Preconditioning of the tumor microenvironment with oncolytic reovirus converts CD3-bispecific antibody treatment into effective immunotherapy
Background T-cell-engaging CD3-bispecific antibodies (CD3-bsAbs) are promising modalities for cancer immunotherapy. Although this therapy has reached clinical practice for hematological malignancies, the absence of sufficient infiltrating T cells is a major barrier for efficacy in solid tumors. In t...
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BMJ Publishing Group
2020-10-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/8/2/e001191.full |
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| author | Rob C Hoeben Sjoerd H van der Burg Thorbald van Hall Christianne Groeneveldt Priscilla Kinderman Diana J M van den Wollenberg Ruben L van den Oever Jim Middelburg Dana A M Mustafa Nadine van Montfoort |
| author_facet | Rob C Hoeben Sjoerd H van der Burg Thorbald van Hall Christianne Groeneveldt Priscilla Kinderman Diana J M van den Wollenberg Ruben L van den Oever Jim Middelburg Dana A M Mustafa Nadine van Montfoort |
| author_sort | Rob C Hoeben |
| collection | DOAJ |
| description | Background T-cell-engaging CD3-bispecific antibodies (CD3-bsAbs) are promising modalities for cancer immunotherapy. Although this therapy has reached clinical practice for hematological malignancies, the absence of sufficient infiltrating T cells is a major barrier for efficacy in solid tumors. In this study, we exploited oncolytic reovirus as a strategy to enhance the efficacy of CD3-bsAbs in immune-silent solid tumors.Methods The mutant p53 and K-ras induced murine pancreatic cancer model KPC3 resembles human pancreatic ductal adenocarcinomas with a desmoplastic tumor microenvironment, low T-cell density and resistance to immunotherapy. Immune-competent KPC3 tumor-bearing mice were intratumorally injected with reovirus type 3 Dearing strain and the reovirus-induced changes in the tumor microenvironment and spleen were analyzed over time by NanoString analysis, quantitative RT-PCR and multicolor flow cytometry. The efficacy of reovirus in combination with systemically injected CD3-bsAbs was evaluated in immune-competent mice with established KPC3 or B16.F10 tumors, and in the close-to-patient human epidermal growth factor receptor 2 (HER2)+ breast cancer model BT474 engrafted in immunocompromised mice with human T cells as effector cells.Results Replication-competent reovirus induced an early interferon signature, followed by a strong influx of natural killer cells and CD8+ T cells, at the cost of FoxP3+ Tregs. Viral replication declined after 7 days and was associated with a systemic activation of lymphocytes and the emergence of intratumoral reovirus-specific CD8+ T cells. Although tumor-infiltrating T cells were mostly reovirus-specific and not tumor-specific, they served as non-exhausted effector cells for the subsequently systemically administered CD3-bsAbs. Combination treatment of reovirus and CD3-bsAbs led to the regression of large, established KPC3, B16.F10 and BT474 tumors. Reovirus as a preconditioning regimen performed significantly better than simultaneous or early administration of CD3-bsAbs. This combination treatment induced regressions of distant lesions that were not injected with reovirus, and systemic administration of both reovirus and CD3-bsAbs also led to tumor control. This suggests that this therapy might also be effective for metastatic disease.Conclusions Oncolytic reovirus administration represents an effective strategy to induce a local interferon response and strong T-cell influx, thereby sensitizing the tumor microenvironment for subsequent CD3-bsAb therapy. This combination therapy warrants further investigation in patients with non-inflamed solid tumors. |
| format | Article |
| id | doaj-art-c3d20f94ac3d4a76b0d4b7271cb48045 |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2020-10-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-c3d20f94ac3d4a76b0d4b7271cb480452024-11-10T15:55:08ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262020-10-018210.1136/jitc-2020-001191Preconditioning of the tumor microenvironment with oncolytic reovirus converts CD3-bispecific antibody treatment into effective immunotherapyRob C Hoeben0Sjoerd H van der Burg1Thorbald van Hall2Christianne Groeneveldt3Priscilla Kinderman4Diana J M van den Wollenberg5Ruben L van den Oever6Jim Middelburg7Dana A M Mustafa8Nadine van Montfoort96Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, the Netherlands1 Oncode institute, Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands1 Medical Oncology, Oncode institute, Leiden University Medical Center, Leiden, The