Hematopoietic transplantation and adoptive cellular therapies are expanding fields with increasingly established and experimental indications. Yet, even as the current approaches grow, the way these cellular therapies are developed and practiced may soon be strikingly different. Gene editing is poised to revolutionize hematopoietic transplantation and adoptive cell therapies, either through the editing of transplanted hematopoietic cells or editing the immune cells mediating curative and other protective responses. This session will present state-of-the-science advances in understanding the basic biology of genome editing, approaches to incorporate such editing into transplant and other cellular therapy settings, and efforts to utilize editing techniques to synthesize new biology that can enhance the efficacy and safety of cellular therapies.
Dr. Feng Zhang will discuss precision genome editing, which can be used to alter specific DNA sequences and can be utilized as a powerful tool for understanding the molecular circuitry underlying cellular processes. Over the past several years, his group and others have harnessed microbial CRISPR-Cas systems for use as platforms for investigating a range of genome and transcriptome manipulations. Dr. Zhang's talk will review the fundamentals of CRISPR-mediated technologies and highlight how further exploration of microbial diversity can contribute to the growing molecular toolbox and ultimately provide new therapeutic avenues for myriad diseases.
Dr. Giuliana Ferrari will discuss experimental gene therapy for hemoglobinopathies based on transplantation of autologous hematopoietic stem cells (HSCs) genetically modified to express therapeutic hemoglobin levels. Beta-thalassemia and sickle cell disease are congenital anemias caused by mutations in the beta-globin gene, resulting in either reduced production of globin chains or abnormal hemoglobin structure. Approaches to genetically modify HSCs for treatment of hemoglobinopathies include: the addition of globin genes by lentiviral vectors and gene editing by nucleases to reactivate fetal hemoglobin either through inhibiting repressors or through reproducing mutations associated with high fetal hemoglobin levels. Early clinical trials are promising, although hurdles limiting broader application remain. Dr. Ferrari will review these current challenges as well as improved strategies for HSC correction.
Dr. Wendell Lim will discuss synthetic biology approaches for engineering next-generation T cell therapies. Chimeric antigen receptor T cells have shown remarkable outcomes for certain malignancies, but targeting others, including solid tumors, has proven challenging. It is difficult to identify unique antigens, to ensure trafficking to tumor sites, and to mount strong anti-tumor responses in immunosuppressive tumor microenvironments. Dr. Lim's group is engineering cells that utilize new sets of sensors and modular control circuits that enable them to execute novel recognition and response programs with improved precision and robustness. These innovative capabilities may allow for development of therapeutic T cells that are far more effective and safer.