View in EDS

Bmi1 Resistance Pathway and Immune Checkpoint Blockade in Lung Cancer.

Saved in:
Bibliographic Details
Title: Bmi1 Resistance Pathway and Immune Checkpoint Blockade in Lung Cancer.
Authors: Chaudhary, K.R.1 (AUTHOR), Halmos, B.2 (AUTHOR), Cheng, H.2 (AUTHOR), Cheng, S.K.1,3 (AUTHOR)
Source: International Journal of Radiation Oncology, Biology, Physics. 2021 Supplement, Vol. 111 Issue 3, pe432-e433. 2p.
Subjects: Immune checkpoint proteins, Lung cancer, Cisplatin, Laboratory mice, Small molecules, Lung tumors
Abstract: Purpose/objective(s): Combined chemotherapy and radiation is a standard therapy for locally advanced lung cancers. However, the resistance mechanisms to these therapies and how they affect further adjuvant immunotherapy are not well understood. Our previous studies have shown that radiation led to the activation of Bmi1 as a mechanism of radiation resistance, which in turn upregulated the inhibitory immune checkpoint ligand PD-L1. Our hypothesis is that inhibition of Bmi1, a target for chemoradiotherapy resistance, with concurrent PD-L1 checkpoint blockade would have a synergistic enhanced immune response after chemoradiation therapy in a preclinical model of lung cancer.Materials/methods: A small molecule inhibitor, PTC-596 (PTC Therapeutics, NJ), has been shown to inhibit the expression of Bmi1. For in vitro studies, we tested the effects of PTC-596 on the expression of both Bmi1 and PD-L1 in several lung tumor cell lines. To create a mouse model that simulates the PACIFIC trial treatment regimen, Lewis lung carcinoma cells (LLC1; 1 x 106 unsorted cells in 100 ul) derived in C57BL/6J strain were injected subcutaneously into the flank of immunocompetent C67BL/6J mice. When average tumor volume reached 100 mm3, the mice were treated with phase 1 treatment of radiation (dose 30 Gy in 10 fractions daily) delivered through SAARP platform and cisplatin (2mg/kg, every 3rd day for 10 days) and then randomized to receive phase 2 treatments: 1). Vehicle control every day; 2). Inhibitory anti-PD-L1 antibody every other day (200mg/kg, every 3 days for 4 cycles); 3). PTC-596 once a day (12.5 mg/kg, once a day); 4). Combined inhibitory anti-PD-1 antibody and PTC-596. Each treatment group had 10 mice.Results: In both human and mouse lung tumor cell lines, fractionated radiation treatments upregulated Bmi1 expression and also increase the frequency of Bmi1-high, PD-L1-high expressing cells. Treatment with PTC-596 downregulated expression of Bmi1 and PD-L1 in these cells. In the PACIFIC study mouse model, cisplatin chemotherapy with fractionated radiation resulted significant growth delay than compared to no treatment. In the phase 2 of adjuvant treatment, the anti-PD-L1 antibody plus PTC-596 combination group, but not in groups receiving either treatment alone, had continued significant tumor size reduction. Immunological markers are being analyzed to determine if the immune response is enhanced.Conclusion: These results suggest that chemoradiation therapy leads to the activation of Bmi1 as a resistance mechanism, which in turn results in the activation of inhibitory immune checkpoint PD-L1 leading to immune escape and acquired resistance to immunotherapy. Treatment with PTC-596 demonstrated synergistic benefits to anti-PD-L1 immunotherapy after pre-chemoradiation treatment of preclinical mouse lung tumor model. [ABSTRACT FROM AUTHOR]
Copyright of International Journal of Radiation Oncology, Biology, Physics is the property of Pergamon Press - An Imprint of Elsevier Science and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
Database: Engineering Source
FullText Text:
  Availability: 0
Header DbId: egs
DbLabel: Engineering Source
An: 152497270
AccessLevel: 6
PubType: Academic Journal
PubTypeId: academicJournal
PreciseRelevancyScore: 0
IllustrationInfo
Items – Name: Title
  Label: Title
  Group: Ti
  Data: Bmi1 Resistance Pathway and Immune Checkpoint Blockade in Lung Cancer.
– Name: Author
  Label: Authors
  Group: Au
  Data: <searchLink fieldCode="AR" term="%22Chaudhary%2C+K%2ER%2E%22">Chaudhary, K.R.</searchLink><relatesTo>1</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Halmos%2C+B%2E%22">Halmos, B.</searchLink><relatesTo>2</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Cheng%2C+H%2E%22">Cheng, H.</searchLink><relatesTo>2</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Cheng%2C+S%2EK%2E%22">Cheng, S.K.</searchLink><relatesTo>1,3</relatesTo> (AUTHOR)
– Name: TitleSource
  Label: Source
  Group: Src
  Data: <searchLink fieldCode="JN" term="%22International+Journal+of+Radiation+Oncology%2C+Biology%2C+Physics%22">International Journal of Radiation Oncology, Biology, Physics</searchLink>. 2021 Supplement, Vol. 111 Issue 3, pe432-e433. 2p.
