Recent advances in engineered T cell therapies targeting B cell malignancies.

Immunotherapy using engineered autologous T cells has been attempted for decades, but clinical trials have only recently demonstrated efficacy. The combination of enhanced manufacturing techniques, highly efficient engineering, appropriate target selection and synthetic receptors with potent T cell activating domains has led to the development of highly-active cellular therapy products. B-cell malignancies have served as the paradigmatic diseases to initially evaluate and subsequently hone engineered T cells targeting cancer. Two engineered receptors, transgenic T cell receptors (tTCRs) and chimeric antigen receptors (CARs), have been explored clinically at several different institutions. The most profound success has been in pediatric and adult acute lymphoblastic leukemia, in which complete response rates after treatment with CD19-directed CAR T cells approach 90%. Success has been slightly less impressive in slower-growing diseases such as chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL), and experience is much more limited in the plasma cell disease multiple myeloma. A great deal of investigation is underway to understand the differences in response rates observed, and enhance the efficacy of these therapies in B cell cancers. Here, we review landmark and recent clinical trials, as well as pre-clinical work that demonstrates significant promise in propelling this field further in the coming years.