Ex vivo expanded patient-derived γδ T-cell immunotherapy enhances neuroblastoma tumor regression in a murine model

An effective therapy regimen for relapsed/refractory high-risk neuroblastoma (NB) includes the anti-GD2 monoclonal antibody, dinutuximab, in combination with temozolomide and irinotecan, supporting a role for chemo-immunotherapy in NB. gamma delta T cells are an attractive anti-tumor immunotherapy because of their direct cytotoxic activity mediated through cell surface receptors NKG2D and CD16. NKG2D facilitates the innate recognition of stress-induced ligands whereas CD16 recognizes antibody bound to tumors and activates mechanisms of antibody-dependent cellular cytotoxicity (ADCC). This study demonstrates an efficient method for expanding and storing gamma delta T cells from NB patient-derived apheresis products at clinically relevant amounts. The expanded patient-derived gamma delta T cells were cytotoxic against the K562 cell line and multiple NB cell lines. Combining gamma delta T cells with dinutuximab led to a 30% increase in tumor cell lysis compared to gamma delta T cells alone. Furthermore, low-dose temozolomide in combination with expanded gamma delta T cells and dinutuximab resulted in increased IFN gamma secretion and increased gamma delta T-cell surface expression of FasL and CD107a. IMR5 NB cell line xenografts established subcutaneously in NSG mice were treated with a regimen of dinutuximab, temozolomide, and gamma delta T cells. This combination caused targeted killing of NB xenografts in vivo, reducing tumor burden and prolonging survival. These data support the continued preclinical testing of dinutuximab and temozolomide in conjunction with gamma delta T-cell immunotherapy for patients with recurrent/refractory NB.