Overcoming resistance to anti-PD immunotherapy in a syngeneic mouse lung cancer model using locoregional virotherapy
| Autor: | Lili Yu, Stephen G. Swisher, Xiaoshan Zhang, Li Wang, Bingliang Fang, J. Wang, Xiang Yan, Xingxiang Pu, Don L. Gibbons, Ismail M. Meraz, Ran Zhang, Reza J. Mehran, Jack A. Roth, Shuhong Wu |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
lcsh:Immunologic diseases. Allergy Combination therapy medicine.medical_treatment Genetic enhancement Immunology lcsh:RC254-282 immune checkpoint inhibitors 03 medical and health sciences 0302 clinical medicine Immune system medicine Immunology and Allergy Virotherapy Lung cancer Original Research p53 gene therapy business.industry Cancer Immunotherapy medicine.disease lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens Oncolytic virus pd-1 blockage therapy lung cancer 030104 developmental biology Oncology 030220 oncology & carcinogenesis Cancer research virotherapy business lcsh:RC581-607 |
| Zdroj: | OncoImmunology, Vol 7, Iss 1 (2018) |
| Popis: | Anti-PD-1 and anti-PD-L1 immunotherapy has provided a new therapeutic opportunity for treatment of advanced-stage non-small cell lung cancer (NSCLC). However, overall objective response rates are approximately 15%-25% in all NSCLC patients who receive anti-PD therapy. Therefore, strategies to overcome primary resistance to anti-PD immunotherapy are urgently needed. We hypothesized that the barrier to the success of anti-PD therapy in most NSCLC patients can be overcome by stimulating the lymphocyte infiltration at cancer sites through locoregional virotherapy. To this end, in this study, we determined combination effects of anti-PD immunotherapy and oncolytic adenoviral vector-mediated tumor necrosis factor-α-related apoptosis-inducing ligand (TRAIL) gene therapy (Ad/E1-TRAIL) or adenoviral-mediated TP53 (Ad/CMV-TP53) gene therapy in syngeneic mice bearing subcutaneous tumors derived from M109 lung cancer cells. Both anti-PD-1 and anti-PD-L1 antibodies failed to elicit obvious therapeutic effects in the M109 tumors. Intratumoral administration of Ad/E1-TRAIL or Ad/CMV-TP53 alone suppressed tumor growth in animals preexposed to an adenovector and bearing subcutaneous tumors derived from M109 cells. However, combining either anti-PD-1 or anti-PD-L1 antibody with these two adenoviral vectors elicited the strongest anticancer activity in mice with existing immunity to adenoviral vectors. Dramatically enhanced intratumoral immune response was detected in this group of combination therapy based on infiltrations of CD4+ and CD8+ lymphocytes and macrophages in tumors. Our results demonstrate that resistance to anti-PD-1 immunotherapy in syngeneic mouse lung cancer can be overcome by locoregional virotherapy. |
| Databáze: | OpenAIRE |
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