Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.
Adoptive transfer of Tumor Infiltrating Lymphocytes (TIL), T-cell receptor (TCR)-transduced PBL and Chimeric Antigen Receptor (CAR)-transduced PBL have proven to be clinically effective. CARs have evolved by introducing cytoplastic costimulatory domains. Higher cytokine secretion and longer persistence of CAR-transduced T-cells in vivo imply important roles of costimulatory signals. In contrast, costimulation of TIL or TCR-transduced PBL in vivo relies on the expression of costimulatory receptors on T-cells and ligands on tumor cells or antigen presenting cells (APCs). One way to give T-cells their desired costimulation signal independent of the endogenous receptor/ligand expression would be to introduce a fusion molecule that is comprised of a receptor whose ligand is frequently expressed on tumor cells and an intra-cellular costimulatory domain. In a pursuit for a “universal costimulator” that is applicable to various tumors, we produced fusions of CD2 and various costimulators such as CD28, 4-1BB, ICOS, CD27 and OX-40 (Figure 1). CD2 is the receptor for CD58 that is expressed on various tumor cells. Since CD2-CD58 complex localizes to the Supramolecular Activation Complex (SMAC) on activation of TCR, CD2-costimulators may signal in a TCR-activation dependent manner. Human PBL were retrovirally transduced with genes that encode NY-ESO-1-reactive TCR and each CD2-costimulator. In vitro co-culture assay showed higher IFN-γ and IL-2 secretion by CD2-CD28 and higher IFN-γ by CD2-OX40. To examine the in vivo effect of these fusion costimulators, vascularized SK23 melanoma tumor was established in NOD scid gamma (NSG) immunodeficient mice and human CD8+ T-cells transduced with anti-NY-ESO1 TCR and each fusion costimulator were injected. Out of five costimulators tested, CD2-CD28 showed a significant enhancement of anti-tumor effect. These results suggest that the CD2-CD28 costimulator may improve TIL and TCR-transduced PBL therapy.