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.2227-9059Fleuren, Emmy D G <br />Orcid: 0000-0001-6202-6861 <br />Terry, Rachael L <br />Orcid: 0000-0002-6260-7372 <br />Meyran, Deborah <br />Orcid: 0000-0003-2723-8185 <br />Omer, Natacha <br />Orcid: 0000-0002-5643-1307 <br />Trapani, Joseph A <br />Haber, Michelle <br />Neeson, Paul J <br />Ekert, Paul G <br />Orcid: 0000-0002-2976-8617 <br />43/ANZSA Sarcoma Research Grant/ <br />Emerging Research Leader Program grant/Can Too Foundation/ <br />Fellowship 2020/ECF1261/Cancer Institute New South Wales/ <br />Pioneering Research Grant Scheme, grant number RSP- 467 00042-19/20/Tour de Cure/ <br />Journal Article <br />Review <br />Biomedicines. 2021 Nov 30;9(12):1798. doi: 10.3390/biomedicines9121798. <br />