Emerging T Cell Engineering Approaches: New Targets and New Cell Sources

The field of chimeric antigen receptors (CARs) in hematologic malignancies has been largely dominated by the adoptive transfer of T cells expressing the CD19-specific CAR for therapy of acute lymphoid leukemia and non-Hodgkin's lymphomas. More recently other target antigens have been tested in phase I studies with the aim to either mitigate the B cell aplasia, caused by CD19-specific CAR-Ts in B-lymphoid malignancies, or to target other malignancies non-expressing CD19. Two new targets such as k-light chain of human immunoglobulins to target B-cell lymphomas and CD30 to target Hodgkin's lymphoma have completed phase I studies showing antitumor activity. Efforts are also dedicated to contain the toxicities associated with the infusion of CD19.CAR-T cells by including safety switches. The inducible-Caspase9 (iC9) may represent a precise strategy to modulate these toxicities by eliminating CAR-Ts in a dose-dependent manner, allowing either a selective containment of CAR-T cell expansion or complete deletion. Finally, while polyclonal activated T cells are generally used in clinical trials as a platform to engraft CARs, other sources like NK cells and NKT cells can potentially be explored in specific clinical situations such as after allogeneic T-cells, since both NK and NKT cells do not carry the risk of graft-versus-host disease (GVHD).