The promise of chimeric antigen receptor T cells (CARTs) in leukaemia

Abstract

The success of genetically engineered T cells that express chimeric antigen receptors (CARTs) has been a momentous step forward in harnessing the potent cancer fighting abilities of the immune system. The efficacy seen in relapsed/refractory (r/r) acute lymphoblastic leukaemia (ALL), not only by inducing remission, but also in maintaining long-term disease control, has been unprecedented. While the foundation for this approach has been firmly set in place, continued development will improve the efficacy, toxicity and applicability to other malignancies of this new class of 'living drugs'. In this review, we provide a comprehensive overview of the most current clinical trial data in both acute and chronic leukaemias, and discuss some of the potential ways to enhance the activity and safety of CART therapy going forward.

Chronic lymphocytic leukaemia: the role of T cells in a B cell disease

“…This could compromise adoptive T cell therapies, such as CAR‐T, which rely on ex vivo expansion and then in vivo persistence of autologous T cells (Rosenberg et al , ; Fraietta et al , ). The development of protocols to optimise CAR‐T cell manufacture and efficacy is an area of intense research activity (Orlowski et al , ), but beyond the scope of this review.…”

Debate: Transplant is Still Necessary in the Era of Targeted Cellular Therapy for ALL

“…High levels of inflammatory cytokines, including interferon-g, soluble IL2ra, and IL-6, which appears central to the CRS process, are noted. 18 Tumor burden, CAR T-cell dosage, and use of lymphodepleting chemotherapy impact the development of CRS. Investigations are underway to determine cytokine profiles that may predict which patient will develop sCRS.…”

Mesenchymal Stem Cells in Myeloid Malignancies: A Focus on Immune Escaping and Therapeutic Implications

“…These approaches are currently aimed at leukemic blast targeting, but MSC patterns might be new targets in the next future. In particular, CART cells, engineered with synthetic polypeptides consisting of an extracellular variable fragment directed to a tumor antigen and an intracellular signaling domain, potentiated by the addition of costimulatory molecules in new generation models, have shown great success in relapsed/refractory ALL and may find a role in AML too, possibly targeting AML-associated/specific antigens like CD33, CD123, Lewis Y antigen, and folate receptor beta [ 123 ]. DLI is effective in reinducing response in AML residual/relapsing disease after allogeneic stem cell transplant and is currently investigated as a way to eradicate minimal residual disease (MRD), which correlates to higher relapse rate and reduced survival in AML [ 124 ].…”