Ample co-stimulatory interactions between antigen-presenting cells and T cells are essential for an effective immune response. Similarly, co-stimulation related immuno-experiences have also been considered critical for the successful tumor eradication by T cells in adoptive immunotherapy cases of: conventional tumor infiltrating T cells for melanoma, chimeric antigen receptor (CAR)-expressing EBV-CTLs for EBV-associated malignancies and the recent CD19 CAR T cells for B-cell neoplasms. However, the specific co-stimulation signals playing the major role in successful immunotherapies are still not identified. Here, a series of constructs has been made to compare the effects of most known co-stimulation molecules, including 4-1BB, CD2, CD27, CD28, CD30, LFA1, GITR, HVEM, ICOS and OX40, in the 1st generation designer T cells bearing anti-CEA scFv-linked CD3ζ signal, and in the 2nd generation designer T cells with anti-CEA scFv linked with CD3ζ plus CD28 signal. Corresponding designer T cells’ function in vitro in proliferation/survival, cytotoxicity and cytokine secretion, and in vivo in animal models, will be tested and compared with the 1st/2nd generation designer T cells. The ones standing out will be delineated for their mechanisms from co-stimulation ligation to specific intracellular signal pathway that lead to the T cell phenotype responsible for final tumor rejection, and will be applied for 3rd generation designer T cell development.
- Copyright © 2013 by The American Association of Immunologists, Inc.