Abstract
Despite aggressive surgery, chemotherapy, and radiotherapy, survival of children and adolescents and young adults (AYAs) with sarcoma has not improved significantly in the past four decades. Immune checkpoint inhibitors (ICIs) are an exciting type of immunotherapy that offer new opportunities for the treatment of paediatric and AYA sarcomas. However, to date, most children do not derive a benefit from this type of treatment as a monotherapy. The immunosuppressive tumour microenvironment is a major barrier limiting their efficacy. Combinations of ICIs, such as anti-PD-1 therapy, with targeted molecular therapies that have immunomodulatory properties may be the key to breaking through immunosuppressive barriers and improving patient outcomes. Preclinical studies have indicated that several receptor tyrosine kinase inhibitors (RTKi) can alter the tumour microenvironment and boost the efficacy of anti-PD-1 therapy. A number of these combinations have entered phase-1/2 clinical trials, mostly in adults, and in most instances have shown efficacy with manageable side-effects. In this review, we discuss the status of ICI therapy in paediatric and AYA sarcomas and the rationale for co-treatment with RTKis. We highlight new opportunities for the integration of ICI therapy with RTK inhibitors, to improve outcomes for children with sarcoma.
Highlights
IntroductionIndividual responses to single agent Immune checkpoint inhibitors (ICIs) have been reported across different paediatric sarcoma subtypes, with outcomes ranging from stable disease (SD) and partial response (PR), to even a complete response in a patient with Ewing sarcoma [9,10,11]
Immunotherapies harness a patient’s own immune system to recognise and kill cancer cells and offer new hope for the treatment of children with sarcomas that are resistant to standard therapies
Immune checkpoint inhibitors (ICIs) have shown some potential in sarcoma, monotherapy approaches are not effective in most patients
Summary
Individual responses to single agent ICIs have been reported across different paediatric sarcoma subtypes, with outcomes ranging from stable disease (SD) and partial response (PR), to even a complete response in a patient with Ewing sarcoma [9,10,11] This illustrates that these inhibitors may be beneficial in selected paediatric sarcomas and provides a rationale to explore therapeutic combinations that may enhance their efficacy in a larger group of paediatric sarcomas that currently do not derive meaningful clinical benefit from these agents as monotherapies. We bring these approaches together and highlight the rationale for combining ICIs with RTKis, report early safety and efficacy data on these combinations in paediatric and AYA sarcoma patients, and highlight a number of successful adult sarcoma trials in this field to help pinpoint the most promising ICI and RTKi combinations that should be considered for future paediatric and AYA sarcoma clinical trials
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