Enhancing the Potential of Immunotherapy in Paediatric Sarcomas: Breaking the Immunosuppressive Barrier with Receptor Tyrosine Kinase Inhibitors

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.

Current Landscape of Immunotherapy for Advanced Sarcoma

“…Tyrosine–kinase inhibitors (TKIs) are progressively gaining ground in CT-refractory sarcoma. In addition to blocking the immune-suppressive effect of VEGF [ 83 ], multi-target TKIs, especially lenvatinib and cabozantinib, seem to decrease the arrival of MDSCs/TAMs to the TME, and increase the infiltration of dendritic cells, NK cells and CD8+ lymphocytes [ 155 ]. This favorable immune-modulating effect provides a rationale for their combination with ICIs.…”

Recent advances on anti-angiogenic multi-receptor tyrosine kinase inhibitors in osteosarcoma and Ewing sarcoma

“…The vast majority of currently active clinical trials in this field are centered around regorafenib and cabozantinib, either as a monotherapy, or in combination with chemotherapy or immunotherapy. The combination of anti-angiogenic multi-RTK inhibitors to immune checkpoint inhibitors is interesting for OS and ES, as the vast majority of these drugs are capable of modulating the tumor microenvironment in such a way that it boosts the efficacy of anti-PD-1 therapy ( 8 ). Of the anti-angiogenic multi-RTK combination therapies clinically trialed in OS so far, the efficacy and tolerability of lenvatinib combined with etoposide and ifosfamide is of interest.…”

“…First-generation Receptor Tyrosine Kinase (RTK)-directed targeted therapies such as highly targetspecific anti-IGF-1R antibodies have shown encouraging clinical effects, albeit in small subsets of patients, and mainly in ES (3)(4)(5)(6)(7). With both the advancement of our understanding in OS and ES biology and the development of novel RTK-targeted drugs, however, increases in clinical benefit (any effect between disease stabilization and complete remission) have been reported with more recently developed small molecule multi-RTK-inhibitors in around 50-80% of thus far molecularly unselected, heavily pretreated OS and ES patients in prospective clinical trials (8,9). These response rates are largely dominated by multi-RTK small molecule inhibitors that combine a strong anti-angiogenic component via inhibition of the vascular endothelial growth factor receptors (VEGFRs) with simultaneous inhibition of other key RTKs implicated in OS and ES progression, including the plateletderived growth factor receptors (PDGFRs), c-KIT, fibroblast growth factor receptors (FGFRs), RET, and/or MET.…”

Immunoregulation by resveratrol; implications for normal tissue protection and tumour suppression

“…Recently, novel immunotherapy drugs such as immune checkpoint blockers (ICBs) have been assessed and approved for treatment of some malignancies 5 . Furthermore, several novel chemotherapy agents such as receptor tyrosine kinase inhibitors (RTKIs) have shown intriguing results 6 . Combined‐modality therapies have also been shown to enhance therapeutic efficacy and extend survival rates among patients in clinical trial studies 7 .…”

“…5 Furthermore, several novel chemotherapy agents such as receptor tyrosine kinase inhibitors (RTKIs) have shown intriguing results. 6 Combined-modality therapies have also been shown to enhance therapeutic efficacy and extend survival rates among patients in clinical trial studies. 7 Recent developments in radiotherapy may help with combined-modality therapies such as radioimmunotherapy.…”