Proceedings of the National Academy of Sciences of the United States of America 105 (2): 623-628 (2008-01-15)

Kieback E.; Charo J.; Sommermeyer D.; Blankenstein T.; Uckert W.

A safeguard eliminates T cell receptor gene-modified autoreactive T cells after adoptive transfer

By transfer of T cell receptor (TCR) genes, antigen specificity of T cells can be redirected to target any antigen. Adoptive transfer of TCR-redirected T cells into patients has shown promising results. However, this immunotherapy bears the risk of autoreactive side effects if the TCR recognizes antigens on self-tissue. Here, we introduce a safeguard based on a TCR-intrinsic depletion mechanism to eliminate autoreactive TCR-redirected T cells in vivo. By the introduction of a 10-aa tag of the human c-myc protein into murine (OT-I, P14) and human (gp100) TCR sequences, we were able to deplete T cells that were transduced with these myc-tagged TCRs with a tag-specific antibody in vitro. T cells transduced with the modified TCR maintained equal properties compared with cells transduced with the wild-type receptor concerning antigen binding and effector function. More importantly, therapeutic in vivo depletion of adoptively transferred T cells rescued mice showing severe signs of autoimmune insulitis from lethal diabetes. This safeguard allows termination of adoptive therapy in case of severe side effects.

Keywords: Mice, Animals, TCR, Suicide, Myc-Tag, Antibody Depletion, Adoptive T Cell Therapy

Type: Article

PubMed: 18182487
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