Current cancer therapeutics often insufficiently eradicate malignant cells due to the surrounding dense tumor stroma. This multi-componential tissue consists of mainly cancer-associated fibroblasts... Show moreCurrent cancer therapeutics often insufficiently eradicate malignant cells due to the surrounding dense tumor stroma. This multi-componential tissue consists of mainly cancer-associated fibroblasts, the (compact) extracellular matrix, tumor vasculature, and tumor-associated macrophages, which all exert crucial roles in maintaining a pro-tumoral niche. Their continuous complex interactions with tumor cells promote tumor progression and metastasis, emphasizing the challenges in tumor therapy development. Over the last decade, advances in oncolytic virotherapy have shown that oncolytic viruses (OVs) are a promising multi-faceted therapeutic platform for simultaneous tumor and stroma targeting. In addition to promoting tumor cell oncolysis and systemic anti-tumor immunity, accumulating data suggest that OVs can also directly target stromal components, facilitating OV replication and spread, as well as promoting anti-tumor activity. This review provides a comprehensive overview of the interactions between native and genetically modified OVs and the different targetable tumor stromal components, and outlines strategies to improve stroma targeting by OVs. Show less
Groeneveldt, C.; Kinderman, P.; Wollenberg, D.J.M. van den; Oever, R.L. van den; Middelburg, J.; Mustafa, D.A.M.; ... ; Montfoort, N. van 2020
Background T-cell-engaging CD3-bispecific antibodies (CD3-bsAbs) are promising modalities for cancer immunotherapy. Although this therapy has reached clinical practice for hematological... Show moreBackground 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 mutantp53andK-rasinduced 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. Show less
Kemp, V.; Hoeben, R.C.; Wollenberg, D.J.M. van den 2016
