TCR β chain–directed bispecific antibodies for the treatment of T cell cancers
- 10 March 2021
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science Translational Medicine
- Vol. 13 (584)
- https://doi.org/10.1126/scitranslmed.abd3595
Abstract
Immunotherapies such as chimeric antigen receptor (CAR) T cells and bispecific antibodies redirect healthy T cells to kill cancer cells expressing the target antigen. The pan-B cell antigen–targeting immunotherapies have been remarkably successful in treating B cell malignancies. Such therapies also result in the near-complete loss of healthy B cells, but this depletion is well tolerated by patients. Although analogous targeting of pan-T cell markers could, in theory, help control T cell cancers, the concomitant healthy T cell depletion would result in severe and unacceptable immunosuppression. Thus, therapies directed against T cell cancers require more selective targeting. Here, we describe an approach to target T cell cancers through T cell receptor (TCR) antigens. Each T cell, normal or malignant, expresses a unique TCR β chain generated from 1 of 30 TCR β chain variable gene families (TRBV1 to TRBV30). We hypothesized that bispecific antibodies targeting a single TRBV family member expressed in malignant T cells could promote killing of these cancer cells, while preserving healthy T cells that express any of the other 29 possible TRBV family members. We addressed this hypothesis by demonstrating that bispecific antibodies targeting TRBV5-5 (α-V5) or TRBV12 (α-V12) specifically lyse relevant malignant T cell lines and patient-derived T cell leukemias in vitro. Treatment with these antibodies also resulted in major tumor regressions in mouse models of human T cell cancers. This approach provides an off-the-shelf, T cell cancer selective targeting approach that preserves enough healthy T cells to maintain cellular immunity.Keywords
Funding Information
- National Institutes of Health (CA62924)
- National Institutes of Health (GM136577)
- National Institutes of Health (R37 CA230400)
- Virginia and D.K. Ludwig Fund for Cancer Research
- Lustgarten Foundation for Pancreatic Cancer Research
- National Institutes of Health T32 grant (5T32CA009071-38)
- The Commonwealth Fund
- National Institutes of Health Cancer Center Support Grant (P30 CA006973)
- National Institutes of Health T32 grant (AR048522)
- Bloomberg-Kimmel Institute for Cancer Immunotherapy
- SITC-Amgen Cancer Immunotherapy in Hematologic Malignancies Fellowship
- JHU MacMillan Pathway to Independence Program
- Burroughs Wellcome Career Award for Medical Scientists
This publication has 88 references indexed in Scilit:
- Dietary gluten triggers concomitant activation of CD4 + and CD8 + αβ T cells and γδ T cells in celiac diseaseProceedings of the National Academy of Sciences of the United States of America, 2013
- Xenogeneic Graft-versus-Host-Disease in NOD-scid IL-2Rγnull Mice Display a T-Effector Memory PhenotypePLOS ONE, 2012
- The Impact of a Large and Frequent Deletion in the Human TCR β Locus on Antiviral ImmunityThe Journal of Immunology, 2012
- Acute leukemia incidence and patient survival among children and adults in the United States, 2001-2007Blood, 2012
- Features and development of CootActa crystallographica. Section D, Structural biology, 2010
- Guidelines for Preventing Infectious Complications among Hematopoietic Cell Transplantation Recipients: A Global PerspectiveTransplantation and Cellular Therapy, 2009
- IMGT(R), the international ImMunoGeneTics information system(R)Nucleic Acids Research, 2008
- Lymphoma survival patterns by WHO subtype in the United States, 1973–2003Cancer Causes & Control, 2008
- T-cell antigen receptor genes and T-cell recognitionNature, 1988
- Treatment of B-Cell Lymphoma with Monoclonal Anti-Idiotype AntibodyThe New England Journal of Medicine, 1982