Table 1.

Types of immune recognition potentially relevant to neuroblastoma immunotherapy.

Immune recognition	Type	Caveat (requires)	Example	Clinical relevance and application
Endogenous	T-cell receptor	Peptide presented by MHC on cell surface	NY-ESO-1 presented by MHC on NBL cells to autologous T cells (71)	Endogenous T-cell responses of patients with HR-NBL are weak, due to the substantial immunosuppressive chemotherapy received. No effective vaccine to stimulate yet tested in NBL.
	Antibody	Cell surface molecule	1. Antibody seen in OMS sees neuroblastoma (111) 2. GD2/GD3	1. Patients with NBL and opsoclonus-myoclonus syndrome (OMS) have induced an endogenous antibody against their neuroblastoma and also to normal CNS, causing this autoimmune syndrome. 2. Vaccination to these gangliosides is inducing antibody to them that may delay/prevent relapse
Synthetic	mAb	Cell surface molecule	GD2 (23)	Three separate mAbs to GD2 ganglioside have been approved for clinical use and have shown antitumor benefit in preventing relapse for patients in remission, for inducing responses for relapsed disease, and for antitumor effects when combined with chemotherapy for relapse, with early data indicating benefit when included with chemotherapy during induction.
	CAR	Cell surface molecule	GD2 (recognized by mAb ScFv) (49, 50, 80)	Several trials are testing CAR-T cells with CARs directed at GD2 through mAb technology, with some showing early signs of antitumor benefit.
	CAR	Cell surface MHC presenting a tumor peptide	PHOX2B peptide presented by HLA-I (95)	Even though PHOX2B is an NBL “driver” expressed only in cytoplasm and nucleus, its peptides are presented on the surface by MHC-I. A mAb against the PHOX2B peptide/MHC-I complex has been put into CAR-T cells and mediates potent tumor destruction in vitro and in vivo in PDX models.
	T-cell receptor	Peptide presented by MHC on cell surface	NY-ESO-1 (69, 112–115)	Using in vitro binding and selection processes, T-cell receptors specific for the NY-ESO-1 antigen (seen on some neuroblastomas and several tumors in adults) can be cloned from lymphocytes and transfected into cells of a cancer patient to get autologous tumor killing in vitro. Clinical testing in other diseases is proceeding.

Note: Different immune recognition mechanisms of different types, each with separate caveats for translation, are indicated for the antigens exemplifying their use, and with mechanistic clinical considerations for each.

Abbreviations: NBL, neuroblastoma; PDX, patient-derived xenograft.