COVD-18. POTENTIAL TO HARNESS SARS-COV-2 NEUROTROPISM IN THE DELIVERY OF ONCOLYTIC VIROTHERAPY FOR THE TREATMENT OF HIGH-GRADE GLIOMA

Abstract BACKGROUND High-grade gliomas (HGG) pose therapeutic challenges stemming from blood brain barrier, infiltrative growth, suppressed immune function, and tumor heterogeneity. Oncolytic viruses (OVs) are gaining traction for addressing these challenges. There is evidence that the SARS-CoV-2 glycoprotein spike binds the ACE-2 receptor in nasal epithelium and reaches the brainstem and thalamus via axonal transport through the olfactory pathway, making it an attractive candidate for OV therapy. Prior studies on chimerization of pathogenic virus-derived glycoprotein spikes with non-pathogenic strains exploit neurotropism of a wild-type virus while improving the safety profile of the resulting OV. We review, 1) the engineering of chimeric OVs used in the treatment of HGG; 2) potential for a novel chimeric virotherapy in which the SARS-CoV-2 glycoprotein spike can be used to deliver OV therapy intranasally; and 3) areas which warrant further investigation to develop this approach for clinical use. METHODS We performed an extensive review of chimeric OVs and specific modifications engineered to optimize safety and efficacy. Additionally, we assessed potential to use these principals to engineer the SARS-CoV-2 glycoprotein spike onto a non-pathogenic, replication competent virus to yield a novel chimeric for noninvasive, intranasal delivery. RESULTS Viruses with pathogenic properties in wild-type have been successfully used as components of OVs and have demonstrated potential in both preclinical and clinical trials. Outcomes show that despite wild-type virulence, notable toxicities were not observed in clinical trials, highlighting the potential of viral pseudotyping as a safe therapeutic approach. CONCLUSIONS The proposed method to utilize the SARS-CoV-2 glycoprotein in a novel chimeric poses advantages including 1) potential for non-invasive delivery, 2) therapy without need for maximal or uniform tumor coverage due to replication competence, 3) ability to reach infiltrative glioma cells, 4) potential to reach the brainstem, and 5) stimulation of host immunity through tumor cell lysis and antigen presentation

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ONCOLYTIC VIROTHERAPY IN GLIOBLASTOMA TREATMENT: PROGRESS AND CHALLENGES IN CLINICAL RESEARCH (LITERATURE REVIEW)

Siberian Journal of Oncology ◽

10.21294/1814-4861-2020-19-6-133-140 ◽

2020 ◽

Vol 19 (6) ◽

pp. 133-140

Author(s):

O. I. Kit ◽

S. N. Ignatov ◽

E. Yu. Zlatnik ◽

N. V. Soldatkina ◽

E. E. Rostorguev ◽

...

Keyword(s):

Clinical Trials ◽

Viral Vectors ◽

Experimental Studies ◽

Research Literature ◽

Oncolytic Viruses ◽

Oncolytic Virotherapy ◽

High Grade ◽

Treatment Progress ◽

Poor Treatment ◽

Target Cancer

Glial tumors comprise about 60 % of primary malignant brain tumors, and 70 % of them show morphological signs of high-grade cancer (High Grade Gliomas III , IV WHO 2016) [1, 2]. Despite a significant technical pre- and intraoperative progress as well as advances in radiotherapy and chemotherapy, the overall median survival is very low, being less than 20 months [3] and less than 12 months in patients with relapse [4]. Recent studies have shown that chemo- and radioresistance is due to the existence of cancer stem cells [5, 6]. Poor treatment outcomes require the development and implementation of new approaches to the treatment of highgrade gliomas. In recent years, increasing attention has been paid to the development of immunotherapeutic treatment approaches, including the development of oncolytic virotherapy. Tropism to target cancer cells, as well as various viral vectors, has been developed using methods of genetic engineering; synergism of viruses and adjuvant therapy has been studied. Despite extensive experimental studies of the mechanism of oncolysis [1], there are only a few reports on Phase I–II clinical trials. This review considers the most successful applications of oncolytic viruses in relation to glioblastoma in animal models and their translation into clinical practice in patients.

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Radiological assessment schedule for high-grade glioma patients during the surveillance period using parametric modeling

Neuro-Oncology ◽

10.1093/neuonc/noaa250 ◽

2020 ◽

Author(s):

So Young Ji ◽

Jongjin Lee ◽

Joo Ho Lee ◽

Soon-Tae Lee ◽

Jae Kyung Won ◽

...

