Abstract LB-287: Pseudocowpox: A next generation viral vector for cancer immunotherapy

• Published in: Cancer research (Chicago, Ill.) Ill.), 2018-07, Vol.78 (13_Supplement), p.LB-287-LB-287
• Main Authors: Rittner, Karola, Ricordel, Marine, Tosch, Caroline, Thioudellet, Christine, Remy-Ziller, Christelle, Claudepierre, Marie-Christine, Hoffmann, Chantal, Schmitt, Doris, Sansas, Benoit, Foloppe, Johann, Erbs, Philippe, Silvestre, Nathalie, Bendjama, Kaïdre, Quemeneur, Eric
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2018-LB-287

Engineered viral vectors are effective approaches to stimulate anti-tumor immunity, and change the tumor immune environment. Several viruses and strains have been developed to express tumor antigens and cytokines, and corresponding products are in advanced clinical trials. However, novel viral strains with improved immunogenic properties are sought. In this perspective, we screened a variety of poxviridae potentially usable in humans: Cowpox (CPX), Pseudocowpox (PCPV), Parapoxvirus Ovis (ORF), Myxoma virus (MYX), Swinepox (SWP), Yaba-like disease virus (YLDV), Raccoonpox (RCN), Cotia virus (CTV), and compared them to the well-established vaccine strain Modified Virus Ankara (MVA), and oncolytic Vaccinia Virus, strain Copenhagen (VV). Both in vitro with human primary immune cells, and in vivo with syngeneic mouse tumor models, PCPV proved to be a very promising vector for immunotherapy. Compared with MVA, PCPV induced a 1000-fold higher expression of IFN-alpha in human PBMCs, whereas SWPV and ORF displayed a lower 10 to 100-fold induction. Other viruses (i.e. VV, RCN, CTV, or MYX) did not raise the IFN-alpha level. PCPV was also shown to increase the level of GM-CSF, and to be safe for PBMCs, in contrast to ORF which displayed some cytotoxic effects. When tested for its capacity to trigger the expression of CD86, a co-stimulatory factor for T-cell activation, PCPV was shown to be superior than MVA in primary moDCs. Furthermore, PCPV treatment increased CD86 expression in human CD163+CD206+ “M2”-type macrophages derived from CD14+ monocytes, suggesting a shift to an antigen-presenting phenotype. In these cells, PCPV increased significantly the secretion of IL-18, IL-6 and IP-10, signing a conversion towards a less suppressive macrophage phenotype. Last, incubation of PCPV in a co-culture model overcame the immunosuppressive effect of MDSCs on human autologous CD8+ T. A GFP-encoding recombinant PCPV vector was generated, and we could demonstrate that PCPV was capable of infecting human primary immune cells, comparably to recombinant MVA vectors, except for activated T cells. A recombinant PCPV encoding for the HPV E7 protein was generated to assess the anti-tumor activity and immunogenicity in a syngeneic murine tumor model. Like MVA-E7, PCPV-E7 induced a strong cellular response (ELISPOT on splenocytes, and frequency of antigen-specific short-lived effector cells), but PCPV-E7 displayed a different cytokine/chemokine profile at the site of injection, with in