Keith A Lawson 1,2 , Ahmed A Mostafa 1,2 , Zhong Qiao Shi 1,2 , Jason Spurrell 1,2 , Wenqian Chen 1,2 , Jun Kawakami 3 , Kathy Gratton 1,2 , Satbir Thakur 1,2 , Donald G Morris 4,2 Show Affiliations »
Abstract
PURPOSE: In addition to their direct cytopathic effects, oncolytic viruses are capable of priming antitumor immune responses. However, strategies to enhance the immunotherapeutic potential of these agents are lacking. Here, we investigated the ability of the multi-tyrosine kinase inhibitor and first-line metastatic renal cell carcinoma (RCC) agent, sunitinib, to augment the antitumor immune response generated by oncolytic reovirus. EXPERIMENTAL DESIGN: In vitro, oncolysis and chemokine production were assessed in a panel of human and murine RCC cell lines after exposure to reovirus, sunitinib, or their combination. In vivo, the RENCA syngeneic murine model of RCC was employed to determine therapeutic and tumor-specific immune responses after treatment with reovirus (intratumoral), sunitinib, or their combination. Parallel investigations employing the KLN205 syngeneic murine model of lung squamous cell carcinoma (NSCLC) were conducted for further validation. RESULTS: Reovirus-mediated oncolysis and chemokine production was observed following RCC infection. Reovirus monotherapy reduced tumor burden and was capable of generating a systemic adaptive antitumor immune response evidenced by increased numbers of tumor-specific CD8+ IFNγ-producing cells. Coadministration of sunitinib with reovirus further reduced tumor burden resulting in improved survival, decreased accumulation of immune suppressor cells, and the establishment of protective immunity upon tumor rechallenge. Similar results were observed for KLN205 tumor-bearing mice, highlighting the potential broad applicability of this approach. CONCLUSIONS: The ability to repurpose sunitinib for augmentation of reovirus' immunotherapeutic efficacy positions this novel combination therapy as an attractive strategy ready for clinical testing against a range of histologies, including RCC and NSCLC. Clin Cancer Res; 22(23); 5839-50. ©2016 AACR. ©2016 American Association for Cancer Research.
PURPOSE: In addition to their direct cytopathic effects, oncolytic viruses are capable of priming antitumor immune responses. However, strategies to enhance the immunotherapeutic potential of these agents are lacking. Here, we investigated the ability of the multi-tyrosine kinase inhibitor and first-line metastatic renal cell carcinoma (RCC ) agent, sunitinib , to augment the antitumor immune response generated by oncolytic reovirus . EXPERIMENTAL DESIGN: In vitro, oncolysis and chemokine production were assessed in a panel of human and murine RCC cell lines after exposure to reovirus , sunitinib , or their combination. In vivo, the RENCA syngeneic murine model of RCC was employed to determine therapeutic and tumor -specific immune responses after treatment with reovirus (intratumoral), sunitinib , or their combination. Parallel investigations employing the KLN205 syngeneic murine model of lung squamous cell carcinoma (NSCLC ) were conducted for further validation. RESULTS: Reovirus -mediated oncolysis and chemokine production was observed following RCC infection . Reovirus monotherapy reduced tumor burden and was capable of generating a systemic adaptive antitumor immune response evidenced by increased numbers of tumor -specific CD8+ IFNγ-producing cells. Coadministration of sunitinib with reovirus further reduced tumor burden resulting in improved survival, decreased accumulation of immune suppressor cells, and the establishment of protective immunity upon tumor rechallenge. Similar results were observed for KLN205 tumor -bearing mice , highlighting the potential broad applicability of this approach. CONCLUSIONS: The ability to repurpose sunitinib for augmentation of reovirus ' immunotherapeutic efficacy positions this novel combination therapy as an attractive strategy ready for clinical testing against a range of histologies, including RCC and NSCLC . Clin Cancer Res; 22(23); 5839-50. ©2016 AACR. ©2016 American Association for Cancer Research.
Entities: Chemical
Disease
Species
Mesh： See more »
Substances： See more »
Year: 2016
PMID： 27220962 DOI： 10.1158/1078-0432.CCR-16-0143
Source DB: PubMed Journal: Clin Cancer Res ISSN： 1078-0432 Impact factor: 12.531