As high-risk neuroblastoma (NB) has a poor prognosis, new therapeutic modalities are needed. We therefore investigated the susceptibility of NB cells to γ-secretase inhibitor I (GSI-I). NOTCH signaling activity, the cellular effects of GSI-I and its mechanisms of cytotoxicity were evaluated in NB cells in vitro and in vivo. The results show that NOTCH signaling is relevant for human NB cells. Of the GSIs screened in vitro GSI-I was the most effective inhibitor of NB cells. Both MYCN-amplified and non-amplified NB cells were susceptible to GSI-I. Among the targets of GSI-I in NB cells were NOTCH and the proteasome. GSI-I caused G2/M arrest that was enhanced by acute activation of MYCN and led to mitotic dysfunction. GSI-I also induced proapoptotic NOXA. Survival of mice bearing an MYCN non-amplified orthotopic patient-derived NB xenograft was significantly prolonged by systemic GSI-I, associated with mitotic catastrophe and reduced angiogenesis, and without evidence of intestinal toxicity. In conclusion, the activity of GSI-I on multiple targets in NB cells and the lack of gastrointestinal toxicity in mice are advantageous and merit further investigations of GSI-I in NB.
BackgroundAttenuated oncolytic measles virus (OMV) is a promising antitumor agent in early-phase clinical trials. However, pre-existing immunity against measles might be a hurdle for OMV therapy.MethodsOMV was inactivated with short-wavelength ultraviolet light (UV-C). Loss of replication and oncolytic activity of UV-inactivated OMV were confirmed by tissue culture infective dose 50 (TCID50) assay using Vero cells and by flow cytometry using Jurkat cells. An enzyme-linked immunosorbent assay was performed to verify that UV-inactivated OMV remained antigenic. Different doses of UV-inactivated OMV were pre-cultured in media supplemented with measles immune serum. The mixture was transferred to Jurkat cells and active OMV was added. Active OMV-induced death of Jurkat cells was monitored by flow cytometry.ResultsUV-inactivation abrogates OMV replication while maintaining its antigenicity. UV-inactivated OMV sequesters pre-existing anti-MV antibodies in Jurkat cell culture, thereby protecting active OMV from neutralization and preserving oncolytic activity.ConclusionWe prove the principle that a non-replicating OMV can serve as a “decoy” for neutralizing anti-MV antibodies, thereby allowing antitumor activity of OMV.
Lymphokine-containing supernatants derived from seven different human lymphoid cell lines and lymphokine-containing supernatants from concanavalin Astimulated murine lymphocytes were found to be capable of reversibly inhibiting the migration of tumor cells in vitro. The tumor cell lines used in these studies were the P815 mastocytoma, Ehrlich ascites, Walker carcinosarcoma, Hepatoma 129, and Sarcoma 37. Preliminary physicochemical evidence suggests that the mediator, here termed TMIF, is distinct from MIF. In any case, these results suggest the possibility that lymphokines other than lymphotoxin or macrophage-activating factors may play a role in tumor immunity.
Background: The prognosis of patients with relapsed and refractory ALL is poor. Oncolytic virotherapy is a promising treatment modality combining cancer cell lysis with immunomodulation. Aims: To determine whether clinical-grade attenuated measles virus (MV) controls relapsed and refractory ALL in vitro and in vivo, to assess resistance mechanisms and to outline targets for immunotherapy in resistant cells. Methods: The clinical-grade MV-NIS strain was used. ALL cell lines insensitive to chemotherapy and ALL xenografts derived from patients that had died from their disease were investigated. In vitro, cells were treated with MV-NIS and viability was determined. NSG mice were transplanted with a relapsed ALL PDX. Treatment was started when the leukemic load was high, i.e. when 20-30% blasts were present in the peripheral blood, and when the disease had heavily infiltrated spleen, liver, bone marrow and CNS. One dose of i.v. MV-NIS was given. Peripheral blast counts and survival of mice were determined. At time of death the presence of MV in leukemic infiltrates was determined by immunohistochemistry and qRT-PCR, MV was isolated from blasts and serum, and infectivity of isolated MV was tested on Vero indicator cells. mRNA from the blasts, including the genome of the MV they were infected with (MV is a mRNA virus), was subjected to mRNA sequencing. Gene set enrichment and mutation analyses were performed. Results: In vitro, MV-NIS effectively killed ALL cell lines insensitive to chemotherapy and cells from relapsed patient ALL. In NSG mice with a high and disseminated load of relapsed patient ALL cells, one injection of i.v. MV-NIS sufficed to rapidly decrease leukemic load leading to long-term survival of the mice. Survival was terminated by late disease exacerbation due to expansion of virus-resistant leukemic cells persistently infected with infectious MV. Genome-wide mRNA sequencing revealed strong enrichment of antiviral pathways in the resistant cells, without mutations in the viral genome that could explain the resistance of the blasts. Conclusions: MV-NIS is preclinically effective against relapsed and refractory ALL in vitro and, initially, in vivo. Late expansion of virus-resistant cancer cells persistently infected with MV is a phenomenon hitherto not described. The viral and antiviral proteins strongly expressed in these cells, which include cell surface proteins, can serve as targets for subsequent immunotherapy. Citation Format: Annika V. Goß, Carmen Dorneburg, Medhanie Mulaw, Chun Xu, Christine Landthaler, Irmela Jeremias, Jiwu Wei, Klaus-Michael Debatin, Christian Beltinger. Long-term survival of mice with relapsed ALL treated by oncolytic measles virus is terminated by expansion of persistently infected virus-resistant blasts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2059.
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