title: Expression of CCL19 from oncolytic vaccinia enhances immunotherapeutic potential while maintaining oncolytic activity.
abstract: Promising phase II clinical results have been reported recently for several oncolytic viral therapeutics, including strains based on vaccinia virus. One reason for this has been an increased appreciation of the critical therapeutic importance of the immune response raised by these viruses. However, the most commonly used approaches to enhance these immunotherapeutic effects in oncolytic viruses, typically though expression of cytokine transgenes, often also result in a reduction in oncolytic activity and premature clearance of the virotherapy from the tumor. Approaches that enhance the immunotherapeutic effects while maintaining oncolytic activity would therefore be beneficial. Here, it is demonstrated that the expression of the chemokine CCL19 (ELC) from an oncolytic vaccinia virus (vvCCL19) results in increased antitumor effects in syngeneic mouse tumor models. This corresponded with increased t cell and dendritic cell infiltration into the tumor. However, vvCCL19 persisted in the tumor at equivalent levels to a control virus without CCL19, demonstrating that oncolytic activity was not curtailed. Instead, vvCCL19 was cleared rapidly and selectively from normal tissues and organs, indicating a potentially increased safety profile. The therapeutic activity of vvCCL19 could be further significantly increased through combination with adoptive transfer of therapeutic immune cells expressing CCR7, the receptor for CCL19. This approach therefore represents a means to increase the safety and therapeutic benefit of oncolytic viruses, used alone or in combination with immune cell therapies.
authors: Department of Surgery, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors: Jun
authors: J
authors: Li
authors: Mark
authors: M
authors: O'Malley
authors: Padma
authors: P
authors: Sampath
authors: Pawel
authors: P
authors: Kalinski
authors: David L
authors: DL
authors: Bartlett
authors: Steve H
authors: SH
authors: Thorne
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000628:therapy* / Q000821:virology; D000818:Animals; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes; D018414:CD8-Positive T-Lymphocytes; D045744:Cell Line, Tumor; D054415:Chemokine CCL19 / Q000378:metabolism*; D003110:Colonic Neoplasms / Q000378:metabolism / Q000628:therapy* / Q000821:virology; D005260:Female; D007167:Immunotherapy; D051379:Mice; D008810:Mice, Inbred C57BL; D055611:Natural Killer T-Cells / Q000276:immunology* / Q000378:metabolism; D050504:Oncolytic Viruses / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D054400:Receptors, CCR7 / Q000378:metabolism; D013154:Spleen / Q000378:metabolism; D014616:Vaccinia virus / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D019562:Viral Load
chemical_list: D054415:Chemokine CCL19; D054400:Receptors, CCR7