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I. Yakoub-Agha et al.
care and supply chain management under the following headings: patient eligibility, screening laboratory tests and imaging and work-up prior to leukapheresis, how to perform leukapheresis, bridging therapy, lym- phodepleting conditioning, product receipt and thawing, infusion of CAR T cells, short-term complications including cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, antibiotic prophylaxis, medium-term complications including cytopenias and B-cell aplasia, nursing and psychological support for patients, long-term follow-up, post-authorization safety surveillance, and regulatory issues. These recommendations are not prescriptive and are intended as guidance in the use of this novel therapeu- tic class.
Introduction
The first experimental attempts to engineer T cells to express chimeric antigen receptors (CAR) were performed 30 years ago.1,2 The ultimate goal was to produce function- al, high-affinity, CAR T cells in which the T-cell receptor is re-directed towards a tumor antigen of choice.3 Following refinements in the signaling properties of a CAR within the context of a T cell, development progressed rapidly from the laboratory to clinical trials and CAR T cells targeting CD19 now represent a novel and promising therapy for patients with refractory/relapsed B-cell malignancies including acute lymphoblastic leukemia (ALL) and diffuse large B-cell lymphoma (DLBCL).3-7 CAR T cells are also being assessed as treatment for other hematologic diseases such as multiple myeloma and acute myeloid leukemia as well as for solid tumors.5,8-10
Tisagenlecleucel (KymriahTM, previously CTL019, Novartis, Basel, Switzerland) consists of autologous CAR T cells genetically modified ex vivo using a lentiviral vec- tor encoding an anti-CD19 CAR that includes a domain of the 4-1BB co-stimulatory molecule. It is indicated for the treatment of children and young adults up to the age of 25 years with relapsed/refractory B-ALL and was approved by the Food and Drug Administration (FDA) on 30th August, 2017. It was subsequently FDA-approved on May 1st, 2018 for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including DLBCL not oth- erwise specified, high-grade B-cell lymphoma and DLBCL arising from follicular lymphoma. The European Medicines Agency (EMA) approved similar indications on August 22nd, 2018.
Axicabtagene ciloleucel, (YescartaTM, previously KTE- C19, Gilead, USA) is an autologous CAR T-cell product which has been genetically modified ex vivo using a retro- viral vector encoding an antibody fragment targeting CD19 and an intracellular domain including the CD28 co- stimulatory molecule. It was FDA-approved on October 18th, 2017 for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including DLBCL not oth- erwise specified, primary mediastinal large B-cell lym- phoma, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma. The EMA approved its use in relapsed or refractory DLBCL and primary mediastinal large B-cell lymphoma after two or more lines of systemic therapy, on August 23rd, 2018.
While CAR T cells are rationally designed, targeted therapies, they nevertheless frequently induce life-threat- ening toxicities that can be mitigated by planning and proper hospital organization. Comprehensive training should be provided to all categories of personnel includ-
ing scientists, nurses and physicians, and close collabora- tion with a range of other specialists, especially intensive care unit staff and the neurology/neuroimaging services, is required.11,12
As CAR T cells represent a novel class of therapy and as both of the currently available products have only been evaluated in phase II studies to date, close post-marketing surveillance is mandatory. The EMA has endorsed the use of the European Blood and Marrow Transplantation (EBMT) registry for the collection of 15-year follow-up data on treated patients in order to ensure that evaluation of the efficacy and safety of commercially available CAR T cells continues on an ongoing basis. The Center for International Blood and Marrow Transplant Research (CIBMTR) fulfills a similar function in the United States of America (USA). The newly updated EBMT Registry Cellular Therapy form is designed to capture the efficacy and side-effects of modern cellular therapies and to pro- vide the required post-marketing surveillance through Post-Authorization Safety Surveillance (PASS) and other studies. The main objective for professionals in the field is to evaluate how these innovative treatments compare with the alternative therapeutic options and current stan- dards-of-care. Phase III studies are underway.13
The clinical use of CAR T cells is early in its evolution and it is, as yet, unclear whether CAR T-cell therapy con- stitutes a definitive treatment or whether disease cure will require further immunologically based consolidation such as allogeneic stem cell transplantation, especially for ALL. In trials on the use of CAR T-cell therapy in DLBCL, long-term disease control is observed in up to 50% of patients. As some of these patients may be cured, allo- geneic transplantation as consolidation may not be neces- sary.14-16 This issue can only be resolved with longer fol- low-up.
Research areas include dual antigen targeting to counter one of the most common resistance mechanisms, which is loss of the targeted antigen, the inclusion of safety switches such as suicide genes in order to mitigate side- effects when they occur, ‘off the shelf’ allogeneic CAR T products, the refinement of co-stimulatory domains to enhance persistence and avoid immune escape, and the use of non-viral vectors and semi-automated on-site pro- duction to simplify the manufacturing process.
Although this field will inevitably change over the com- ing years, these first EBMT guidelines on CAR T cells are intended to provide practical, clinically relevant recom- mendations for hematologists and other cancer specialists and their teams involved in the administration of CAR T- cell therapies, especially the commercially available prod- ucts. These guidelines may also be a useful resource for other stakeholders such as pharmacists or health service administrators involved in the planning and delivery of
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haematologica | 2020; 105(2)