High-risk neuroblastoma as a model for immunotherapy of non-immunogenic cancers: where might we be in 20 years?

Children and adults diagnosed with malignancies that are not curable in 2025 with surgery alone require multimodal therapy. For decades, this has included radiation therapy and/or chemotherapy. This approach can be curative for many patients with certain cancers, such as acute lymphoblastic leukemia, Wilms tumor, Hodgkin's disease, and testicular cancer. For those who are not being cured, additional therapies are needed. The last 15 years have shown that those previously incurable patients are now having a chance for a cure using immunotherapy in the form of immune checkpoint inhibition (ICI). However, with the exception of rare patients with mutations in their DNA repair pathways associated with very high neoantigen loads, most patients receiving ICI therapy are not cured by it. This pertains to virtually all patients with some tumors, such as prostate or gastrointestinal (GI) cancers and even for a majority of those patients with advanced cancers classified as "immunogenic", such as melanoma, renal cell cancer, and lung cancer. One feature of these many patients not responding to ICI is that their tumors are immunologically cold. Namely, they are characterized by low actionable neoantigen load, low or absent major histocompatibility complex expression, and/or an immune-hostile tumor microenvironment. These features are typical of high-risk neuroblastoma (HR-NBL). Despite its cold features, substantial progress has been made in advancing the treatment of HR-NBL using different forms of immunotherapy. This manuscript describes a clinical goal for HR-NBL for 20 years from now. In addition, it extrapolates from this experience and anticipated progress for HR-NBL to how these concepts might apply to improving treatments for patients with more common, yet cold, cancers of adults.