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The doubling potential of T lymphocytes allows clinical-grade production of a bank of genetically modified monoclonal T-cell populations.
- Source :
-
Cytotherapy (Elsevier Inc.) . Mar2018, Vol. 20 Issue 3, p436-452. 17p. - Publication Year :
- 2018
-
Abstract
- Background aims To produce an anti-leukemic effect after hematopoietic stem cell transplantation we have long considered the theoretical possibility of using banks of HLA-DP specific T-cell clones transduced with a suicide gene. For that application as for any others, a clonal strategy is constrained by the population doubling (PD) potential of T cells, which has been rarely explored or exploited. Methods We used clinical-grade conditions and two donors who were homozygous and identical for all HLA-alleles except HLA-DP. After mixed lymphocyte culture and transduction, we obtained 14 HLA-DP–specific T-cell clones transduced with the HSV-TK suicide gene. Clones were then selected on the basis of their specificity and functional characteristics and evaluated for their doubling potential. Results After these steps of selection the clone NAT-DP4 (TK) , specific for HLA-DPB1*04:01/04:02, which produced high levels of interferon-γ (IFNγ), tumor necrosis factor (TNF), interleukin-2 (IL-2) and granulocyte-macrophage colony-stimulating factor (GM-CSF), was fully sequenced. It has two copies of the HSV-TK suicide transgene whose localizations were determined. Four billion NAT-DP4 (TK) cells were frozen after 50 PDs. Thawed NAT-DP4 (TK) cells retain the potential to undergo 50 additional PDs, a potential very far beyond that required to produce a biological effect. This PD potential was confirmed on 6/16 additional different T-cell clones. This type of well-defined clone can also support a second genetic modification with CAR constructs. Conclusion The possibility of choosing rare donors and exploiting the natural proliferative potential of T lymphocytes may dramatically reduce the clinical and immunologic complexity of adoptive transfer protocols that rely on the use of third-party T-cell populations. [ABSTRACT FROM AUTHOR]
- Subjects :
- *T cells
*MONOCLONAL antibodies
*CLONING
*LYMPHOCYTES
*ANTINEOPLASTIC antibiotics
Subjects
Details
- Language :
- English
- ISSN :
- 14653249
- Volume :
- 20
- Issue :
- 3
- Database :
- Academic Search Index
- Journal :
- Cytotherapy (Elsevier Inc.)
- Publication Type :
- Academic Journal
- Accession number :
- 128393570
- Full Text :
- https://doi.org/10.1016/j.jcyt.2017.12.002