Redirecting T cells to treat solid pediatric cancers Abstract The capacity of single-agent therapy with immune checkpoint inhibitors to control solid cancers by unleashing preexisting local antitumor T cell responses has renewed interest in the broader use of T cells as anticancer therapeutics. At the same time, durable responses of refractory B-lineage malignancies to chimeric-receptor engineered T cells illustrate that T cells can be effectively redirected to cancers that lack preexisting tumor antigen-specific T cells, as most typical childhood cancers. This review summarizes strategies by which T cells can be modified to recognize defined antigens, with a focus on chimeric-receptor engineering. We provide an overview of candidate target antigens currently investigated in advanced preclinical and early clinical trials in pediatric malignancies and discuss the prerequisites for an adequate in vivo function of engineered T cells in the microenvironment of solid tumors and intrinsic and extrinsic limitations of current redirected T cell therapies. We further address innovative solutions to recruit therapeutic T cells to tumors, overcome the unreliable and heterogenous expression of most known tumor-associated antigens, and prevent functional inactivation of T cells in the hostile microenvironment of solid childhood tumors.

Immunotherapy in pediatric acute lymphoblastic leukemia Abstract The 5-year survival rate for children and adolescents with acute lymphoblastic leukemia (ALL) has improved to more than 90% in high-income countries. However, further increases in the intensity of conventional chemotherapy would be associated with significant adverse effects; therefore, novel approaches are necessary. The last decade has seen significant advances in targeted therapy with immunotherapy and molecular therapeutics, as well as advances in risk stratification for therapy based on somatic and germline genetic analysis and monitoring of minimal residual disease. For immunotherapy, the approval of antibody-based therapy (with blinatumomab in 2014 and inotuzumab ozogamicin in 2017) and T cell–based therapy (with tisagenlecleucel in 2017) by the US Food and Drug Administration has significantly improved the response rate and outcomes in patients with relapsed/refractory B-ALL. These strategies have also been tested in the frontline setting, and immunotherapy against a new ALL-associated antigen has been developed. Incorporating effective immunotherapy into ALL therapy would enable the intensity of conventional chemotherapy to be decreased and thereby reduce associated toxicity, leading to further improvement in survival and quality of life for patients with ALL.

Novel therapy for pediatric and adolescent kidney cancer Abstract Pediatric and adolescent renal tumors account for approximately 7% of all new cancer diagnoses in the USA each year. The prognosis and treatment are varied based on factors including the underlying histology and tumor stage, with survival rates ranging from greater than 90% in favorable histology Wilms tumor to almost universally fatal in other disease types, including those patients with advanced stage malignant rhabdoid tumor and renal medullary carcinoma. In recent years, our understanding of the underlying genetic drivers of the different types of pediatric kidney cancer has dramatically increased, opening the door to utilization of new targeted biologic agents alone or in combination with conventional chemotherapy to improve outcomes. Several ongoing clinical trials are investigating the use of a variety of targeted agents in pediatric patients with underlying genetic aberrations. In this manuscript, the underlying biology and early phase clinical trials relevant to pediatric renal cancers are reviewed.

Minimally invasive surgery to treat embryonal tumors of childhood Abstract Minimally invasive surgery (MIS) to resect primary and metastatic pediatric embryonal tumors offers the potential for reduced postoperative morbidity with smaller wounds, less pain, fewer surgical site infections, decreased blood loss, shorter hospital stays, and less disruption to treatment regimens. However, significant controversy surrounds the question of whether a high-fidelity oncologic resection of childhood embryonal tumors with gross total resection, negative margins, and appropriate lymph node sampling can be achieved through MIS. This review outlines the diverse applications of MIS to treat definitively pediatric embryonal malignancies, including this approach to metastatic deposits. It outlines specific patient populations and presentations that may be particularly amenable to the minimally invasive approach. This work further summarizes the current evidence supporting the efficacy of MIS to accomplish a definitive, oncologic resection without compromising relapse-free or overall survival. Finally, the review offers technical considerations to consider in order to achieve a safe and complete resection.

