Triggering Anti-Tumor Killing with Aptamers

T-cell mediated killing of tumor cells is a critical process in fighting cancer. However, even when T-cells are recruited to tumor cells, they often are not stimulated to kill the tumor. This is due to a requirement for co-stimulation in which the tumor cell itself must secrete a ligand that activates a specific receptor on T-cells. This in turn activates the T-cell killing function. Many tumors do not secrete such co-stimulatory ligands, thereby abrogating the T-cell mediated anti-tumor effects. A possible solution to this problem is to provide the co-stimulatory ligands to T-cells.

As discussed in an article within the November 2011 issue of Molecular Therapy, Eli Gilboa, PhD and colleagues have devised a clever and powerful solution to the co-stimulation challenge. In this study they used in vitro evolved RNA aptamers which bind specifically and with high affinity to cell surface receptors, thereby mimicking the function of the natural ligands. They specifically developed aptamers that bind the T-cell specific 4-1BB receptor, which must dimerize to function. To activate this receptor, they made a dimeric 4-1BB aptamer that triggers receptor dimerization. In order to enhance the specificity of the activated T-cell killing, a third aptamer was linked to the dimerized 4-1BB aptamers. They reasoned that linking the third aptamer would allow selective recognition of tumors bearing the cell surface receptor for the aptamer, which in combination with the T-cell activating aptamers should result in selective killing of tumor cells.

To test this approach, they linked a third aptamer which binds the prostate specific membrane antigen (PSMA) to the 4-1BB dimeric aptamers. They tested the trimeric aptamer by inserting a modified version of PSMA into colon carcinoma cells. The PSMA on the surface of these cells can bind but not internalize the trimeric aptamer. This clever approach allows the aptamers to act as co-stimulatory ligands which recruit T-cells to the tumor cells and also provide the co-stimulatory signals required to activate T-cell killing. They demonstrated the anti-tumor activity of this trimeric aptamer in vivo and showed that the T-cell mediated killing of PSMA bearing tumor cells was effective at a 10 fold lower concentration than 4-1BB specific antibodies or dimeric aptamers. This novel approach for activating anti-tumor T-cell function should be safer and applicable to other receptors.

This approach represents a potent strategy for selectively activating the immune system to eradicate cancers.