Immune Checkpoint Inhibitors for Pediatric Cancers: Is It Still a Stalemate?

Abstract

The knowledge surrounding the application of immune checkpoint inhibitors (ICIs) in the treatment of pediatric cancers is continuously expanding and evolving. These therapies work by enhancing the body's natural immune response against tumors, which may have been suppressed by certain pathways. The effectiveness of ICIs in treating adult cancers has been widely acknowledged. However, the results of early phase I/II clinical trials that exclusively targeted the use of ICIs for treating different pediatric cancers have been underwhelming. The response rates to ICIs have generally been modest, except for cases of pediatric classic Hodgkin lymphoma. There seems to be a notable disparity in the immunogenicity of childhood cancers compared to adult cancers, potentially accounting for this phenomenon. On average, childhood cancers tend to have significantly fewer neoantigens. In recent times, there has been a renewed sense of optimism regarding the potential benefits of ICI therapies for specific groups of children with cancer. In initial research, individuals diagnosed with pediatric hypermutated and SMARCB1-deficient cancers have shown remarkable positive outcomes when treated with ICI therapies. This is likely due to the underlying biological factors that promote the expression of neoantigens and inflammation within the tumor. Ongoing trials are diligently assessing the effectiveness of ICIs for pediatric cancer patients in these specific subsets. This review aimed to analyze the safety and effectiveness of ICIs in pediatric patients with different types of highly advanced malignancies.

Keywords: SMARCB1-deficient; hypermutated; immune checkpoint inhibitors; pediatric cancer.

Figure 2

This figure illustrates the intricate signaling interactions between tumor cells, tumor-associated macrophages, and tumor-infiltrating lymphocytes within the medulloblastoma microenvironment. This figure is based on the research conducted by Kurdi et al. (2023) [43]. MB: medulloblastoma; NK: natural killer; TAM: tumor-associated macrophage; TIL: tumor-infiltrating lymphocyte; TIM-3: T-cell immunoglobulin and mucin domain 3.

Figure 1

Timeline of critical milestones for developing immune checkpoint inhibitors. Abbreviations: CTLA-4, cytotoxic T-lymphocyte-associated protein 4; ICI, immune checkpoint inhibitor; MMR, mismatch repair; MSI, microsatellite instability; PD-1, programmed death-1; PD-L1, programmed death-ligand 1; TMD, tumor mutational burden. Figure generated by authors based on the existing literature [9,10,30,31,32,33].

Figure 3

The studies conducted by Davis et al. (2021) [64] were used to derive the bottom-right corner of Figure 3, while the left part of Figure 3 was derived from Long et al. (2022) [3]. These studies demonstrated that tumors with deficiencies in MMRD and SMARCB-1 have reignited interest in the potential use of ICIs in these patients. MMRD: mismatch repair deficiency; SMARCB-1: SWI/SNF-Related, Matrix-Associated, Actin-Dependent Regulator Of Chromatin, Subfamily B, Member 1.

Figure 4

Exploring combination therapies to address resistance in ICI therapy. The process of generating an effective tumor-directed T-cell response involves several steps. These include the formation of tumor-specific T cells, the activation of effector T-cell function, and the development of effector memory T cells. This figure is derived from the study of Fujiwara et al. (2020) [33].

Figure 5

Exploring the pathophysiological mechanisms in CIP. By utilizing ICI, T cells can overcome the immunosuppression caused by cancer. The activation of different pathways leads to the proliferation of B and plasma cells, which in turn produce autoimmune antibodies like anti-CD74. In addition, they trigger the release of inflammatory cytokines such as IL-1β, TNF-α, and CXCL-10, which can affect various cell types. In addition, T cells, such as Tcm, Th, and clonal T cells, undergo expansion in response to various factors within the tumor microenvironment, the tumor’s mutational burden, and self-antigens located in the lung tissue. The combination of these various pathways can cause inflammation in the lungs, leading to CIP. The role of myeloid cells in CIP is clear, although the exact mechanisms are still not fully understood. Their role in T-cell activation and expansion can be influenced by the T-cell and cytokine environment, potentially leading to pulmonary injury. The presence of clear lines in CIP signifies the existence of established mechanisms, whereas the presence of dotted lines suggests potential mechanisms. This figure is derived from the study of Ghanbar et al. (2024) [94].