Aptamers are single-stranded oligonucleotide ligands that exhibit high affinities and specificities for their targets. These molecules have been extensively used in therapeutics. Several aptamers have recently been described to modulate immune receptors in cancer immunotherapy. We were pioneers in the development of the first-in-class agonistic aptamers against costimulatory receptors. In this project we aim at identifying anti-CD3 and TCR aptamers that could function as allosteric regulators of CD3 and TCR. We will study in collaboration other groups of the consortium how the anti CD3 and TCR aptamers affect at the TCR nanocluster formation. We expect to potentiate the TCR signal provided by weak tumor-antigen derived peptides presented in MCH-I or MCH-II. In this way we hope to increase the activation threshold of tumor-antigen specific lymphocytes for cancer immunotherapy. We would also plan to combine the anti-CD3 aptamers with other costimulatory aptamers that have already been selected, such as 4-1BB, OX40 and CD28, as well as with new aptamers that would be selected against ICOS and CD27. All this immuno-stimulatory aptamers would be anchored together into a biomaterial scaffold to enhance the signalosome activation on the surface of T lymphocytes. We plan to analyze and quantify how the aptamer scaffold interaction affect at the recognition of the T lymphocyte with the antigen presenting cell in collaboration with other groups of the consortium. We plan to test these therapeutic approaches in different relevant murine tumor models of melanoma and colon cancer. We would also assess the nature of the immune response that is elicited with this type of therapeutic intervention.