Prospective immunotherapies in childhood sarcomas: PD1/PDL1 blockade in combination with tumor vaccines

Brown

Expert Opinion on Investigational Drugs

2016

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.

Section: Nivolumab and Pembrozilumabmentioning

confidence: 99%

Drugs in early clinical development for the treatment of osteosarcoma

Brown

Expert Opinion on Investigational Drugs

2016

Journal of Bone Oncology

“…Brain metastasis in osteosarcoma is frequently preceded by lung metastasis [1] . Although considerable progress had been made, survival rates remain dismal for those patients with advanced metastatic diseases and recurrence [2] . Osteosarcoma is considered as one of the classic chemo- and radio-resistant brain metastasis, therefore it is important to explore the use of multiple modalities in order to improve the therapeutic ratio and overcome the inherent resistance [1] , [3] .…”

Section: Introductionmentioning

confidence: 99%

Irradiation enhanced the effects of PD-1 blockade in brain metastatic osteosarcoma

Xia

Qian

2018

Brain metastasis of osteosarcoma are rare but carry a dismal prognosis. Despite the advances in both systemic immunotherapy and localized radiation, it is still difficult to treat brain metastasis, with less than 12 months of survival from the time of diagnosis for most patients. Currently, there is interest in combining strategies to take advantage of the potential synergy. In this study, the mouse model of metastatic osteosarcoma to brain was used to explore the ability of local radiation and anti-PD-1 blockade to induce beneficial anti-tumor immune responses against distant, unirradiated brain metastatic tumors. Immune markers from the peripheral blood and tumor tissue were analyzed by flow cytometry, real-time PCR and western blot. The combination treatment produced a stronger systemic anti-tumor response than either treatment alone, shown by the reduced tumor burden and larger numbers of cytotoxic CD8+ T cells in the unirradiated tumors, indicating an abscopal effect. These data suggested that combination treatment of irradiation with anti-PD-1 immunotherapy can induce abscopal anti-tumor responses and improve both local and distant control.

“…24 Immunotherapies have emerged as one of the most---promising modalities to treat cancer and have involved the use of drugs that target immune checkpoints. 128 In recent years, immunotherapy with specific immune checkpoint inhibitor provides a promising way to break tumor immunosuppressive environment. 129 Programmed death---ligand 1 (PD---L1), a protein overexpressed on cancer cell membrane, contributes to the suppression of the immune system.…”

Section: Photoimmunotherapymentioning

confidence: 99%

“…130 The therapeutic anti---PD---L1 antibody is designed to block the PD---1/PD---L1 interaction and reverse tumor---mediated immunosuppression. 112,128,131,132 Immune blockade inhibitors targeting PD---1 or its ligand PD---L1, have emerged as one of the most---promising immune therapy modalities to treat systemic cancer. 133,134 But currently, they work only for a limited number of patients and can become ineffective with time.…”

Section: Photoimmunotherapymentioning

confidence: 99%

Multifunctional Gold Nanostars for Cancer Theranostics

Liu¹

2018

Springer Theses

The prevalence of cancer has increasingly become a significant threat to human health and as such, there exists a strong need for developing novel methods for early detection and effective therapy. Nanotheranostics, a combination of diagnostic and therapeutic functions into a single nanoplatform, has great potential to be used for cancer management by allowing detection, real-time tracking, image-guided therapy and therapeutic response monitoring. Gold nanostars (GNS) with tip-enhanced plasmonics have become one of the most promising platforms for cancer nanotheranostics. This work is aimed at addressing the challenges of sensitive cancer detection, metastasis treatment and recurrence prevention by combining state-of-the-art nanotechnology, molecular imaging and immunotherapy. A multifunctional GNS nanoprobe is developed with capabilities ranging from non-invasive, multi-modality cancer detection using positron emission tomography (PET), magnetic resonance imaging (MRI) and X-ray computed tomography (CT), to intraoperative tumor margin delineation with surface enhanced Raman spectroscopy (SERS) and high-resolution nanoprobe tracking with two-photon photoluminescence (TPL), as well as cancer treatment with photoimmunotherapy. The GNS nanoprobe with PET scans is particularly exceptional in detecting brain malignancies as small as 0.5 mm. To the best of our knowledge, the developed GNS nanoprobe for PET imaging provides the most v sensitive means of brain tumor detection reported so far. In addition, the GNS nanoprobe exhibits superior performance as photon-to-heat transducer and can be used for specific photothermal therapy (PTT). More importantly, GNS-mediated PTT combined with checkpoint inhibitor immunotherapy has been found to trigger a memorized immunoresponse to treat cancer metastasis and prevent recurrence in mouse model studies. Furthermore, a 6-month in vivo toxicity study including body weight monitoring, blood chemistry test and histopathology examination demonstrate GNS nanoparticles' biocompatibility. Therefore, the multifunctional GNS nanoprobe exhibits superior cancer detection and treatment capabilities and has great promise for future clinical translation in cancer management.