Until the second half of the past century, leukaemia, the most frequent cancer in the paediatric age group, was an incurable disease. In 1948, Sidney Farber was the first researcher to demonstrate that a drug that inhibited the folate pathway, aminopterin, could achieve temporary remissions of leukaemia.1 Later, Donald Pinkel introduced the concept of “total therapy”, an approach in which the combination of chemotherapy agents synergistically induced prolonged remissions.1 Successive optimisations of this initial strategy have succeeded in turning childhood acute leukaemia a curable disease in most cases.2–4 However, even in developed countries today, cancer continues to be the leading disease-related cause of death in children and adolescents.

The development and impact of cancer treatments in the past decade is the fruit of decades of research.5–11 Unlike conventional treatments, immunotherapy aims to utilise, manipulate and augment the defences of the organism to attack and eliminate tumour cells. At present, cancer immunotherapy is the largest field in ongoing clinical trials worldwide. The term “cancer immunotherapy” encompasses a broad range of therapeutic options, including monoclonal antibodies, immune checkpoint inhibitors, vaccines, oncolytic viruses, cytokines, adjuvant immunotherapy and adoptive immunotherapy with T cell and natural killer (NK) cell transfers (Table 1). However, the recent and renewed momentum of immunotherapy and the greatest clinical and social interest it is currently attracting revolves around adoptive immunotherapy strategies based on the genetic modification of lymphocyte T cell receptors (TCRs) and the development of chimeric antigen receptors (CARs), with more than 700 clinical trials underway worldwide investigating their use for treatment of blood cancers and, to a lesser extent, solid tumours.

Paediatric haematology and oncology departments and units in Spain are exhibiting a clear interest in immunotherapy.12,13 This interest is evinced in the efforts made in the past and present by many institutions in forming multidisciplinary teams and adapting or creating the necessary infrastructures to implement these pioneering therapeutic programmes (either as treatment facilities or simultaneously as development and treatment facilities), or with active participation in preclinical development and clinical trials of these novel therapies. A consultation made in 2018 within the Group on Immunotherapy and Advanced Therapies of the la Sociedad Española de Hematología y Oncología Pediátricas (Spanish Society of Paediatric Haematology and Oncology) found that as many as 13 sites had an interest in CAR-T cells, NK cells, tumour-infiltrating lymphocytes, oncolytic viruses and monoclonal antibodies for treatment of both solid tumours (sarcomas and central nervous system tumours) and mainly of leukaemias. Furthermore, 9 facilities reported having their own infrastructure or access to authorised facilities for administration of cellular therapies and the manufacture of advanced targeted therapies (ATTs), while 4 facilities were accredited by the Joint Accreditation Committee International Society for Cellular Therapy Europe & European Group for Blood and Marrow Transplantation (JACIE) and another 4 were in the process of pursueing this accreditation.

Chimeric antigen receptor (CAR) T cell therapy emerged from the combination of advances in cancer humoral-targeted immunotherapies14 and the genetic manipulation of T cells (CAR-T cells).15,16 A CAR-T cell has antigen-recognition domains obtained from the variable regions of the heavy and light chains of a specific monoclonal antibody joined to form a single-chain Fv (scFv) domain. This scFv domain is fused to an intracellular CD3ζ TCR signalling motif. In the early days, Dr Zelig Eshhar called this strategy “T-body”.17 The first CAR T cells developed through this approach are known as first-generation CAR T cells.

At present, this technique has evolved to incorporate signalling motifs from different domains from costimulatory molecules such as CD28, OX40 or 41BB, giving rise to second- and third-generation CAR T cells. As an alternative to scFV, it is also possible to use domains from receptors such as NKG2D, CD16 or Erb-B.18,19 In theory it is possible to design CAR T cells to target any extracellular antigen, but those that target antigen CD19 (CART-19), which is expressed in B-cell lymphomas and B-cell acute lymphoblastic leukaemia (ALL) have been most clinically successful to date, and 2 commercial autologous T cell brands, Kymriah® (tisagenlecleucel, manufactured by Novartis) and Yescarta® (axicabtagene ciloleucel, manufactured by Gilead/Kite Pharma) started to be marketed in the United States in autumn of 2017 and in the European Union in summer of 2018.20–22

In Spain, academic institutions are developing CAR T-19 therapies parallel to the development in industry. The first public hospitals that promoted this strategy were the Hospital Clínic and the Hospital Sant Joan de Déu in Barcelona for treatment of paediatric patients with B-cell ALL and adults with B CD19+ lymphoma.23 At present, clinical trials of CAR T cells in Spain are underway in both industry and academic settings.

