Advances in chimeric antigen receptor immunotherapy for chronic lymphocytic leukemia.

Despite the recent advances with targeted therapies in chronic lymphocytic leukemia (CLL), allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative option. However, this procedure is associated with significant morbidity and mortality due to high rates of infection and the toxicity of graft versus host disease (GVHD). One of the principle aims of cellular immunotherapy is to target the malignant cells without damaging the other tissues of the body. T lymphocytes offer the opportunity to do this, due to the exquisite specificity that they exhibit as part of the adaptive immune response. Chimeric antigen receptor (CAR) T cells are lymphocytes that have been genetically modified to express the antigen binding component of an immunoglobulin molecule coupled to T-cell signaling domains. The use of an immunoglobulin molecule eliminates MHC restriction, enabling the same CAR to be used for several different patients and increasing the feasibility of widespread clinical use. They can be constructed to target a huge range of antigens, allowing the targeting of cancer cells with unprecedented levels of specificity. The addition of co-stimulatory domains to the CAR construct has enhanced the efficacy and durability of these T cells, which are under investigation in several clinical trials. The early results from these trials have been very encouraging with dramatic responses being observed in heavily pre-treated patients with otherwise poor risk disease.