1. Local therapy with an engineered oncolytic adenovirus enables antitumor response in non-injected melanoma tumors in mice treated with aPD-1
- Author
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Dafne C. A. Quixabeira, Victor Cervera-Carrascon, Joao M. Santos, James H.A. Clubb, Tatiana V. Kudling, Saru Basnet, Camilla Heiniö, Susanna Grönberg-Vähä-Koskela, Marjukka Anttila, Riikka Havunen, Anna Kanerva, Akseli Hemminki, Research Programs Unit, TRIMM - Translational Immunology Research Program, Department of Oncology, HUS Comprehensive Cancer Center, Medicum, HUS Gynecology and Obstetrics, Akseli Eetu Hemminki / Principal Investigator, Clinicum, and Department of Obstetrics and Gynecology
- Subjects
lymphocytes ,PROMOTES ,Adenoviridae Infections ,3122 Cancers ,Immunology ,Oncolytic adenovirus ,Adenoviridae ,DELIVERY ,03 medical and health sciences ,Mice ,0302 clinical medicine ,melanoma ,Tumor Microenvironment ,Immunology and Allergy ,Animals ,RC254-282 ,030304 developmental biology ,Oncolytic Virotherapy ,0303 health sciences ,IL-2 ,TNFa ,NECROSIS-FACTOR-ALPHA ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC581-607 ,T-CELL IMMUNITY ,3. Good health ,Oncology ,030220 oncology & carcinogenesis ,INNATE IMMUNITY ,SURVIVAL ,Interleukin-2 ,3111 Biomedicine ,aPD-1 ,Immunotherapy ,Immunologic diseases. Allergy ,RESISTANCE ,Research Article - Abstract
Intratumoral immunotherapies are entering clinical use but concerns remain regarding their effects on non-injected tumors. Here, we studied the impact of local treatment with an adenovirus coding for TNFa and IL-2 on systemic antitumor response in animals receiving aPD-1 (anti-programmed cell death protein 1) therapy. Using bilateral murine melanoma models, we tested systemic tumor response to combined therapy with anti-PD-1 and an adenovirus coding for TNFa and IL-2 ("virus"). Virus was given intratumorally (to one of the two tumors only) and aPD-1 monoclonal antibody systemically. We evaluated both tumors' response to treatment, overall survival, metastasis development, and immunological mechanisms involved with response. Consistent tumor control was observed in both injected and non-injected tumors, including complete response in all treated animals receiving aPD-1+ virus therapy. Mechanistically, virus injections enabled potent effector lymphocyte response locally, with systemic effects in non-injected tumors facilitated by aPD-1 treatment. Moreover, adenovirus therapy demonstrated immunological memory formation. Virus therapy was effective in preventing metastasis development. Local treatment with TNFa and IL-2 coding adenovirus enhanced systemic response to aPD-1 therapy, by re-shaping the microenvironment of both injected and non-injected tumors. Therefore, our pre-clinical data support the rationale for a trial utilizing a combination of aPD-1 plus virus for the treatment of human cancer.
- Published
- 2022