From a regulatory standpoint and for the purpose of development and manufacture, CAR T cells are considered advanced targeted therapies. The development and trial of medicines comprehends several phases aimed at guaranteeing the fundamental quality, safety and efficacy requirements expected of any drug.24–27 Preclinical in vitro and in vivo studies are the proof-of-concept phase that precedes performance of clinical trials. Confirmation of efficacy in phase III trials allows application for marketing authorization in the European Union. Until a few years ago, advanced targeted therapies had limited commercial success, but at present the industry has taken on this challenge and is developing these treatments. Nevertheless, academia continues to be the main drive of technological advancement in this type of therapies, which is reflected in the growing number of collaborations between academic institutions and industry partners.

CAR-T cell immunotherapy is associated with significant morbidity, especially in patients with a heavy tumour burden. The management of potential complications, such as cytokine release syndrome, neurologic changes, prolonged cytopenias or B-cell aplasia, requires multidisciplinary teams with experience in these complications, some of which are specific to CAR-T cell therapy and others commonly found in the context of allogeneic stem cell transplantation.

The delivery of treatments based on CAR-T cell immunotherapy requires a multidisciplinary team of different health professionals to carry out each phase of the process from administration to the patient through post-administration care: investigation of the clinical case and admission to the treatment protocol, collection of source material, submission of material to the external manufacturer or in-house manufacturing facility, patient conditioning with lymphodepleting chemotherapy, CAR-T cell infusion, follow-up and treatment of early and late post-infusion complications and legal and regulatory aspects.28–30 Therefore, the team responsible for the process must include different specialists and be well coordinated: haematologists, oncologists, intensive care physicians, paediatricians, neurologists, immunologists, biologists, geneticists, pharmacists, hospital pharmacists, regulation experts, nurses, professionals in different supportive care specialities and experts in different quality assurance systems. Since November 2018, the National Health System of Spain (Sistema Nacional de Salud, SNS) has established a National Plan for the delivery of ATTs and the administration of CAR-T cells, with establishment of regional plans by each regional government. The aim of the plan was to structure the delivery of these therapies in a planned, equitable, safe and efficient manner under conditions guaranteeing quality, safety and efficacy standards. The plan was developed in collaboration with the governments of each autonomous community of Spain, scientific societies and patient associations, and included a strategic plan to promote public research and for the translation of research to clinical practice and the in-house manufacturing of CAR-T cells by academic institutions. On March 4, 2019, the ministry established criteria and standards for the designation of centres authorised to use CAR-T cell therapies in the public health system.

In April 2019, the Spanish Ministry of Health published the list of the Spanish centres authorised for delivery of CAR- T cell therapy. It designated 8 centres for treatment of adult patients with refractory or recurrent diffuse large B-cell lymphoma (DLBCL) or refractory B-cell ALL. In the case of paediatric patients, it has designated 3 centres for treatment of refractory B-cell ALL. In addition, it designated 3 centres for delivery of CAR-T cell therapy in case capacity is exceeded in the other centres: 2 for adults and 1 for paediatric patients.

Centres authorised to deliver CAR-T cell therapy must have multidisciplinary units to address every aspect involved in the use of this treatment and the clinical management of the patients. The team must include the professional in charge of the CAR-T cell programme, clinicians involved in care delivery and other professionals. Fig. 1 presents a flow chart of the care delivery process for CAR-T cell therapy.

Figure 1.

Flow chart of the care delivery process for CAR-T cell therapy.

AC, autonomous community; CAR, chimeric antigen receptor; IC, informed consent; SNS: Spanish National Health System.

(0.41MB).

