Chemokine Expression From Oncolytic Vaccinia Virus Enhances Vaccine Therapies of Cancer

Abstract

Tumor vaccines can induce robust immune responses targeting tumor antigens in the clinic, but antitumor effects have been disappointing. One reason for this is ineffective tumor infiltration of the cytotoxic T lymphocytes (CTLs) produced. Oncolytic viruses are capable of selectively replicating within tumor tissue and can induce a strong immune response. We therefore sought to determine whether these therapies could be rationally combined such that modulation of the tumor microenvironment by the viral therapy could help direct beneficial CTLs induced by the vaccine. As such, we examined the effects of expressing chemokines from oncolytic vaccinia virus, including CCL5 (RANTES), whose receptors are expressed on CTLs induced by different vaccines, including type-1-polarized dendritic cells (DC1). vvCCL5, an oncolytic vaccinia virus expressing CCL5, induced chemotaxis of lymphocyte populations in vitro and in vivo, and displayed improved safety in vivo. Interestingly, enhanced therapeutic benefits with vvCCL5 in vivo correlated with increased persistence of the viral agent exclusively within the tumor. When tumor-bearing mice were both vaccinated with DC1 and treated with vvCCL5 a further significant enhancement in tumor response was achieved which correlated with increased levels of tumor infiltrating lymphocytes. This approach therefore represents a novel means of combining biological therapies for cancer treatment.

Armed Oncolytic Virus Enhances Immune Functions of Chimeric Antigen Receptor–Modified T Cells in Solid Tumors

“…There is also additional evidence that tumors infected with OVs can trigger danger signals by dendritic cells and promote cross-antigen presentation, ultimately leading to the elicitation of innate and adaptive immune responses(42). Thus, the positive effects of armed OVs observed in our own and other models(36, 43) may be further amplified in patients due to the recruitment of other components of the immune system.…”

“…While we and others have previously focused on identifying chemokines specifically produced by tumor cells and on engineering CAR-T cells with the cognate receptor(20–22), here we selected RANTES as a broadly applicable chemokine because its receptors CCR1, CCR3, and CCR5 are retained by ex vivo expanded T cells(22, 36). This assures that upon adoptive transfer T cells will migrate to multiple types of tumors if they are forced to release RANTES.…”

GLI2 Transcription Factor Mediates Cytokine Cross-talk in the Tumor Microenvironment

“…is a known cytokine serving as an autocrine or paracrine growth factor for tumor and stromal cells, and is a mediator of the complex networks existing between tumor cells and the stromal microenvironment (27)(28)(29)(30). However, the molecular mechanism underlying this cellular event remains (2)) or scramble (Scr) shRNA control in the presence or absence of the GLI2 expression construct.…”

Pexa-Vec double agent engineered vaccinia: oncolytic and active immunotherapeutic

“…Kirn et al reported protective immunity following tumor eradication with an oncolytic vaccinia virus expressing interferon-b in an immunocompetent tumor model, and that animals were refractory to subsequent tumor challenge [49]. In addition, Li et al reported that expression of the chemokine Chemokine (C-C motif) ligand 5 (regulated on activation, normal T cell expressed and secreted; RANTES) resulted in increased lymphocyte chemotaxis to tumors and increased efficacy when compared to the parental vvDD vector [50].…”