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Treating tumors with a vaccinia virus expressing IFN? illustrates the complex relationships between oncolytic ability and immunogenicity.

ABSTRACT: Since previous work using a nonreplicating adenovirus-expressing mouse interferon-? (Ad.mIFN?) showed promising preclinical activity, we postulated that a vector-expressing IFN? at high levels that could also replicate would be even more beneficial. Accordingly a replication competent, recombinant vaccinia viral vector-expressing mIFN? (VV.mIFN?) was tested. VV.mIFN?-induced antitumor responses in two syngeneic mouse flank models of lung cancer. Although VV.mIFN? had equivalent in vivo efficacy in both murine tumor models, the mechanisms of tumor killing were completely different. In LKRM2 tumors, viral replication was minimal and the tumor killing mechanism was due to activation of immune responses through induction of a local inflammatory response and production of antitumor CD8 T-cells. In contrast, in TC-1 tumors, the vector replicated well, induced an innate immune response, but antitumor activity was primarily due to a direct oncolytic effect. However, the VV.mIFN? vector was able to augment the efficacy of an antitumor vaccine in the TC-1 tumor model in association with increased numbers of infiltrating CD8 T-cells. These data show the complex relationships between oncolytic viruses and the immune system which, if understood and harnessed correctly, could potentially be used to enhance the efficacy of immunotherapy.

SUBMITTER: Wang LC

PROVIDER: S-EPMC3321606 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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Treating tumors with a vaccinia virus expressing IFNβ illustrates the complex relationships between oncolytic ability and immunogenicity.

Wang Liang-Chuan S LC Lynn Rachel C RC Cheng Guanjun G Alexander Edward E Kapoor Veena V Moon Edmund K EK Sun Jing J Fridlender Zvi G ZG Isaacs Stuart N SN Thorne Stephen H SH Albelda Steven M SM

Molecular therapy : the journal of the American Society of Gene Therapy 20111018 4

Since previous work using a nonreplicating adenovirus-expressing mouse interferon-β (Ad.mIFNβ) showed promising preclinical activity, we postulated that a vector-expressing IFNβ at high levels that could also replicate would be even more beneficial. Accordingly a replication competent, recombinant vaccinia viral vector-expressing mIFNβ (VV.mIFNβ) was tested. VV.mIFNβ-induced antitumor responses in two syngeneic mouse flank models of lung cancer. Although VV.mIFNβ had equivalent in vivo efficacy ...[more]

PMID: 22008913

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Project description:This study determined the influence of intravenous (i.v.) oncolytic vaccinia virus mpJX-594 (mpJX) on antitumor activity of anti-programmed death receptor-1 antibody (aPD1) in functional and metastatic pancreatic neuroendocrine tumors (PanNETs). One i.v. dose of mpJX, engineered for mice with the same plasmid design as clinical virus Pexa-Vec, was administered alone or with repeated dosing of aPD1 (mpJX+aPD1) to two contrasting genetic models of PanNET: one developing benign insulin-secreting tumors (RIP1-Tag2;C57BL/6J mice) and the other developing liver metastases (RIP1-Tag2;AB6F1 mice). Experiments revealed that aPD1 had synergistic actions with mpJX on CD8+ T cell and natural killer (NK) cell influx, apoptosis, and suppression of proliferation in PanNETs. After mpJX+aPD1, the 53-fold increase in apoptosis (5 days) and 85% reduction in proliferation (20 days) exceeded the sum of mpJX and aPD1 given separately. mpJX+aPD1 also stabilized blood insulin and glucose in mice with functional PanNETs, regressed liver metastases in mice with aggressive PanNETs, and prolonged survival of both. The findings revealed that mpJX+aPD1 converted “cold” PanNETs into immunogenic tumors with widespread cytotoxic T cell influx, tumor cell killing, and suppression of proliferation. Reduction of tumor insulin secretion from functional PanNETs prolonged survival, and anti-metastatic actions on aggressive PanNETs reduced the metastatic burden to less than before treatment. The findings support the efficacy of the vaccinia virus with aPD1 for functional and metastatic PanNETs. Graphical abstract Vaccinia virus mpJX-594 administered intravenously to mice with pancreatic neuroendocrine tumors increases the antitumor response of an anti-PD1 antibody by turning immunologically “cold” tumors into “hot” tumors. Synergistic actions of the treatment combination amplify cytotoxic T cell influx and lead to smaller, less functional primary tumors and to the regression of metastases.

Dataset Information

Treating tumors with a vaccinia virus expressing IFN? illustrates the complex relationships between oncolytic ability and immunogenicity.

Publications

Treating tumors with a vaccinia virus expressing IFNβ illustrates the complex relationships between oncolytic ability and immunogenicity.

Similar Datasets

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