(593ag) Engineering Chimeric Antigen Receptors for Logical Computation

Adoptive T-cell therapy is a promising cancer treatment strategy that seeks to strengthen and redirect the patient’s immune system against tumor cells. In particular, autologous T cells genetically modified to express tumor-targeting receptors known as chimeric antigen receptors (CARs) have demonstrated safety and efficacy in treating recalcitrant malignancies including leukemia and metastatic melanoma. However, current CAR designs remain single-input, single-output signal-processing units that are vulnerable to significant obstacles, including mutational escape by tumor cells and off-target killing of normal cells. Here, we present the development of next-generation CARs that incorporate Boolean-logic computation to address these challenges. We have applied synthetic biology techniques to the modular design and rapid construction of OR-, AND-, and NOT-gate CARs. Results of functional studies in primary human T-cell culture will be presented. By conferring engineered T cells with the ability to compute multiple input signals before triggering cell-mediated killing of target cells, these novel CAR constructs will enable more precise tumor eradication, leading to a safer and more effective cell-based cancer therapy.