Immunotherapies for pediatric cancer: current landscape and future perspectives

Abstract

The advent of immunotherapy has revolutionized how we manage and treat cancer. While the majority of immunotherapy-related studies performed to date have focused on adult malignancies, a handful of these therapies have also recently found success within the pediatric space. In this review, we examine the immunotherapeutic agents that have achieved the approval of the US Food and Drug Administration for treating childhood cancers, highlighting their development, mechanisms of action, and the lessons learned from the seminal clinical trials that ultimately led to their approval. We also shine a spotlight on several emerging immunotherapeutic modalities that we believe are poised to have a positive impact on the treatment of pediatric malignancies in the near future.

The Landscape of Pediatric Precision Oncology: Program Design, Actionable Alterations, and Clinical Trial Development

“…Anti-GD2 therapy with dinutuximab increased the survival of patients with high-risk neuroblastoma and is implemented into frontline therapy [116]. Immune checkpoint inhibition holds great promise in children with an inherited deficiency in DNA mismatch repair [117], and many clinical trials are ongoing to explore opportunities in childhood cancer [118]. However, one of the defining traits of pediatric tumors is their low mutational burden and relative lack of neoantigen expression, which limits their susceptibility to immune targeting.…”

Immune-checkpoint blockade of CTLA-4 (CD152) in antigen-specific human T-cell responses differs profoundly between neonates, children, and adults

“…[32][33][34][35] Whereas quite some Phase I/II studies with ICI in pediatric tumors have been disappointing, it was shown to be promising in Hodgkin and non-Hodgkins lymphoma. [36][37][38] Of importance, initiated childhood cancers as they occur in neonates, toddlers, and infants are usually different than adult ones, they show less mutational load, which adult cells acquire gradually over time, making childhood cancers less likely to be recognized by the adaptive immune response. Pediatric tumors rather arise from embryonal cells than epithelial cells and others such as ALL are often associated with a compromised immune response.…”

“…Due to the low levels of neoantigens of childhood tumors (in addition to other factors limiting antigen recognition), it has already been proposed to use combination therapy in pediatric cancers, aiming at enhancing other therapeutic approaches by ICIs. [36][37][38] The initial recognition of the tumor, is triggered for this purpose by other therapeutic approaches, such as radiotherapy, or for activating and directing polyclonal T-cell responses with bispecific antibodies (e.g. a fusion protein of anti-CD3 and a tumor antigen, e.g.…”

PD-1/PD-L1 in Cancer: Pathophysiological, Diagnostic and Therapeutic Aspects

“…The results indicated that Nivolumab was safe and well tolerated in children and young adults and showed clinical benefits in lymphoma, while no significant single-agent activity was observed in the other pediatric solid tumors. Importantly, however, this study defines the recommended phase 2 dose and establishes a Nivolumab safety profile for children, which can serve as the basis for its potential study in combination regimens for childhood cancers [ 144 , 145 ]. In this context, an actively recruiting Phase II clinical trial is evaluating the efficacy of Nivolumab in combination with ipilimumab in children with high-grade primary central nervous system (CNS) malignancies (NCT03130959) [ 141 ].…”

“…Pembrolizumab was approved by the FDA in 2017 for the treatment of children with refractory Hodgkin lymphoma or patients with relapsed tumors [ 145 ]. An ongoing clinical trial is investigating the use of Pembrolizumab in children with PD-L1-positive advanced, relapsed or refractory solid tumors or lymphoma or with advanced melanoma (NCT02332668).…”