Ganglioside GD2 expression is maintained upon recurrence in patients with osteosarcoma

Poon, Vincent; Roth, Michael; Piperdi, Sajida; Geller, David S.; Gill, Jonathan; Rudzinski, Erin R.; Hawkins, Douglas S.; Görlick, Richard

doi:10.1186/s13569-014-0020-9

Cited by 58 publications

(46 citation statements)

References 10 publications

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“…Despite this, we were encouraged by preliminary results suggesting clinical benefit of a first generation GD2-specific CAR in patients with neuroblastoma and sought to assess the efficacy of a costimulation-endowed CAR against pediatric sarcomas. We assessed GD2 expression on three common histologies and confirmed that it is expressed on essentially all osteosarcomas, with a sizable fraction of primary and metastatic tumors expressing a high level (22,39,40). Our results confirm those from Kailayangiri et al demonstrating GD2 on Ewing sarcoma cell lines, although we did not observe significant expression of GD2 on Ewing sarcoma tissues (23).…”

Section: Discussionmentioning

confidence: 75%

Reduction of MDSCs with All-trans Retinoic Acid Improves CAR Therapy Efficacy for Sarcomas

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et al. 2016

Cancer Immunology Research

283

228

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Genetically engineered T cells expressing CD19-specific chimeric antigen receptors (CARs) have shown impressive activity against B cell malignancies, and preliminary results suggest that T cells expressing a first generation disialoganglioside (GD2)-specific CAR can also provide clinical benefit in patients with neuroblastoma. We sought to assess the potential of GD2-CAR therapies to treat pediatric sarcomas. We observed that 18/18 (100%) of osteosarcomas, 2/15 (13%) of rhabdomyosarcomas, and 7/35 (20%) of Ewing sarcomas expressed GD2. T cells engineered to express a third generation GD2-CAR incorporating the 14g2a-scFv with the CD28, OX40, and CD3ζ signaling domains (14g2a.CD28.OX40.ζ) mediated efficient and comparable lysis of both GD2+ sarcoma and neuroblastoma cell lines in vitro. However in xenograft models, GD2-CAR T cells had no antitumor effect against GD2+ sarcoma, despite effectively controlling GD2+ neuroblastoma. We observed that pediatric sarcoma xenografts, but not neuroblastoma xenografts, induced large populations of monocytic and granulocytic murine myeloid-derived suppressor cells (MDSCs) that inhibited human CAR T-cell responses in vitro. Treatment of sarcoma-bearing mice with all-trans retinoic acid (ATRA) largely eradicated monocytic MDSCs and diminished the suppressive capacity of granulocytic MDSCs. Combined therapy using GD2-CAR T cells plus ATRA significantly improved antitumor efficacy against sarcoma xenografts. We conclude that retinoids provide a clinically accessible class of agents capable of diminishing the suppressive effects of MDSCs, and that co-administration of retinoids may enhance the efficacy of CAR therapies targeting solid tumors.

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Section: Discussionmentioning

confidence: 75%

Reduction of MDSCs with All-trans Retinoic Acid Improves CAR Therapy Efficacy for Sarcomas

Long

Highfill

Cui

et al. 2016

Cancer Immunology Research

283

228

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“…Ten years later, a phase I clinical trial revealed that a human+mouse chimeric monoclonal antibody (mAb) ch 14.18 directed against disialoganglioside (GD2) appeared to be clinically safe and effective with no specific toxicity after repeated administration [129]. An immunohistochemical study demonstrated that all the osteosarcoma tumours analysed were positive for GD2 in a series composed of 44 patients [130], and persisted upon recurrence [131]. '# " $%, GD2 was suspected of enhancing the aggressiveness of the osteosarcoma [132].…”

Section: Disialoganglioside (Gd2)mentioning

confidence: 99%

Drugs in early clinical development for the treatment of osteosarcoma

Heymann

Brown

Heymann

2016

Expert Opinion on Investigational Drugs

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Osteosarcomas are the main malignant primary bone tumours found in children and young adults. Conventional treatment is based on diagnosis and resection surgery, combined with polychemotherapy. This is a protocol that was established in the 1970s.Unfortunately, this therapeutic approach has reached a plateau of efficacy and the patient survival rate has not improved in the last four decades. New therapeutic approaches are thus required to improve the prognosis for osteosarcoma patients.From the databases available and published scientific literature, the present review gives an overview of the drugs currently in early clinical development for the treatment of osteosarcoma. For each drug, a short description is given of the relevant scientific data supporting its development.Multidrug targeted approaches are set to emerge, given the heterogeneity of osteosarcoma subtypes and the multitude of therapeutic responses. The key role played by the microenvironment in the disease increases the number of therapeutic targets (such as macrophages or osteoclasts), as well as the master proteins that control cell proliferation or cell death. Ongoing phase I/II trials are important steps, not only for identifying new therapies with greater safety and efficacy, but also for better defining the role played by the microenvironment in the pathogenesis of osteosarcoma.

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“…Nearly all osteosarcomas tumors expressed GD2 by immunohistochemistry in a recent investigation;[25] subsequent analysis showed that in relapsed patients, GD2 expression was universally maintained upon recurrence. [26] Several trials utilizing varied forms of anti-GD2 therapy are currently open (NCT02173093; NCT00743496; NCT02107963; NCT02502786). Clinical trials are currently in development for the use of denosumab, glembatumumab vedotin, and dinutuximab for the treatment of recurrent and refractory osteosarcoma.…”

Section: Introductionmentioning

confidence: 99%

Future directions in the treatment of osteosarcoma

Bishop

Janeway

Görlick

2016

Current Opinion in Pediatrics

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242

211

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Purpose of Review Overall survival rates for osteosarcoma have remained essentially unchanged over the past three decades despite attempts to improve outcome via dose intensification and modification based on response. This review describes recent findings from contemporary clinical trials, advances in comprehension of osteosarcoma biology and genomic complexity, and potential opportunities using targeted and immune-mediated therapies. Recent Findings Recent results from international collaborative trials have failed to demonstrate an ability to improve outcomes using a design in which the randomized question is dictated based on histologic response to preoperative chemotherapy. Novel prognostic markers assessable at diagnosis are vital to identifying subsets of osteosarcoma. Clinical trials focus has now shifted to serial phase II studies of novel agents to evaluate for activity in recurrent and refractory disease. In-depth analyses have revealed profound genomic instability and heterogeneity across patients, with nearly universal TP53 aberration. While driver mutational events have not clearly been established, frequent derangements in specific pathways may suggest opportunities for therapeutic exploitation. Genomic complexity may lend support to a role for immune-mediated therapies. Summary Rigorous preclinical investigations are potentially generating novel strategies for treatment of osteosarcoma that will inform the next generation of clinical trials, with the opportunity to identify agents that will improve survival outcomes.

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Ganglioside GD2 expression is maintained upon recurrence in patients with osteosarcoma

Cited by 58 publications

References 10 publications

Reduction of MDSCs with All-trans Retinoic Acid Improves CAR Therapy Efficacy for Sarcomas

Reduction of MDSCs with All-trans Retinoic Acid Improves CAR Therapy Efficacy for Sarcomas

Drugs in early clinical development for the treatment of osteosarcoma

Future directions in the treatment of osteosarcoma

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