Initiation of immunotherapy with activated natural killer cells and anti-GD2 antibody dinutuximab prior to resection of primary neuroblastoma prolongs survival in mice

Abstract

BackgroundImmunotherapy with anti-disialoganglioside dinutuximab has improved survival for children with high-risk neuroblastoma (NB) when given after induction chemotherapy and surgery. However, disease recurrence and resistance persist. Dinutuximab efficacy has not been evaluated when initiated before primary tumor removal. Using a surgical mouse model of human NB, we examined if initiating dinutuximab plus ex vivo-activated natural killer (aNK) cells before resection of the primary tumor improves survival.MethodsIn vitro, human NB cells (SMS-KCNR-Fluc, CHLA-255-Fluc) were treated with dinutuximab and/or aNK cells and cytotoxicity was measured. In vivo, NB cells (SMS-KCNR-Fluc, CHLA-255-Fluc, or COG-N-415x PDX) were injected into the kidney of NOD-scid gamma mice. Mice received eight intravenous infusions of aNK cells plus dinutuximab beginning either 12 days before or 2 days after resection of primary tumors. Tumors in control mice were treated by resection alone or with immunotherapy alone. Disease was quantified by bioluminescent imaging and survival was monitored. aNK cell infiltration into primary tumors was quantified by flow cytometry and immunohistochemistry at varying timepoints.ResultsIn vitro, aNK cells and dinutuximab were more cytotoxic than either treatment alone. In vivo, treatment with aNK cells plus dinutuximab prior to resection of the primary tumor was most effective in limiting metastatic disease and prolonging survival. aNK cell infiltration into xenograft tumors was observed after 1 day and peaked at 5 days following injection.ConclusionDinutuximab plus aNK cell immunotherapy initiated before resection of primary tumors decreases disease burden and prolongs survival in an experimental mouse model of NB. These findings support the clinical investigation of this treatment strategy during induction therapy in patients with high-risk NB.

Oncolytic virotherapy reverses the immunosuppressive tumor microenvironment and its potential in combination with immunotherapy

“…Upregulation of TIM3 on CD8 + T cells and TIM3 ligand on tumor cells induced by OVs contributed to the resistance to PD-1 blockade. This study suggested that targeting multiple ICB pathways is a rational approach to overcome resistance to single ICB treatment and achieve optimal synergy with OVT [ 134 ].…”

A Novel pH-Sensitive Multifunctional DNA Nanomedicine: An Enhanced and Harmless GD2 Aptamer-Mediated Strategy for Guiding Neuroblastoma Antitumor Therapy

“…Among them, the anti-GD2 monoclonal antibody dinutuximab (ch14.18) has been approved by the US Food and Drug Administration, and dinutuximab β (ch14.18/ CHO) has been approved by the European Medicines Agency for high-risk neuroblastoma treatment. 8 Nevertheless, GD2 antibodies can cause severe side effects, such as capillary leak syndrome, hypersensitivity reactions, intense neuropathic pain, infection, and fever. The root of these side effects is that although GD2 is overexpressed on NB tumor cells, it is also expressed in low amounts on peripheral nerves, peripheral sensory nerve fibers, mesenchymal stem cells, brain parenchyma, etc.…”

“…Therefore, these properties make GD2 a promising target for NBtargeted therapy. 8 To date, GD2 has been treated as an attractive antigen for NB drug development and has great potential to achieve substantial clinical benefits in NB therapy. Several anti-GD2 antibodies have been evaluated.…”

“…[8][9][10] Among them, dinutuximab, the first GD2 antibody approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for neuroblastoma treatment, has shown excellent effects on the OS rates of patients in several clinical trials. 8,11,12 However, dinutuximab may also cause several side effects, with the most major adverse events including pain, fever, hypertension, and urticarial reactions. [13][14][15] These symptoms can generally be controlled but sometimes they may not.…”

Combining Immunocytokine and Ex Vivo Activated NK Cells as a Platform for Enhancing Graft-Versus-Tumor Effects Against GD2+ Murine Neuroblastoma

“…Because of the availability of clinical grade cytokines and artificial antigen presenting cells (aAPCs), infusion of high numbers of purified, ex vivo activated NK cells are emerging from preclinical models into clinical trials. NK cells have already been shown to have cytotoxicity in vitro against a variety of NBL cell lines ( 17 ) and primary patient tumors ( 18 , 19 ) as well as in vivo with xenograft NBL models ( 20 ). In addition, the lymphopenic environment induced from the conditioning regimen for allogeneic HSCT is conducive for NK cell expansion given the presence of high levels of IL-15 ( 21 ).…”