Keyword(s):

Standard Treatment ◽

Risk Group ◽

High Grade Glioma ◽

Parametric Model ◽

Parametric Modeling ◽

Progression Rate ◽

High Grade ◽

Radiological Assessment ◽

Wild Type

Abstract Background An optimal radiological surveillance plan is crucial for high-grade glioma (HGG) patients, which is determined arbitrarily in daily clinical practice. We propose the radiological assessment schedule using a parametric model of standardized progression-free survival (PFS) curves. Methods A total of 277 HGG patients (178 glioblastoma (GBM) and 99 anaplastic astrocytoma (AA)) from a single institute who completed the standard treatment protocol were enrolled in this cohort study and retrospectively analyzed. The patients were stratified into each layered risk group by genetic signatures and residual mass or through recursive partitioning analysis. PFS curves were estimated using the piecewise exponential survival model. The criterion of a 10% progression rate among the remaining patients at each observation period was used to determine the optimal radiological assessment time point. Results The optimal follow-up intervals for MRI evaluations of the isocitrate dehydrogenase (IDH) wild-type GBM was every 7.4 weeks until 120 weeks after the end of standard treatment, followed by a 22-week inflection period and every 27.6 weeks thereafter. For the IDH mutated GBM, scans every 13.2 weeks until 151 weeks are recommended. The optimal follow-up intervals were every 22.8 weeks for the IDH wild-type AA, and 41.2 weeks for the IDH mutated AA until 241 weeks. Tailored radiological assessment schedules were suggested for each layered risk groups of the GBM and the AA patients. Conclusions The optimal schedule of radiological assessments for each layered risk group of patients with HGG could be determined from the parametric model of PFS.

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ATIM-09. SUCCESSFUL EXPERIENCE WITH CLINICAL TRIALS FOR HIGH GRADE GLIOMA IN A COMMUNITY SETTING

Neuro-Oncology ◽

10.1093/neuonc/now212.074 ◽

2016 ◽

Vol 18 (suppl_6) ◽

pp. vi19-vi19

Author(s):

Lars Anker ◽

Lavinia Dobrea ◽

Joy Nakhla ◽

Viorela Pop ◽

Lawrence Wagman

Keyword(s):

Clinical Trials ◽

Community Setting ◽

High Grade Glioma ◽

High Grade

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Oncolytic Virotherapy for Malignant Tumor: Current Clinical Status

Current Pharmaceutical Design ◽

10.2174/1381612825666191104090544 ◽

2020 ◽

Vol 25 (40) ◽

pp. 4251-4263 ◽

Cited By ~ 2

Author(s):

Yuhui Zhang ◽

Zhuoming Liu

Keyword(s):

Clinical Trials ◽

Clinical Status ◽

Genetically Engineered ◽

Oncolytic Viruses ◽

Therapeutic Effects ◽

The Us ◽

Melanoma Patients ◽

Virus Interaction ◽

Tumor Cell Lysis ◽

Significant Therapeutic Effect

Oncolytic viruses, as novel biological anti-tumor agents, provide anti-tumor therapeutic effects by different mechanisms including directly selective tumor cell lysis and secondary systemic anti-tumor immune responses. Some wide-type and genetically engineered oncolytic viruses have been applied in clinical trials. Among them, T-Vec has a significant therapeutic effect on melanoma patients and received the approval of the US Food and Drug Administration (FDA) as the first oncolytic virus to treat cancer in the US. However, the mechanisms of virus interaction with tumor and immune systems have not been clearly elucidated and there are still no “gold standards” for instructions of virotherapy in clinical trials. This Review collected the recent clinical trials data from 2005 to summarize the basic oncolytic viruses biology, describe the application in recent clinical trials, and discuss the challenges in the application of oncolytic viruses in clinical trials.

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DDRE-14. OPTIMIZING MDM2 INHIBITION FOR THE TREATMENT OF HIGH-GRADE GLIOMA

Neuro-Oncology ◽

10.1093/neuonc/noab196.298 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi77-vi77

Author(s):

Veronica Rendo ◽

Leslie Lupien ◽

Nicholas Khuu ◽

Kristine Pelton ◽

Lara Elcavage ◽

...

Keyword(s):

High Grade Glioma ◽

Tp53 Gene ◽

Resistance Mechanisms ◽

High Grade ◽

Wild Type ◽

Tp53 Mutations ◽

Activating Mutations ◽

Cycle Arrest ◽

Transcriptional Changes ◽

Mdm2 Inhibitor

Abstract A majority of high grade gliomas retain a wild-type TP53 gene and are amenable to strategies for activation of the pathway to inhibit tumor growth. The interaction between p53 and MDM2 has served as target for such strategies currently in clinical trials for glioblastoma. As the effects and resistance mechanisms of MDM2 inhibition (MDM2i) remain poorly understood in glioma, we performed genomic and transcriptomic analyses in patient-derived models to better characterize sensitive tumors and identify putative biomarkers of drug response. Treatment with an MDM2 inhibitor (KRT232/AMG232) impaired the growth of cell lines with wild-type TP53 status, particularly in tumors with amplification of MDM2/4 or PPM1D activating mutations. Treatment with KRT232 upregulated both cell cycle arrest and apoptotic cellular responses, with unique temporal and transcriptional differences correlated with MDM2/4 or PPM1D status. In other tumors resistance to MDM2i is mainly mediated by TP53 mutations, but in a subset of chronic KRT232-treated glioma models we noted lack of TP53 mutations and identified cell state and transcriptional changes as potentially more treatable mediators of resistance.

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