Treatment of metastatic pediatric solid tumors remain a significant challenge, particularly in relapsed and refractory settings. Standard treatment has included surgical resection, radiation, chemotherapy, and, in the case of neuroblastoma, immunotherapy. Despite such intensive therapy, cancer recurrence is common, and most tumors become refractory to prior therapy, leaving patients with few conventional treatment options. Natural killer (NK) cells are non-major histocompatibility complex (MHC)-restricted lymphocytes that boast several complex killing mechanisms but at an added advantage of not causing graft-versus-host disease, making use of allogeneic NK cells a potential therapeutic option. On top of their killing capacity, NK cells also produce several cytokines and growth factors that act as key regulators of the adaptive immune system, positioning themselves as ideal effector cells for stimulating heavily pretreated immune systems. Despite this promise, clinical efficacy of adoptive NK cell therapy to date has been inconsistent, prompting a detailed understanding of the biological pathways within NK cells that can be leveraged to develop “next generation” NK cell therapies. Here, we review advances in current approaches to optimizing the NK cell antitumor response including combination with other immunotherapies, cytokines, checkpoint inhibition, and engineering NK cells with chimeric antigen receptors (CARs) for the treatment of pediatric solid tumors.

Understanding the role of immune checkpoints has undeniably changed the landscape of cancer immunotherapy. Programmed cell death protein 1 (PD-1) is induced after T cells are activated and serves as a marker of activation that provides inhibitory signals to T cells after engagement of its ligand, programmed death ligand 1 (PD-L1). PD-1 is also a marker of chronic antigen stimulation, since checkpoint blockade with monoclonal antibodies against PD-1 abrogates T cell exhaustion, generating robust antitumor responses (1, 2). Cancers that have been clinically approved for PD-1 inhibition include melanoma, renal cell carcinoma, metastatic non-small cell lung cancer, urothelial carcinoma, classical Hodgkin lymphoma, and others (3, 4). Interestingly PD-1 blockade can induce responses in various cancers with low expression of major histocompatibility complex class I (MHCI), necessary for cytotoxic CD8 + T cell recognition, suggesting enhanced cytolytic activity by CD4 + T cells or effector cells capable of cytotoxicity independently of MHC.NK cells are cytotoxic lymphocytes that can eliminate virally infected cells and tumors using cytotoxicity mechanisms similar to CD8 + T cells, but that do not require recognition of MHC (5). Using deductive reasoning from the "missing self " hypothesis, blocking PD-1 on NK cells may augment antitumor effects for tumors that are refractory to T cell treatments due to low MHC expression (6). The fundamental basis behind applying checkpoint blockade against PD-1 on NK cells must, of course, assume that NK cells express PD-1.

Advancements in cancer screening and implementation of targeted treatments have significantly improved survival rates to 85% for pediatric and AYA survivors. Greater than 75% of survivors will live to experience the long-term adverse outcomes of cancer therapies, termed late effects (LE), that disrupt quality of life (QoL). Infertility and poor reproductive outcomes are significant disruptors of QoL in survivorship, affecting 12–88% of survivors who receive at-risk therapies. To mitigate risk, fertility preservation (FP) counseling is recommended as standard of care prior to gonadotoxic therapy. However, disparities in FP counseling, implementation of FP interventions, and screening for gynecologic late effects in survivorship persist. Barriers to care include a lack of provider and patient knowledge of the safety and breadth of current FP options, misconceptions about the duration of time required to implement FP therapies, cost, and health care team bias. Developing strategies to address barriers and implement established guidelines are necessary to ensure equity and improve quality of care across populations.

Highlights Metastatic melanoma to the ovary is uncommon and can occur years after initial diagnosis. Ovarian metastatic melanoma can mimic various benign lesions on imaging and clinical history is key. If any suspicion in pregnancy, placenta should be evaluated due to possibility of transplacental transmission.