282448 Engineering Chimeric Antigen Receptors for Logical Computation

Wednesday, October 31, 2012
Hall B (Convention Center )
Yvonne Y. Chen, Harvard Society of Fellows, Cambridge, MA, Michael C. Jensen, Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, WA and Pamela Silver, Systems Biology, Harvard Medical School, Boston, MA

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.

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