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Oncolytic virotherapy for small-cell lung cancer induces immune infiltration and prolongs survival.

ABSTRACT: Oncolytic virotherapy has been proposed as an ablative and immunostimulatory treatment strategy for solid tumors that are resistant to immunotherapy alone; however, there is a need to optimize host immune activation using preclinical immunocompetent models in previously untested common adult tumors. We studied a modified oncolytic myxoma virus (MYXV) that shows high efficiency for tumor-specific cytotoxicity in small-cell lung cancer (SCLC), a neuroendocrine carcinoma with high mortality and modest response rates to immune checkpoint inhibitors. Using an immunocompetent SCLC mouse model, we demonstrated the safety of intrapulmonary MYXV delivery with efficient tumor-specific viral replication and cytotoxicity associated with induction of immune cell infiltration. We observed increased SCLC survival following intrapulmonary MYXV that was enhanced by combined low-dose cisplatin. We also tested intratumoral MYXV delivery and observed immune cell infiltration associated with tumor necrosis and growth inhibition in syngeneic murine allograft tumors. Freshly collected primary human SCLC tumor cells were permissive to MYXV and intratumoral delivery into patient-derived xenografts resulted in extensive tumor necrosis. We confirmed MYXV cytotoxicity in classic and variant SCLC subtypes as well as cisplatin-resistant cells. Data from 26 SCLC human patients showed negligible immune cell infiltration, supporting testing MYXV as an ablative and immune-enhancing therapy.

SUBMITTER: Kellish P

PROVIDER: S-EPMC6546459 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Oncolytic virotherapy for small-cell lung cancer induces immune infiltration and prolongs survival.

Kellish Patrick P Shabashvili Daniil D Rahman Masmudur M MM Nawab Akbar A Guijarro Maria V MV Zhang Min M Cao Chunxia C Moussatche Nissin N Boyle Theresa T Antonia Scott S Reinhard Mary M Hartzell Connor C Jantz Michael M Mehta Hiren J HJ McFadden Grant G Kaye Frederic J FJ Zajac-Kaye Maria M

The Journal of clinical investigation 20190429 6

Oncolytic virotherapy has been proposed as an ablative and immunostimulatory treatment strategy for solid tumors that are resistant to immunotherapy alone; however, there is a need to optimize host immune activation using preclinical immunocompetent models in previously untested common adult tumors. We studied a modified oncolytic myxoma virus (MYXV) that shows high efficiency for tumor-specific cytotoxicity in small-cell lung cancer (SCLC), a neuroendocrine carcinoma with high mortality and mod ...[more]

PMID: 31033480

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Project description:Introduction: Antrodia cinnamomea (AC) is an extremely rare medicinal fungus native to forested regions of Taiwan. It possesses numerous biological activities, especially anti-tumor effects shown in various in vitro cancer cells and in vivo animal models. However, there are few clinical reports about AC as a treatment for cancer patients. This report attempts to demonstrate the therapeutic effect of dish-cultured AC (DAC) on a small cell lung cancer (SCLC) patient taken orally for an extended duration. Patient concerns: An 88-year-old male with a history of diabetes mellitus and hypertension visited the outpatient department with the symptoms of dyspnea and a cough for two weeks. After a diagnosis of SCLC, the patient declined both chemotherapy and radiotherapy because of the side effects and only accepted supportive care without additional therapy. Diagnosis: Limited-stage SCLC (T4N2M1a, stage IV) after the chest radiograph, computed tomography-guided biopsy, and pathological diagnosis. Interventions: The patient was prescribed DAC with an increasing dosage, from 5 g/d up to 10 g/d DAC, for six months, without radiation or chemotherapy treatment. Outcomes: DAC caused the tumor to shrink substantially. Surprisingly, the patient survived for 32 months without relapse after six months of DAC treatment. Laboratory examinations indicated that the patient's health had improved significantly, reverting to near normal levels. Notably, he had a good quality of life with a high Barthel index score. Unfortunately, this patient died of septic shock caused by acute cholangitis. Conclusion: DAC may exert an anti-cancer effect, which can lead to tumor regression. This is supposed to be achieved by the combined DAC's immunomodulatory, anti-angiogenic, anti-metastatic, anti-proliferative, and pro-apoptotic effects mediated through multiple signaling pathways. We propose that DAC can be used as a complementary medicine to prolong the life expectancy and improve the life quality of SCLC patients.

Project description:Background: An imbalance in the redox homeostasis has been reported in multiple cancers and is associated with a poor prognosis of disease. However, the prognostic value of redox-related genes in non-small-cell lung cancer (NSCLC) remains unclear. Methods: RNA sequencing data, DNA methylation data, mutation, and clinical data of NSCLC patients were downloaded from The Cancer Genome Atlas and Gene Expression Omnibus databases. Redox-related differentially expressed genes (DEGs) were used to construct the prognostic signature using least absolute shrinkage and selection operator (LASSO) regression analysis. Kaplan-Meier survival curve and receiver operator characteristic (ROC) curve analyses were applied to validate the accuracy of the gene signature. Nomogram and calibration plots of the nomogram were constructed to predict prognosis. Pathway analysis was performed using gene set enrichment analysis. The correlations of risk score with tumor stage, immune infiltration, DNA methylation, tumor mutation burden (TMB), and chemotherapy sensitivity were evaluated. The prognostic signature was validated using GSE31210, GSE26939, and GSE68465 datasets. Real-time polymerase chain reaction (PCR) was used to validate dysregulated genes in NSCLC. Results: A prognostic signature was constructed using the LASSO regression analysis and was represented as a risk score. The high-risk group was significantly correlated with worse overall survival (OS) (p < 0.001). The area under the ROC curve (AUC) at the 5-year stage was 0.657. The risk score was precisely correlated with the tumor stage and was an independent prognostic factor for NSCLC. The constructed nomogram accurately predicted the OS of patients after 1-, 3-, and 5-year periods. DNA replication, cell cycle, and ECM receptor interaction were the main pathways enriched in the high-risk group. In addition, the high-risk score was correlated with higher TMB, lower methylation levels, increased infiltrating macrophages, activated memory CD4+ T cells, and a higher sensitivity to chemotherapy. The signature was validated in GSE31210, GSE26939, and GSE68465 datasets. Real-time PCR validated dysregulated mRNA expression levels in NSCLC. Conclusions: A prognostic redox-related gene signature was successfully established in NSCLC, with potential applications in the clinical setting.

Dataset Information

Oncolytic virotherapy for small-cell lung cancer induces immune infiltration and prolongs survival.

Publications

Oncolytic virotherapy for small-cell lung cancer induces immune infiltration and prolongs survival.

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