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The anticancer potential of the immune system has long been recognized in haematological malignancies, with allogeneic stem cell transplantation and donor lymphocyte infusions now established as standards of care for acute myeloid leukaemia (AML), acute lymphoblastic leukaemia (ALL) and some types of lymphomas. In addition, immunomodulatory drugs and monoclonal antibodies that trigger antibody-dependent cell-mediated cytotoxicity have been shown to be effective treatments for multiple myeloma and B cell lymphomas (e.g. B cell non-Hodgkin lymphoma [B-NHL]). The accessibility of bone marrow and lymph nodes (the predominant sites of haematological tumours) to circulating immune cells, as well as their susceptibility to immune cell-mediated killing, makes them an obvious target for adoptive T cell therapy (ACT). It was, however, the discovery that T lymphocytes could be retargeted to tumour cells, independently of the major histocompatibility complex (MHC), using chimeric antigen receptors (CARs) that fuelled interest in the field of ACT for haematological malignancies.

A CAR T cell is an artificial T cell receptor (TCR) consisting of an antigen-binding domain derived from a monoclonal antibody (single-chain variable fragment), an activation domain (cluster of differentiation [CD] 3ζ) and a co-stimulatory domain (typically CD28 or CD4–1bb).1 The target antigen is generally expressed strongly and homogenously on the surface of tumour cells, with little or no expression on normal cells, and ideally plays a role in tumour survival.

Results from CAR T cell trials in haematological malignancies

CD19, an antigen expressed on normal B lymphocytes and B cell lineage malignancies, was the target of the initial CAR T cell products, given its relative specificity and strong expression in chronic lymphocytic leukaemia (CLL), B cell ALL (B-ALL) and B-NHL.

Initial studies with first generation CAR T cells lacking a co-stimulatory domain failed to show persistence of the CAR T cell in vivo, or any clinical activity. The first reports of the successful use of CD19 CAR T cells came in 2011 from groups led by Michel Sadelain, Carl June and Steven Rosenberg using second generation CAR T cells in CLL, B-ALL and follicular NHL.24 These studies highlighted the importance of having a co-stimulatory domain within the CAR T cell construct and the need to use lymphodepleting drugs to facilitate CAR T cell expansion. After these early promising results a number of other phase I studies were conducted in relapsed paediatric and adult B-ALL patients showing highly impressive complete response rates of 70–90% irrespective of which CD19 CAR T cell was used. The long-term outcome from CD19 CAR T cell treatment was confirmed by the Determine Efficacy and Safety of Tisagenlecleucel in Pediatric Patients with Relapsed and Refractory B-Cell ALL (ELIANA) study, which showed an overall remission rate of 81%, event-free survival of 50% and overall survival of 76%, 12 months after CAR T cell treatment in patients <21 years with relapsed B-ALL.5 Although the initial strategy was to offer an allogeneic stem cell transplant as consolidation ...

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