The CD20/alphaCD20 'suicide' system: novel vectors with improved safety and expression profiles and efficient elimination of CD20-transgenic T cells.
Adoptive transfer of T lymphocytes is an attractive strategy for many experimental treatment strategies for cancer. Unfortunately, manipulated T cells could be responsible for serious adverse events. Retroviral CD20-transduced T cells may be able to control these unwanted effects. CD20-positive cells are sensitive to rituximab (RTX), a monoclonal antibody specific for CD20. This permits their selective elimination in vivo in case of adverse events. To this end, a system is required that permits efficient and safe transduction of donor T cells and effective elimination of CD20-positive T cells. We constructed different CD20-encoding retroviral vectors and investigated the impact of inclusion of the woodchuck post-transcriptional regulatory element (WPRE) and the chicken hypersensitivity site 4 insulator elements on the levels, homogeneity and stability of CD20 expression. Importantly, inclusion of either WPRE or insulator elements in the retroviral vector resulted in a dramatic improvement in the stability of CD20 expression. The insulator element also led to a much more homogeneous level of CD20 expression. We also show the efficient elimination of the CD20-transgenic T cells via RTX by different effector mechanisms. In conclusion, we have constructed CD20-encoding retroviral vectors with improved efficiency and safety profiles, which can be used as a suicide strategy.
van Meerten
T
T
Jordan Laboratory for Hemato-Oncology, Department of Haematology, University Medical Center Utrecht, Heidelberglaan 100, Utrecht, The Netherlands.
Claessen
M-J
MJ
Hagenbeek
A
A
Ebeling
S B
SB
D019264:Adoptive Transfer / Q000009:adverse effects* / Q000379:methods; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20 / Q000235:genetics*; D016923:Cell Death; D002999:Clone Cells; D005434:Flow Cytometry; D015870:Gene Expression; D041722:Genes, Transgenic, Suicide; D005818:Genetic Engineering; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D006086:Graft vs Host Disease / Q000209:etiology / Q000276:immunology / Q000628:therapy*; D006801:Humans; D008212:Lymphocyte Depletion; D012190:Retroviridae / Q000235:genetics; D000069283:Rituximab; D013601:T-Lymphocytes / Q000378:metabolism* / Q000473:pathology; D014161:Transduction, Genetic / Q000379:methods
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D000069283:Rituximab