publication has 48 references indexed in Scilit:
- Receptor Affinity and Extracellular Domain Modifications Affect Tumor Recognition by ROR1-Specific Chimeric Antigen Receptor T CellsClinical Cancer Research, 2013
- Chimeric Antigen Receptor–Modified T Cells for Acute Lymphoid LeukemiaNew England Journal of Medicine, 2013
- Anti-CD20 Antibody Therapy for B-Cell LymphomasNew England Journal of Medicine, 2012
- Antibody-Based Immunotherapy of CancerCell, 2012
- Chimeric Antigen Receptor–Modified T Cells in Chronic Lymphoid LeukemiaNew England Journal of Medicine, 2011
- Genotypes of NK Cell KIR Receptors, Their Ligands, and Fcγ Receptors in the Response of Neuroblastoma Patients to Hu14.18-IL2 ImmunotherapyCancer Research, 2010
- Anti-GD2 Antibody with GM-CSF, Interleukin-2, and Isotretinoin for NeuroblastomaNew England Journal of Medicine, 2010
- Expansion of Highly Cytotoxic Human Natural Killer Cells for Cancer Cell TherapyCancer Research, 2009
- Virus-specific T cells engineered to coexpress tumor-specific receptors: persistence and antitumor activity in individuals with neuroblastomaNature Medicine, 2008
- Increased natural killer cell expression of CD16, augmented binding and ADCC activity to rituximab among individuals expressing the FcγRIIIa-158 V/V and V/F polymorphismBlood, 2007