Synergistic cytotoxicity of oncolytic reovirus in combination with cisplatin–paclitaxel doublet chemotherapy

Abstract

Oncolytic reovirus is currently under active investigation in a range of tumour types. Early phase studies have shown that this agent has modest monotherapy efficacy and its future development is likely to focus on combination regimens with cytotoxic chemotherapy. Indeed, phase I/II clinical trials have confirmed that reovirus can be safely combined with cytotoxic drugs, including a platin—taxane doublet regimen, which is currently being tested in a phase III clinical trial in patients with relapsed/metastatic head and neck cancer. Therefore, we have tested this triple (reovirus, cisplatin, paclitaxel) combination therapy in a panel of four head and neck cancer cell lines. Using the combination index (CI) method, the triple therapy demonstrated synergistic cytotoxicity in vitro in both malignant and non-malignant cell lines. In head and neck cancer cell lines, this was associated with enhanced caspase 3 and 7 cleavage, but no increase in viral replication. In vitro analyses confirmed colocalisation of markers of reovirus infection and caspase 3. Triple therapy was significantly more effective than reovirus or cisplatin—paclitaxel in athymic nude mice. These data suggest that the combination of reovirus plus platin—taxane doublet chemotherapy has significant activity in head and neck cancer and underpin the current phase III study in this indication.

Strategic Combinations: The Future of Oncolytic Virotherapy with Reovirus

“…Reovirus has also demonstrated efficacy in chemotherapeutic combinations in tumor models of head and neck cancer. Relative to reovirus monotherapy, combination treatment with reovirus, paclitaxel, and cisplatin significantly increased survival in nude mouse tumor model of Cal27, a human cell line from tongue epithelium (49). Importantly, the authors report that there was no increased cytotoxicity produced by the combination platin-taxel chemotherapy and reovirus.…”

Oncoterapia viral en la leucemia

“…Hablando específicamente de la oncoterapia viral en la leucemia, al haber pocos estudios experimentales aún en I I I I II II II II II II II II IT IP IV IV IV IV IV IV IV IV IV IV IV [26][27][28][29][30][31][32][33][34][35][36][37][38][39] . Por estas razones, el reovirus debe ser el virus modificado utilizado en la oncoterapia para la leucemia.…”

Evolution of Reovirus in Cancer Therapy

“…Interestingly, these combination studies revealed that the use of reovirus along with common chemotherapeutic agents, such as cisplatin, docetaxel, or cisplatin-paclitaxel doublet chemotherapy or radiotherapy, had synergistic effects in vitro and in vivo. [21][22][23],45] For example, a study conducted by Sei et al investigated the in vitro combination effects of reovirus with a variety of chemotherapeutic agents (cisplatin, gemcitabine, vinblastine, and paclitaxel) against human non-small-cell lung cancer (NSCLC) cells. [25] Additionally, strong synergistic effects were observed only in those cell lines that were sensitive to monotherapy of the respective chemotherapeutic agent.…”