NetherlandsDepartment of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands3 Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands2 Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands3 Department of Medical Oncology, Leiden University Medical Center, Leiden, The NetherlandsDepartment of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, The NetherlandsDepartment of Pathology, Erasmus Medical Center, Rotterdam, The NetherlandsDepartment of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The NetherlandsBackground T-cell-engaging CD3-bispecific antibodies (CD3-bsAbs) are promising modalities for cancer immunotherapy. Although this therapy has reached clinical practice for hematological malignancies, the absence of sufficient infiltrating T cells is a major barrier for efficacy in solid tumors. In this study, we exploited oncolytic reovirus as a strategy to enhance the efficacy of CD3-bsAbs in immune-silent solid tumors.Methods The mutant p53 and K-ras induced murine pancreatic cancer model KPC3 resembles human pancreatic ductal adenocarcinomas with a desmoplastic tumor microenvironment, low T-cell density and resistance to immunotherapy. Immune-competent KPC3 tumor-bearing mice were intratumorally injected with reovirus type 3 Dearing strain and the reovirus-induced changes in the tumor microenvironment and spleen were analyzed over time by NanoString analysis, quantitative RT-PCR and multicolor flow cytometry. The efficacy of reovirus in combination with systemically injected CD3-bsAbs was evaluated in immune-competent mice with established KPC3 or B16.F10 tumors, and in the close-to-patient human epidermal growth factor receptor 2 (HER2)+ breast cancer model BT474 engrafted in immunocompromised mice with human T cells as effector cells.Results Replication-competent reovirus induced an early interferon signature, followed by a strong influx of natural killer cells and CD8+ T cells, at the cost of FoxP3+ Tregs. Viral replication declined after 7 days and was associated with a systemic activation of lymphocytes and the emergence of intratumoral reovirus-specific CD8+ T cells. Although tumor-infiltrating T cells were mostly reovirus-specific and not tumor-specific, they served as non-exhausted effector cells for the subsequently systemically administered CD3-bsAbs. Combination treatment of reovirus and CD3-bsAbs led to the regression of large, established KPC3, B16.F10 and BT474 tumors. Reovirus as a preconditioning regimen performed significantly better than simultaneous or early administration of CD3-bsAbs. This combination treatment induced regressions of distant lesions that were not injected with reovirus, and systemic administration of both reovirus and CD3-bsAbs also led to tumor control. This suggests that this therapy might also be effective for metastatic disease.Conclusions Oncolytic reovirus administration represents an effective strategy to induce a local interferon response and strong T-cell influx, thereby sensitizing the tumor microenvironment for subsequent CD3-bsAb therapy. This combination therapy warrants further investigation in patients with non-inflamed solid tumors.https://jitc.bmj.com/content/8/2/e001191.full |
| spellingShingle | Rob C Hoeben Sjoerd H van der Burg Thorbald van Hall Christianne Groeneveldt Priscilla Kinderman Diana J M van den Wollenberg Ruben L van den Oever Jim Middelburg Dana A M Mustafa Nadine van Montfoort Preconditioning of the tumor microenvironment with oncolytic reovirus converts CD3-bispecific antibody treatment into effective immunotherapy Journal for ImmunoTherapy of Cancer |
| title | Preconditioning of the tumor microenvironment with oncolytic reovirus converts CD3-bispecific antibody treatment into effective immunotherapy |
| title_full | Preconditioning of the tumor microenvironment with oncolytic reovirus converts CD3-bispecific antibody treatment into effective immunotherapy |
| title_fullStr | Preconditioning of the tumor microenvironment with oncolytic reovirus converts CD3-bispecific antibody treatment into effective immunotherapy |
| title_full_unstemmed | Preconditioning of the tumor microenvironment with oncolytic reovirus converts CD3-bispecific antibody treatment into effective immunotherapy |
| title_short | Preconditioning of the tumor microenvironment with oncolytic reovirus converts CD3-bispecific antibody treatment into effective immunotherapy |
| title_sort | preconditioning of the tumor microenvironment with oncolytic reovirus converts cd3 bispecific antibody treatment into effective immunotherapy |
| url | https://jitc.bmj.com/content/8/2/e001191.full |
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