Synergistic anti-tumor efficacy of immunogenic adenovirus ONCOS-102 (Ad5/3-D24-GM-CSF) and standard of care chemotherapy in preclinical mesothelioma model

Our plain-English summary of Synergistic anti-tumor efficacy of immunogenic adenovirus ONCOS-102 (Ad5/3-D24-GM-CSF) and standard of care chemotherapy in preclinical mesothelioma model, by L. Kuryk, E. Haavisto, M. Garofalo, et al (International Journal of Cancer, 2016).

The study

• Authors: L. Kuryk, E. Haavisto, M. Garofalo, C. Capasso, M. Hirvinen, S. Pesonen, T. Ranki, L. Vassilev, V. Cerullo
• Journal: International Journal of Cancer
• Published: 2016;139(8):1883-93
• Cited by: 49 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Malignant mesothelioma (MM) is a rare cancer type caused mainly by asbestos exposure. The median overall survival time of a mesothelioma cancer patient is less than 1-year from diagnosis. Currently there are no curative treatment modalities for malignant mesothelioma, however treatments such as surgery, chemotherapy and radiotherapy can help to improve patient prognosis and increase life expectancy. Pemetrexed-Cisplatin is the only standard of care (SoC) chemotherapy for malignant mesothelioma, but the median PFS/OS (progression-free survival/overall survival) from the initiation of treatment is only up to 12 months. Therefore, new treatment strategies against malignant mesothelioma are in high demand. ONCOS-102 is a dual targeting, chimeric oncolytic adenovirus, coding for human GM-CSF. The safety and immune activating properties of ONCOS-102 have already been assessed in phase 1 study (NCT01598129). In this preclinical study, we evaluated the antineoplastic activity of combination treatment with SoC chemotherapy (Pemetrexed, Cisplatin, Carboplatin) and ONCOS-102 in xenograft BALB/c model of human malignant mesothelioma. We demonstrated that ONCOS-102 is able to induce immunogenic cell death of human mesothelioma cell lines in vitro and showed anti-tumor activity in the treatment of refractory H226 malignant pleural mesothelioma (MPM) xenograft model. While chemotherapy alone showed no anti-tumor activity in the mesothelioma mouse model, ONCOS-102 was able to slow down tumor growth. Interestingly, a synergistic anti-tumor effect was seen when ONCOS-102 was combined with chemotherapy regimens. These findings give a rationale for the clinical testing of ONCOS-102 in combination with first-line chemotherapy in patients suffering from malignant mesothelioma.

© 2016 UICC.

In plain English

This was a preclinical laboratory and animal study of the oncolytic adenovirus ONCOS-102 (Ad5/3-D24-GM-CSF) combined with chemotherapy for malignant mesothelioma. In vitro, three human mesothelioma cell lines (JL-1 epithelioid, MSTO-211H biphasic, H226 epithelial) were treated with ONCOS-102 at 10 viral particles per cell, with pemetrexed plus cisplatin or carboplatin, or with both. At 3 days the virus alone killed 24% of MSTO-211H, 11% of H226 and 18% of JL-1 cells, while chemotherapy alone killed 11-12% of H226 and 10% of JL-1 cells but 63% and 73% of MSTO-211H cells. Markers of immunogenic cell death (calreticulin exposure, ATP and HMGB1 release) were highest with virus plus chemotherapy. In BALB/c nude mice bearing subcutaneous H226 tumours (seven mice, 14 tumours per group), chemotherapy alone did not significantly reduce tumour growth; at Day 60 tumour size was 97% of initial for virus priming plus pemetrexed-cisplatin versus 473% for mock. Viral DNA was detected only in tumours, not in serum or liver; human GM-CSF concentration was highest in tumours. The authors concluded their findings support combining ONCOS-102 with standard chemotherapy for malignant pleural mesothelioma.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Preclinical study: in vitro cell-line experiments plus a human mesothelioma xenograft experiment in nude mice
• Who was studied: Three human mesothelioma cell lines (JL-1 epithelioid, MSTO-211H biphasic, NCI-H226 epithelial) in vitro, and BALB/c nude mice bearing subcutaneous H226 tumours, seven mice and 14 tumours per group, treated over two months (University of Helsinki, Finland)
• Exposure: Oncolytic adenovirus ONCOS-102 (Ad5/3-D24-GM-CSF), alone or with standard of care chemotherapy (pemetrexed, cisplatin, carboplatin); in mice 1E8 VP per mouse intratumorally and pemetrexed 10 mg/kg, cisplatin 1.5 mg/kg, carboplatin 8 mg/kg intraperitoneally
• Main results:
  • In vitro, ONCOS-102 at 10 VP/cell killed 24% of MSTO-211H, 11% of H226 and 18% of JL-1 cells in 3 days
  • In vitro, chemotherapy alone killed 11-12% of H226 and 10% of JL-1 cells, but 63% and 73% of MSTO-211H cells with pemetrexed plus cisplatin and pemetrexed plus carboplatin respectively
  • Combining ONCOS-102 with chemotherapy significantly increased cytotoxicity in H226 and JL-1 cells compared with either treatment alone
  • Immunogenic cell death markers were greatest with the combination in all three cell lines
  • In the mouse model, neither chemotherapy regimen significantly reduced tumour growth
  • At Day 60, tumour size as a percentage of initial size was 97% for ONCOS-102 priming plus pemetrexed-cisplatin, 138% for simultaneous virus plus pemetrexed-cisplatin, 206% for virus alone, 473% for mock, 563% for pemetrexed-cisplatin and 672% for pemetrexed-carboplatin
  • Two animals showed complete regression of both tumours: one treated with ONCOS-102 plus pemetrexed plus cisplatin by Day 21, and one with ONCOS-102 priming plus pemetrexed plus cisplatin by Day 45
  • By the synergy (FTV) calculation, ratios greater than 1 were taken to indicate a synergistic effect of virus plus chemotherapy in vivo on Days 21, 48 and 60
  • Virus was detected only in tumours, not in serum or liver
  • Human GM-CSF produced by ONCOS-102 had its highest concentration in tumours
• The authors' conclusion: The authors concluded that their findings support combining ONCOS-102 with standard of care chemotherapy for treating malignant pleural mesothelioma
• Limitations the authors state:
  • The immune-modulating effect of the GM-CSF transgene could not act in this model because the mice were immunodeficient
  • The authors attributed the lack of chemotherapy effect in part to the suboptimal dose regimen used
  • The mechanism behind the observed effect was stated to be unknown

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Chemotherapy, Mesothelioma, Asbestos Exposure, Median Overall Survival, Prognosis, Life Expectancy, Pemetrexed (Alimta), Cisplatin.

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• Enhanced antitumor efficacy of fiber-modified, midkine promoter-regulated oncolytic adenovirus in human malignant mesothelioma — M. Takagi-Kimura, T. Yamano, et al. (2013)
• Tumor Treating Fields (TTFields) downregulate the Fanconi Anemia-BRCA pathway and increase the efficacy of chemotherapy in malignant pleural mesothelioma preclinical models — H. Mumblat, A. Martinez-Conde, et al. (2021)
• Complete regression of human malignant mesothelioma xenografts following local injection of midkine promoter-driven oncolytic adenovirus — S. Kubo, Y. Kawasaki, et al. (2010)
• A novel translational approach for human malignant pleural mesothelioma: heparanase-assisted dual virotherapy — Y. Watanabe, T. Kojima, et al. (2010)
• Preclinical demonstration of synergistic Active Nutrients/Drug (AND) combination as a potential treatment for malignant pleural mesothelioma — V. Volta, E. Ranzato, et al. (2013)

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