Immunology and immunotherapy of neuroblastoma

Abstract

Purpose This review demonstrates the importance of immunobiology and immunotherapy research for understanding and treating neuroblastoma. Principal results The first suggestions of immune system-neuroblastoma interactions came from in vitro experiments showing that lymphocytes from patients were cytotoxic for their own tumor cells and from evaluations of tumors from patients that showed infiltrations of immune system cells. With the development of monoclonal antibody (mAb) technology, a number of mAbs were generated against neuroblastoma cells lines and were used to define tumor associated antigens. Disialoganglioside (GD2) is one such antigen that is highly expressed by virtually all neuroblastoma cells and so is a useful target for both identification and treatment of tumor cells with mAbs. Preclinical research using in vitro and transplantable tumor models of neuroblastoma has demonstrated that cytotoxic T lymphocytes (CTLs) can specifically recognize and kill tumor cells as a result of vaccination or of genetic engineering that endows them with chimeric antigen receptors. However, CTL based clinical trials have not progressed beyond pilot and phase I studies. In contrast, anti-GD2 mAbs have been extensively studied and modified in pre-clinical experiments and have progressed from phase I through phase III clinical trials. Thus, the one proven beneficial immunotherapy for patients with high-risk neuroblastoma uses a chimeric anti-GD2 mAb combined with IL-2 and GM-CSF to treat patients after they have received intensive cyto-reductive chemotherapy, irradiation, and surgery. Ongoing pre-clinical and clinical research emphasizes vaccine, adoptive cell therapy, and mAb strategies. Recently it was shown that the neuroblastoma microenvironment is immunosuppressive and tumor growth promoting, and strategies to overcome this are being developed to enhance anti-tumor immunotherapy. Conclusions Our understanding of the immunobiology of neuroblastoma has increased immensely over the past 40 years, and clinical translation has shown that mAb based immunotherapy can contribute to improving treatment for high-risk patients. Continued immunobiology and pre-clinical therapeutic research will be translated into even more effective immunotherapeutic strategies that will be integrated with new cytotoxic drug and irradiation therapies to improve survival and quality of life for patients with high-risk neuroblastoma.

Downregulation of c-Myc is involved in TLR3-mediated tumor death of neuroblastoma xenografts

“…17 Recently, immunotherapy has become the limelight for the treatment of children with aggressive and high-risk NB to improve survival and reducing relapse rate. 18,19 Our previous studies disclosed that a high level of Toll-like receptor 3 (TLR3) is associated with a favorable prognosis in NB patients, and different levels of TLR3 expression are shown in NB cell lines. 20,21 TLR3, which is localized in endosomes or on cell surfaces in conventional dendritic cells, serves as a sensor of viral infection to recognize double-stranded RNA and triggers antiviral signal transduction in innate immunity.…”

Specificities of Autologous Haematopoietic Stem Cell Transplantation in Children: A Single Centre Experience

“…For other tumour patients, and patients in partial remission before the transplantation, survival may be increased by introducing double AHSCT with post-transplant immunomodulatory therapy [23][24][25][26][27].…”

“…Another problem in improving the success of AHSCT is treatment of minimal residual disease. We believe a promising avenue for minimal residual disease treatment after AHSCT might lie in the use of immunomodulatory therapeutics [24][25][26][27].…”

Targeting of heme oxygenase‐1 as a novel immune regulator of neuroblastoma

“…3 Thus, aggressive NB develops harmful characteristics to overcome cellular stress initiated by classical chemotherapeutics while possessing properties to disarm an activated immune system. 3,4 Both cell protection and immune escape have been described in a variety of tumors, 5,6 but their molecular and cellular interdependence in cancer, in particular in NB, is still poorly understood. Heme oxygenase (HO)-1 emerges as a promising candidate to link cell protection and immune escape.…”

“…[13][14][15][16][17][18] The secretion of soluble suppressor molecules, such as MHC class I chain-related gene A protein (sMICA), sHLA-G, the macrophage migration inhibitory factor (MIF) and TGF-beta, is also well-documented immune tolerance mechanisms in NB. 3,4 Moreover, immune evasion in NB was linked to unfavorable prognostic MYCN amplification (MNA 1 ), which was demonstrated to repress monocyte chemoattractant protein-1/CC chemokine ligand 2 (MCP-1/CCL2) and influence local NKT cell recruitment. 19 We recently described a novel program of immune tolerance triggered by NB-derived galectin-1 to negatively regulate DCs and T-cell function.…”