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Introduction
The development of immune-based treatment (immunotherapy) for childhood cancer is a rapidly advancing field with impressive results already achieved in children with leukaemia.1 ,2 For cancers resistant to conventional treatments, harnessing the power and specificity of the immune system to fight cancer is one of several current avenues of research. The immune system is essential for controlling cancer progression by continual surveillance and elimination of transformed cells. This protective process is hindered by the ability of cancer cells to develop mechanisms enabling them to ‘hide’ from immune destruction (including downregulation of tumour-associated antigens and major histocompatibility complex (MHC) class I, and the creation of an immunosuppressive tumour microenvironment). The aims of cancer immunotherapy are to enhance existing antitumour immune responses (active immunotherapy), including cancer vaccines and immune checkpoint inhibitors, or to enable the immune system to specifically recognise and kill cancer cells (passive immunotherapy) (table 1).
Classification of immune-based therapies for childhood cancer
The identification of targetable tumour antigens is fundamental to the development of successful ‘passive’ immunotherapies. Ideally, targets should be highly expressed on cancer cells with little or no expression on normal tissue in order to avoid the potential for ‘on-target, off-tumour’ toxicities. B-lymphocyte antigen CD19 and disialoganglioside GD2 have been selected as suitable antigens for paediatric leukaemia and neuroblastoma immunotherapy clinical trials, respectively.1 ,3 However, neither of these targets are wholly cancer-specific; for example, CD19-directed therapy causes depletion of healthy B-cells, and GD2 is expressed at low level on normal peripheral nerves.
This article gives a brief overview of the main types of immunotherapy currently under development (table 2) and addresses some of the main caveats surrounding translation to clinical practice.
Overview of cancer immunotherapy approaches
What types of cancer immunotherapy are being developed?
Monoclonal antibodies
Over the last two decades, the development of monoclonal antibodies to treat cancer has yielded considerable success. Monoclonal antibodies directly targeting tumour antigens have now been incorporated into many standard paediatric treatment protocols.3 Bispecific antibodies and bispecific T cell engagers bind two targets and can therefore simultaneously bind a tumour antigen and cytotoxic T cell.5
Antibodies have also been engineered to block immune checkpoints. PD-1 and CTLA-4 are examples of inhibitory coreceptors that provide an ‘immunological break’ to uncontrolled T cell activation. Monoclonal antibodies that target these checkpoints can augment existing inhibited immune responses to cancer. PD-1 blockade has shown great promise in clinical trials for metastatic melanoma6 and other adult cancers, and its efficacy is now being tested in paediatric malignancies. Sensitivity to PD-1 blockade is related to higher mutational burden7; therefore, paediatric malignancies may not be as susceptible to immune checkpoint blockade as adult cancers.
Adoptive cell therapy
Adoptive cell therapy is an example of ‘personalised medicine’ where autologous tumour-specific T cells are manufactured in the laboratory before re-infusion back into the patient. Approaches in children include the culturing and genetic modification of T cells to promote activation, proliferation and tumour specificity (figure 1).
Production of autologous chimaeric antigen receptor (CAR)-engineered T cells for patient infusion.
Tumour specificity of T cells from peripheral blood can be achieved by genetic modification with antigen-specific T cell receptors (TCRs) or chimaeric antigen receptors (CARs). CARs combine an extracellular antibody-derived antigen-binding domain with an intracellular T cell activation domain (figure 1). CARs have the additional advantage of being unrestricted by MHC, unlike TCRs.
Clinical trials using CD19-directed CAR T cells for children with refractory leukaemia have achieved greater than 70% remission rates.1 A research priority is now to translate expertise to solid tumours, and a key challenge will be engineering CAR T cells that effectively traffic to tumour sites and form immunological memory.
Naturally occurring tumour-reactive T cells can also be derived and propagated from tumour tissue itself under special culture conditions (known as tumour-infiltrating lymphocytes), although there has been little clinical experience to date for childhood solid tumours.
Cancer vaccines
An example of active immunotherapy is through vaccination; however, clinical trials aimed at inducing antitumour immune responses have so far been disappointingly ineffective in children with cancer.
Translating immunotherapy into clinical practice
The development of novel immunotherapies must include rigorous preclinical testing to fully assess any potential harm to patients. Toxicities can be divided into two groups: those related to autoimmunity (‘on-target, off tumour effects’) and those relating to an increase in circulating cytokines (eg, leading to cytokine-release syndrome).8 Learning how to recognise and manage these toxicities will be key, following translation to large-scale clinical trials.
The manufacture of a personalised immunotherapeutic is a highly complex and labour-intensive process that is currently restricted to just a few centres in the UK. Hence, currently, treatment is limited to a small number of patients within a clinical trial setting. CD19 CAR T cells however are now being commercialised for much wider application, and one exciting development is ‘off the shelf’ rather than ‘patient-specific’ therapies achievable through ‘genome editing’ in which third party donor cells can be silenced for immune attack through deletion of genes such as MHC.
Conclusion
There has been a paradigm shift in adult oncology through the developments of cancer immunotherapy. For paediatrics, a major rate-limiting step has been the identification of optimal targetable tumour antigens. Combinational therapies with standard treatments or other immune-based treatments to overcome the immunoinhibitory microenvironment is a current research priority.
Footnotes
Contributors AC drafted the manuscript. JA provided critical review of the draft. Both authors approved the final version.
Funding AC is a Clinical Research Training Fellow supported by the Wellcome Trust, Great Ormond Street Hospital Children's Charity and Great Ormond Street Hospital Biomedical Research Centre. JA is funded by the Great Ormond Street Charity leadership award and Great Ormond Street Hospital NIHR Biomedical Research Centre.
Competing interests None declared.
Provenance and peer review Commissioned; externally peer reviewed.