Joint-preservation surgery for pediatric osteosarcoma of the knee joint Abstract The multi-disciplinary approach involving imaging, multi-agent chemotherapy, meticulous surgical procedures, and careful postoperative care has facilitated an increase in the use of limb-sparing surgery for pediatric osteosarcoma. Osteosarcoma usually occurs around the metaphysis of the distal femur or proximal tibia and needs wide excision with the adjacent joint and replacement by a megaprosthesis. The recent advancement in imaging modalities and surgical techniques supports joint-preservation surgery (JPS), involving the preservation of the adjacent epiphysis, for select patients following careful assessment of the tumor margins and precise tumor excision. An advantage of this surgery is that it maintains the adjacent joint and preserves the growth of the residual epiphysis, which provides excellent limb function. Various reconstruction options are available, including allograft, tumor-devitalized autograft, vascularized fibula graft, distraction osteogenesis, and custom-made implants. However, several complications are inevitable with these options, such as loosening, non-union at the host-graft junction, infection, fracture, implant loosening, breakage, deformity, limb-length discrepancy related to the reconstruction methods, or patient growth in pediatric osteosarcoma. Surgeons should fully understand the advantages and disadvantages of this procedure. In this review, we discuss the concept of JPS, types of reconstruction methods, and current treatment outcomes. It is our opinion that the further analysis by multi-institutional setting is necessary to clarify long-term outcomes and establish global guidelines on the indications and surgical procedure for JPS.

MicroRNA as a prognostic biomarker for survival in childhood acute lymphoblastic leukemia: a systematic review Abstract Recent studies suggest abnormal microRNA (miRNA) expression may have potential prognostic value in childhood acute lymphoblastic leukemia (ALL). In this systematic review, we searched different databases (PubMed, ASH, ASCO, and SIOP) for studies published from 2008 to 2018 that evaluated the prognostic impact of miRNAs in childhood ALL. We also used DIANA-miRPath v3.0 to further characterize the functional role of the significant prognostic miRNAs identified in our systematic review. Here we evaluate 15 studies with a total of 38 different miRNAs and 1545 children with B-cell ALL (B-ALL) or T-cell ALL (T-ALL) recruited over approximately 3 decades (1984–2016) with different treatment protocols and ethnicities. Out of the 15 studies examined, 14 reported 32 dysregulated miRNAs with significant prognostic impact in pediatric ALL patients. Only one Brazilian study reported no significant prognostic effect of 7 miRNAs, while the seventh miRNA (miR-100) showed prognostic significance in a Chinese study. Using DIANA-TarBase v7.0 of DIANA-miRPath v3.0, pathway enrichment analysis revealed 25 miRNAs modulated 24 molecular pathways involved in cancer development. To remove the effect of salvage therapy, 9 studies carried out multivariate cox regression analysis for both relapse-free survival and disease-free survival to develop a panel of 23 miRNAs acting as independent prognostic biomarkers. To enhance the clinical application, utility, and validity of the miRNAs discussed here, their potential prognostic value should be confirmed in larger cohort studies within different ethnicities and different ALL protocols adjusted for other contemporary validated prognostic factors in childhood ALL.

Pathological and therapeutic aspects of matrix metalloproteinases: implications in childhood leukemia Abstract Matrix metalloproteinases (MMPs) play a major role in extracellular matrix remodeling and are involved in tumor cell invasion. Cancers such as childhood leukemia are characterized by their capacity to infiltrate different organs. MMP production by leukemic cells may indicate a leukemic subtype or subpopulation with a more invasive phenotype. Therefore, clarifying the action mechanisms of MMPs as prognostic predictors or MMP targeting as a therapeutic strategy is necessary. MMP-targeting drugs have been developed for the treatment of hematological malignancies. In this review, we highlight current advances in understanding the molecular mechanisms and pathological characteristics of various MMPs, as well as recent therapeutic advances targeting MMPs in childhood leukemia. Several studies have been conducted on the therapeutic efficacy of MMP inhibitors in cancer, such as collagen peptidomimetics, nonpeptidomimetic inhibitors of MMP active sites, bisphosphonates, and tetracycline derivatives. Here, we conclude that more clinical trials are necessary to estimate the role of selective MMP inhibitors in the treatment and prevention of childhood leukemia.

