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Precision/Personalized Pediatric Oncology and Immune Therapies: Rather Customize Than Randomize

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Although survival rates for childhood cancers have improved remarkably in recent decades, it is still the leading cause of death by disease in children, while their prognosis continues to be poor. The growing ability to analyze tumors to understand their development, progression and immune evasion opens new ...

Although survival rates for childhood cancers have improved remarkably in recent decades, it is still the leading cause of death by disease in children, while their prognosis continues to be poor. The growing ability to analyze tumors to understand their development, progression and immune evasion opens new horizons for precision therapies using novel targeted and immune therapies.

Even if pediatric tumors have a low mutational burden and poor cell infiltrate, they are readily engaging the immune system and constitute a potentially effective therapeutic target. Until now, good responses to immune checkpoint inhibitors in children were seen mostly in lymphomas and some rare tumors, therefore, new standardized and integrated approaches to properly assess tumor microenvironment in children are needed.

While numerous pediatric cancer immunotherapies seem effective, methods to define precisely mutational burden in children should be developed. This is difficult because most cancer cells participate in more than one tumor-related signaling pathways, followed by additional molecular changes and an increased risk of developing resistance to standard treatments. Therefore, novel combinatorial treatments need to be discovered, based on a stronger scientific rationale than the traditional approach of evidence-based medicine. The new clinical trial design should be n-of-1, where each patient will have their own cancer treatment regimen.

Such findings may also aid basic research in examining the molecular underpinnings of why these cancers occur, their developmental links, and in understanding the crucial role of the children’s immune system in how we can live with and fight these different and yet difficult-to-treat cancers. However, precision oncology still encounters several unresolved hurdles, including tumor heterogeneity and recurrence, as well as unexplained drug resistance and lack of effective ways to monitor response to targeted and immune therapies.

This collection of multidisciplinary articles addresses novel biological findings in pediatric oncology, mathematical models for n-of-1 trials, innovative technologies and infrastructure, advanced computational platforms, analytical methodologies, and ethical issues.

Topics covered by this article series will concentrate on areas of biggest uncertainties, such as:
1) Therapeutic strategies, incorporating inhibition of multiple molecular pathways needed to address the considerable differences in tumors between individuals, the heterogeneity within a single tumor, as well as the differences between the primary tumor, its metastatic lesions, and recurrent disease.
2) Evaluation and prioritization of targets & pathways as the understanding of pediatric tumor genomics, transcriptomics, proteomics, and other "omics", and how these aberrations correlate with clinical outcomes, which is still poorly understood.
3) Design of clinical studies with new drugs which is so far driven by the pharma industry intention to file an adult indication with very limited comprehensive biomarker-based combination trials calling thus for n-of-1 methodology.
4) Incorporation of less expensive immune approaches and therapies like dendritic cell vaccines into clinical practice.


Keywords: Precision/personalized pediatric oncology, immune therapies, precision, pediatric oncology


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