Preconditioning of the tumor microenvironment with oncolytic reovirus converts CD3-bispecific antibody treatment into effective immunotherapy
In: J Immunother Cancer, 2020
academicJournal
Zugriff:
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 ...
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Preconditioning of the tumor microenvironment with oncolytic reovirus converts CD3-bispecific antibody treatment into effective immunotherapy
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Autor/in / Beteiligte Person: | Groeneveldt, Christianne ; Kinderman, Priscilla ; van den Wollenberg, Diana J M ; van den Oever, Ruben L ; Middelburg, Jim ; Mustafa, Dana A M ; Hoeben, Rob C ; van der Burg, Sjoerd H ; van Hall, Thorbald ; van Montfoort, Nadine |
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Zeitschrift: | J Immunother Cancer, 2020 |
Veröffentlichung: | BMJ Publishing Group, 2020 |
Medientyp: | academicJournal |
DOI: | 10.1136/jitc-2020-001191 |
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