CAR T Cell Therapy for Neuroblastoma

Richards, Rebecca M.; Sotillo, Elena; Majzner, Robbie G.

doi:10.3389/fimmu.2018.02380

Cited by 131 publications

(114 citation statements)

References 192 publications

(211 reference statements)

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“…66 For example, CAR-T cells targeting GD2 are being explored in the clinic for treatment of NB. 67 Additionally, like PD-L1, our TCGA analysis revealed several other immunosuppressive factors (eg, CTLA-4, TGF-β, IL-10) that are correlated with high STING expression in human NB ( figure 1A) and may therefore also be promising targets in the design of combination regimens leveraging STING agonists. Similarly, STING-NPs may synergize with approved treatments for NB (eg, chemotherapy, radiation therapy, anti-GD2 therapy) by generating an immunosupportive context for antigen cross-presentation and T cell priming of locally liberated tumor antigen.…”

Section: Open Accessmentioning

confidence: 88%

Potent STING activation stimulates immunogenic cell death to enhance antitumor immunity in neuroblastoma

Wang-Bishop

Wehbe

Shae

et al. 2020

J Immunother Cancer

119

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BackgroundNeuroblastoma (NB) is a childhood cancer for which new treatment options are needed. The success of immune checkpoint blockade in the treatment of adult solid tumors has prompted the exploration of immunotherapy in NB; however, clinical evidence indicates that the vast majority of NB patients do not respond to single-agent checkpoint inhibitors. This motivates a need for therapeutic strategies to increase NB tumor immunogenicity. The goal of this study was to evaluate a new immunotherapeutic strategy for NB based on potent activation of the stimulator of interferon genes (STING) pathway.MethodsTo promote STING activation in NB cells and tumors, we utilized STING-activating nanoparticles (STING-NPs) that are designed to mediate efficient cytosolic delivery of the endogenous STING ligand, 2’3’-cGAMP. We investigated tumor-intrinsic responses to STING activation in both MYCN-amplified and non-amplified NB cell lines, evaluating effects on STING signaling, apoptosis, and the induction of immunogenic cell death. The effects of intratumoral administration of STING-NPs on CD8+T cell infiltration, tumor growth, and response to response to PD-L1 checkpoint blockade were evaluated in syngeneic models of MYCN-amplified and non-amplified NB.ResultsThe efficient cytosolic delivery of 2’3’-cGAMP enabled by STING-NPs triggered tumor-intrinsic STING signaling effects in both MYCN-amplified and non-amplified NB cell lines, resulting in increased expression of interferon-stimulated genes and pro-inflammatory cytokines as well as NB cell death at concentrations 2000-fold to 10000-fold lower than free 2’3’-cGAMP. STING-mediated cell death in NB was associated with release or expression of several danger associated molecular patterns that are hallmarks of immunogenic cell death, which was further validated via cell-based vaccination and tumor challenge studies. Intratumoral administration of STING-NPs enhanced STING activation relative to free 2’3’-cGAMP in NB tumor models, converting poorly immunogenic tumors into tumoricidal and T cell-inflamed microenvironments and resulting in inhibition of tumor growth, increased survival, and induction of immunological memory that protected against tumor re-challenge. In a model of MYCN-amplified NB, STING-NPs generated an abscopal response that inhibited distal tumor growth and improved response to PD-L1 immune checkpoint blockade.ConclusionsWe have demonstrated that activation of the STING pathway, here enabled by a nanomedicine approach, stimulates immunogenic cell death and remodels the tumor immune microenvironment to inhibit NB tumor growth and improve responses to immune checkpoint blockade, providing a multifaceted immunotherapeutic approach with potential to enhance immunotherapy outcomes in NB.

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Section: Open Accessmentioning

confidence: 88%

Potent STING activation stimulates immunogenic cell death to enhance antitumor immunity in neuroblastoma

Wang-Bishop

Wehbe

Shae

et al. 2020

J Immunother Cancer

119

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“…In fact, several therapeutic antibodies targeting GD2 were developed, and later the mAb Dinutuximab was approved for patients with high-risk neuroblastoma 3 . Moreover, targeting GD2 with CAR T cells has shown some efficiency in early clinical studies 51 . We have demonstrated previously the efficiency of targeting GD2 with UniCAR T cells 38 .…”

Section: Discussionmentioning

confidence: 99%

“UniCAR”-modified off-the-shelf NK-92 cells for targeting of GD2-expressing tumour cells

Mitwasi

Feldmann

Arndt

et al. 2020

Sci Rep

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Antigen-specific redirection of immune effector cells with chimeric antigen receptors (CARs) demonstrated high therapeutic potential for targeting cancers of different origins. Beside CART cells, natural killer (NK) cells represent promising alternative effectors that can be combined with CAR technology. Unlike T cells, primary NK cells and the NK cell line NK-92 can be applied as allogeneic off-the-shelf products with a reduced risk of toxicities. We previously established a modular universal CAR (UniCAR) platform which consists of UniCAR-expressing immune cells that cannot recognize target antigens directly but are redirected by a tumour-specific target module (TM). The TM contains an antigen-binding moiety fused to a peptide epitope which is recognized by the UniCAR molecule, thereby allowing an on/off switch of CAR activity, and facilitating flexible targeting of various tumour antigens depending on the presence and specificity of the TM. Here, we provide proof of concept that it is feasible to generate a universal off-the-shelf cellular therapeutic based on UniCAR NK-92 cells targeted to tumours expressing the disialoganglioside GD2 by GD2-specific TMs that are either based on an antibody-derived single-chain fragment variable (scFv) or an IgG4 backbone. Redirected UniCAR NK-92 cells induced specific killing of GD2-expressing cells in vitro and in vivo, associated with enhanced production of interferon-γ. Analysis of radiolabelled proteins demonstrated that the IgG4-based format increased the in vivo half-life of the TM markedly in comparison to the scFv-based molecule. In summary, UniCAR NK-92 cells represent a universal off-the-shelf platform that is highly effective and flexible, allowing the use of different TM formats for specific tumour targeting.

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“…There are currently many open clinical trials of CAR-T therapy for patients with relapse or progression neuroblastoma. 16 Our data showed that CAR-T therapy was well tolerated; it provided a short-term therapeutic effect for patients with refractory and recurrent neuroblastoma. However, it did not improve the long-term survival rate.…”

Section: Treatment For Neuroblastoma Includes Chemotherapy S U Rg Ementioning

confidence: 61%

Treatment and outcomes of 1041 pediatric patients with neuroblastoma who received multidisciplinary care in China

Qin

Chen

et al. 2020

Pediatric Investigation

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CAR T Cell Therapy for Neuroblastoma

Cited by 131 publications

References 192 publications

Potent STING activation stimulates immunogenic cell death to enhance antitumor immunity in neuroblastoma

Potent STING activation stimulates immunogenic cell death to enhance antitumor immunity in neuroblastoma

“UniCAR”-modified off-the-shelf NK-92 cells for targeting of GD2-expressing tumour cells

Treatment and outcomes of 1041 pediatric patients with neuroblastoma who received multidisciplinary care in China

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