In December 2018, the Spanish Ministry of Health, Consumption and Social Welfare announced the funding for the first CAR-T cell therapy (CART-19, tisagenlecleucel) to be used in the public health system for treatment of refractory B-cell ALL and DLBCL, and the first case of a paediatric patient with B-cell ALL cured with this therapy was recently reported by the Hospital Sant Joan de Déu. In July 2019, the Ministry approved the price and funding of the second commercial CAR- T cell therapy (CART-19, axicabtagene ciloleucel) for treatment of adults with 2 types of non-Hodgkin lymphoma: DLBCL and primary mediastinal large B-cell lymphoma. In Spain, the funding of both of these treatments (tisagenlecleucel and axicabtagene ciloleucel) is subject to two-sided risk payment agreement. We ought to underscore that to the cost of the product we have to add the costs of hospitalization, supportive care and specific drugs for complications and interleukin-6 inhibitors.37

CAR-T cell therapies have been quickly introduced to the clinical setting due to the need to treat patients with refractory disease or multiple recurrences. In the specific case of B-cell ALL, the response rates are historically greater compared to the rates observed in chronic lymphocytic leukaemia and high-grade lymphomas. The reasons for this differential response, in the case of CART-19 in B-cell ALL, lymphoma and chronic lymphocytic leukaemia, may be multiple and intrinsic to the tumour cell. However, a growing body of evidence suggests that the quality of the autologous T cells used as effector cells to be CAR-transduced has a substantial impact on treatment response. Unfortunately, the “functionality” of T cells has been frequently assessed in clinical samples obtained at the time of diagnosis, whereas few studies have prospectively assessed the quality of T cells in recurrences or in more advanced stages of disease. Therefore, studies are needed that include functional assessments of T cells in stages of disease close to the potential inclusion of a patient in a CAR-T cell trial. These studies should be longitudinal and compare the characteristics and function of T cells at diagnosis with those of healthy donors matched for age, and the differences in paired samples of T cells collected at diagnosis and at the time of recurrence. These studies should collect data on: a) the number of T cells available for use in adoptive immunotherapy; b) the distribution of lymphocyte populations with particular emphasis on γδ and memory T cells; c) the proliferative, activation and proinflammatory capacity in response to antigen exposure, and d) the expression of immune checkpoints, which tend to increase significantly in advanced stages of disease, thus facilitating immune evasion and T cell depletion.38,39 The manufacture of universal donor-derived allogeneic CAR-T cells and their availability as cryopreserved therapies is a challenge for the upcoming future. To achieve this objective, we need to develop safer gene editing systems to both guarantee effective transduction and allow the use of T cells in a human leukocyte antigen (HLA)–independent manner.

On the other hand, the main limitation of CAR-T cell therapy at present, in addition to the complications of treatment, is its cost and the complexity of its manufacture. The possibility of using CAR-T cells produced in academia is both a great challenge and a great opportunity. Lastly, therapies from other effector cell sources, such as NK cells (CAR-NK) derived from umbilical cord blood or the memory T cell populations, must be developed to overcome all the current limitations of CAR-T cell therapy.

We are experiencing a revolutionary time in the management of paediatric cancer patients as immunotherapy is added to conventional treatments with extraordinary impact. To date, CAR T-19 therapy has been the most successful immunotherapy modality and has already been approved for use in children and young adults up to age 25 years with refractory or second relapse B-cell ALL. For the time being, 2 commercial brands have received approval for CAR-T cell therapy, although only one has been authorised for the paediatric age group, and a logistics model must be established in accordance with pharmaceutical standards for their global manufacture and distribution to a large number of patients whose adequacy will be tested with experience. On the other hand, anything concerning bridging therapy prior to CAR-T cell administration and the subsequent management of complications will correspond to another learning curve, so each facility will also have to establish its own standards regarding the use of these products. The in-house manufacturing model, with production within each facility in a closed model, and the simplification of the construction of strictly controlled facilities in adherence with the quality and safety standards that apply to any facilities that manufacture medicinal products will make it possible to, on one hand, optimise processes and their costs while increasing patient safety and ensuring excellence of care and competitive care delivery as strategies are disseminated with this decentralization, and on the other to promote teaching and research in the field of paediatric haematology and oncology.

The authors have no conflicts of interest to declare.