Current Knowledge and Perspectives of Immunotherapies for Neuroblastoma

Abstract

Neuroblastoma (NBL) cells highly express disialoganglioside GD2, which is restricted and weakly expressed in selected healthy cells, making it a desirable target of immunotherapy. Over the past two decades, application of dinutuximab, an anti-GD2 monoclonal antibody (mAb), has been one of the few new therapies to substantially improve outcomes to current levels. Given the persistent challenge of relapse and therapeutic resistance, there is an urgent need for new effective and tolerable treatment options for high-risk NBL. Recent breakthroughs in immune checkpoint inhibitor (ICI) therapeutics have not translated into high-risk NBL, like many other major pediatric solid tumors. Given the suppressed tumor microenvironment (TME), single ICIs like anti-CTLA4 and anti-PD1 have not demonstrated significant antitumor response rates. Meanwhile, emerging studies are reporting novel advancements in GD2-based therapies, targeted therapies, nanomedicines, and other immunotherapies such as adoptive transfer of natural killer (NK) cells and chimeric antigen receptors (CARs), and these hold interesting promise for the future of high-risk NBL patient care. Herein, we summarize the current state of the art in NBL therapeutic options and highlight the unique challenges posed by NBL that have limited the successful adoption of immune-modifying therapies. Through this review, we aim to direct the field's attention to opportunities that may benefit from a combination immunotherapy strategy.

Keywords: immunosuppression; immunotherapy; neuroblastoma; tumor microenvironment.

Figure 1

Overview of modern risk-adapted treatment regimen for neuroblastoma. These treatment schemes are tailored to an individual patient’s risk of relapse and include observation or surgery alone for the low-risk group; multiple rounds of chemotherapy with surgery for the intermediate risk group; and a multimodal strategy combining chemotherapy, surgery, high-dose chemotherapy with autologous stem cell rescue, radiation, and immunotherapy for the high-risk group. This figure was created with BioRender.com.

Figure 2

Barriers imposed by neuroblastoma (NBL) for effective immune-based treatments. Multiple mechanisms contribute to an immunosuppressive tumor microenvironment and function as barriers to effective adoption of immune-based treatments in NBL. These include overexpression of the “don’t eat me” signal CD47, low mutational burden and thus low neoantigen load, which prevents the effective recruitment of tumor-infiltrating lymphocytes (TILs) and limits effective antigen presentation by macrophages and dendritic cells (DCs). Moreover, the NBL tumor microenvironment (TME) is also infiltrated by a variety of anti-inflammatory immune cells, including tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), and secreted immunosuppressive factors, including TGFβ, indoleamine 2,3-dioxygenase (IDO), Arg-2, HMGB-1, and other pro-angiogenic factors. Regulatory T cells (Tregs) in the NBL TME further interfere with the effector T cells and natural killer (NK)-cell function. Moreover, non-immune cells such as mesenchymal stromal cells (MSCs), fibroblasts, Schwann cells, and endothelial cells each play unique roles in contributing to an immunosuppressed TME in NBL. This figure was created with BioRender.com.

Figure 3

Current and emerging therapies to potentially overcome the barriers imposed by neuroblastoma (NBL) for effective treatments. This simplified scheme includes current and emerging immunotherapies targeting the barriers imposed by NBL and thus leading to promising potential for effective treatments. ALK inhibitors and AURKA inhibitors would target the NBL tumor cells directly. Likewise, sEVs have the potential to increase detection of NBL by immune cells and elicit effective killing mechanisms. Cytokine-based therapies could overcome the immunosuppressive cytokines and chemokines to shift local inflammation from tumor-supportive to tumor-killing. Depletion strategies utilizing anti-CD11b may mitigate the immunosuppression in the tumor microenvironment. Anti-GD2 antibodies can enhance the antibody-dependent cell mediated cytotoxicity and tumor phagocytosis. Similarly, anti-CD47 antibodies could enhance phagocytosis of tumor cells. Though ICIs do not show significant benefits as single-agent treatments, the combination of ICIs with other immunotherapies may enhance their efficacy in NBL. Artificial expression of CARs on autologous T cells or invariant NK T cells may further boost adaptive immunity against NBL. This figure was created with BioRender.com.