Pediatric diffuse intrinsic pontine glioma: where do we stand? Abstract Pediatric diffuse intrinsic pontine glioma (DIPG) represents approximately 20% of all pediatric CNS tumors. However, disease outcomes are dismal with a median survival of less than 1 year and a 2-year overall survival rate of less than 10%. Despite extensive efforts to improve survival outcomes, progress towards clinical improvement has been largely stagnant throughout the last 4 decades. Focal radiotherapy remains the standard of care with no promising single-agent alternatives and no evidence for improvement with the addition of a long list of systemic therapies. A better understanding of the biology of DIPG, though not easy due to obstacles in obtaining pathological material to study, is promising for the development of specific individualized treatment for this fatal disease. Recent studies have found epigenetic mutations to be successful predictors and prognostic factors for developing future management policies. The aim of this review is to give a global overview about the epidemiology, diagnosis, and treatment of DIPG. We further examine the controversial biopsy and autopsy issue that is unique to DIPG and assess the subsequent impact this issue has on the research efforts and clinical management of DIPG.

Wilms tumor, medulloblastoma, and rhabdomyosarcoma in adult patients: lessons learned from the pediatric experience Abstract Wilms tumor (or nephroblastoma), rhabdomyosarcoma, and medulloblastoma, common embryonal tumors in children, can occasionally occur in adults, for whom survival is significantly inferior than pediatric patients. Available data on adults with Wilms tumor consist of case or case series reports. Among other factors, the unfamiliarity of adult oncologists and pathologists with nephroblastoma and consequent delays in initiating the appropriate risk-adapted chemotherapy may negatively influence outcomes. The survival decrement in adults with rhabdomyosarcoma has been attributed to the lack of centralized care, the inconsistent use of standard protocol-driven multimodal therapy, and lower chemotherapy tolerance in adult patients. In children with medulloblastoma, evidence from randomized clinical trials has led to risk-tailored therapies tuned on histology, extent of initial disease, and biological features. Such refinements are still missing for adults due to the lack of similar trials and studies that might provide the same or a different understanding regarding patients’ individual prognosis, treatment morbidity, and quality of life. Recent experiences have suggested that applying or adjusting pediatric protocols to adult patients with these tumors is feasible and can improve survival. Here, we provide an evaluation of the current evidence for the management of Wilms tumor, rhabdomyosarcoma, and medulloblastoma arising in adults. This review aims to promote the referral of adolescents and adults with pediatric tumors to pediatric centers for inclusion into pediatric protocols, or into protocols and studies specifically designed for that age group with the cooperation between pediatric and adult oncologists.

Aberrantly expressed microRNAs and their implications in childhood central nervous system tumors Abstract Even though the treatment of childhood cancer has evolved significantly in recent decades, aggressive central nervous system (CNS) tumors are still a leading cause of morbidity and mortality in this population. Consequently, the identification of molecular targets that can be incorporated into diagnostic practice, effectively predict prognosis, follow treatment response, and materialize into potential targeted therapeutic approaches are still warranted. Since the first evidence of the participation of miRNAs in cancer development and progression 20 years ago, notable progress has been made in the basic understanding of the contribution of their dysregulation as epigenetic driver of tumorigenesis. Nevertheless, among the plethora of articles in the literature, microRNA profiling of pediatric tumors are scarce. This article gives an overview of the recent advances in the diagnostic/prognostic potential of miRNAs in a selection of pediatric CNS tumors: medulloblastoma, ependymoma, pilocytic astrocytoma, glioblastoma, diffuse intrinsic pontine glioma, atypical teratoid/rhabdoid tumors, and choroid plexus tumors.