– Name: Subject
  Label: Subjects
  Group: Su
  Data: <searchLink fieldCode="DE" term="%22Immune+checkpoint+proteins%22">Immune checkpoint proteins</searchLink><br /><searchLink fieldCode="DE" term="%22Lung+cancer%22">Lung cancer</searchLink><br /><searchLink fieldCode="DE" term="%22Cisplatin%22">Cisplatin</searchLink><br /><searchLink fieldCode="DE" term="%22Laboratory+mice%22">Laboratory mice</searchLink><br /><searchLink fieldCode="DE" term="%22Small+molecules%22">Small molecules</searchLink><br /><searchLink fieldCode="DE" term="%22Lung+tumors%22">Lung tumors</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: <bold>Purpose/objective(s): </bold>Combined chemotherapy and radiation is a standard therapy for locally advanced lung cancers. However, the resistance mechanisms to these therapies and how they affect further adjuvant immunotherapy are not well understood. Our previous studies have shown that radiation led to the activation of Bmi1 as a mechanism of radiation resistance, which in turn upregulated the inhibitory immune checkpoint ligand PD-L1. Our hypothesis is that inhibition of Bmi1, a target for chemoradiotherapy resistance, with concurrent PD-L1 checkpoint blockade would have a synergistic enhanced immune response after chemoradiation therapy in a preclinical model of lung cancer.<bold>Materials/methods: </bold>A small molecule inhibitor, PTC-596 (PTC Therapeutics, NJ), has been shown to inhibit the expression of Bmi1. For in vitro studies, we tested the effects of PTC-596 on the expression of both Bmi1 and PD-L1 in several lung tumor cell lines. To create a mouse model that simulates the PACIFIC trial treatment regimen, Lewis lung carcinoma cells (LLC1; 1 x 106 unsorted cells in 100 ul) derived in C57BL/6J strain were injected subcutaneously into the flank of immunocompetent C67BL/6J mice. When average tumor volume reached 100 mm3, the mice were treated with phase 1 treatment of radiation (dose 30 Gy in 10 fractions daily) delivered through SAARP platform and cisplatin (2mg/kg, every 3rd day for 10 days) and then randomized to receive phase 2 treatments: 1). Vehicle control every day; 2). Inhibitory anti-PD-L1 antibody every other day (200mg/kg, every 3 days for 4 cycles); 3). PTC-596 once a day (12.5 mg/kg, once a day); 4). Combined inhibitory anti-PD-1 antibody and PTC-596. Each treatment group had 10 mice.<bold>Results: </bold>In both human and mouse lung tumor cell lines, fractionated radiation treatments upregulated Bmi1 expression and also increase the frequency of Bmi1-high, PD-L1-high expressing cells. Treatment with PTC-596 downregulated expression of Bmi1 and PD-L1 in these cells. In the PACIFIC study mouse model, cisplatin chemotherapy with fractionated radiation resulted significant growth delay than compared to no treatment. In the phase 2 of adjuvant treatment, the anti-PD-L1 antibody plus PTC-596 combination group, but not in groups receiving either treatment alone, had continued significant tumor size reduction. Immunological markers are being analyzed to determine if the immune response is enhanced.<bold>Conclusion: </bold>These results suggest that chemoradiation therapy leads to the activation of Bmi1 as a resistance mechanism, which in turn results in the activation of inhibitory immune checkpoint PD-L1 leading to immune escape and acquired resistance to immunotherapy. Treatment with PTC-596 demonstrated synergistic benefits to anti-PD-L1 immunotherapy after pre-chemoradiation treatment of preclinical mouse lung tumor model. [ABSTRACT FROM AUTHOR]
– Name: AbstractSuppliedCopyright
  Label:
  Group: Ab
  Data: <i>Copyright of International Journal of Radiation Oncology, Biology, Physics is the property of Pergamon Press - An Imprint of Elsevier Science and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
PLink https://search.ebscohost.com/login.aspx?direct=true&site=eds-live&db=egs&AN=152497270
RecordInfo BibRecord:
  BibEntity:
    Identifiers:
      – Type: doi
        Value: 10.1016/j.ijrobp.2021.07.1229
    Languages:
      – Code: eng
        Text: English
    PhysicalDescription:
      Pagination:
        PageCount: 2
        StartPage: e432
    Subjects:
      – SubjectFull: Immune checkpoint proteins
        Type: general
      – SubjectFull: Lung cancer
        Type: general
      – SubjectFull: Cisplatin
        Type: general
      – SubjectFull: Laboratory mice
        Type: general
      – SubjectFull: Small molecules
        Type: general
      – SubjectFull: Lung tumors
        Type: general
    Titles:
      – TitleFull: Bmi1 Resistance Pathway and Immune Checkpoint Blockade in Lung Cancer.
        Type: main
  BibRelationships:
    HasContributorRelationships:
      – PersonEntity:
          Name:
            NameFull: Chaudhary, K.R.
      – PersonEntity:
          Name:
            NameFull: Halmos, B.
      – PersonEntity:
          Name:
            NameFull: Cheng, H.
      – PersonEntity:
          Name:
            NameFull: Cheng, S.K.
    IsPartOfRelationships:
      – BibEntity:
          Dates:
            – D: 02
              M: 11
              Text: 2021 Supplement
              Type: published
              Y: 2021
          Identifiers:
            – Type: issn-print
              Value: 03603016
          Numbering:
            – Type: volume
              Value: 111
            – Type: issue
              Value: 3
          Titles:
            – TitleFull: International Journal of Radiation Oncology, Biology, Physics
              Type: main
ResultId 1