Intraperitoneal administration of a modified vaccinia virus Ankara confers single-chain interleukin-12 expression to the omentum and achieves immune-mediated efficacy against peritoneal carcinomatosis.

Background: Peritoneal carcinomatosis is an advanced stage of cancer in which the disease has spread to the peritoneal cavity. In order to restore antitumor immunity subverted by tumor cells in this location, we evaluated intraperitoneal administrations of modified vaccinia virus Ankara (MVA) engineered to express single-chain interleukin 12 (scIL-12) to increase antitumor immune responses.

Methods: MVA encoding scIL-12 (MVA.

Armored modified vaccinia Ankara in cancer immunotherapy.

Cancer immunotherapy relies on unleashing the patient´s immune system against tumor cells. Cancer vaccines aim to stimulate both the innate and adaptive arms of immunity to achieve durable clinical responses. Some roadblocks for a successful cancer vaccine in the clinic include the tumor antigen of choice, the adjuvants employed to strengthen antitumor-specific immune responses, and the risks associated with enhancing immune-related adverse effects in patients.

Preclinical development of a first-in-class vaccine encoding HER2, Brachyury and CD40L for antibody enhanced tumor eradication.

The induction of antiviral innate immunity by systemic immunization with live virus can be employed to positively impact the response to therapeutic vaccination. We previously demonstrated that systemic immunization with a non-replicating MVA encoding CD40 ligand (CD40L) enhances innate immune cell activation and function, and triggers potent antitumor CD8 T cell responses in different murine tumor models. Antitumor efficacy was increased when combined with tumor targeting antibodies.

Synergistic antitumor response with recombinant modified virus Ankara armed with CD40L and CD137L against peritoneal carcinomatosis.

Recombinant-modified vaccinia virus Ankara (rMVA) is known to elicit potent antitumor immune responses in preclinical models due to its inherent ability to activate the innate immune system and the activation of adaptive responses mediated by the expression of tumor antigens and costimulus-providing molecules, such as CD40L and CD137L. Here, we evaluated different rMVA vectors in preclinical peritoneal carcinomatosis models (ID8.OVA-/GFP and MC38).

CD137 (4-1BB) costimulation of CD8 T cells is more potent when provided in cis than in trans with respect to CD3-TCR stimulation.

CD137 (4-1BB; TNFSR9) is an activation-induced surface receptor that through costimulation effects provide antigen-primed T cells with augmented survival, proliferation and effector functions as well as metabolic advantages. These immunobiological mechanisms are being utilised for cancer immunotherapy with agonist CD137-binding and crosslinking-inducing agents that elicit CD137 intracellular signaling. In this study, side-by-side comparisons show that provision of CD137 costimulation in-cis with regard to the TCR-CD3-ligating cell is superior to that provided in-trans in terms of T cell activation, proliferation, survival, cytokine secretion and mitochondrial fitness in mouse and human.

Statins act as transient type I interferon inhibitors to enable the antitumor activity of modified vaccinia Ankara viral vectors.

Background: Modified vaccinia virus Ankara (MVA) are genetically engineered non-replicating viral vectors. Intratumoral administration of MVA induces a cyclic GMP-AMP synthase-mediated type I interferon (IFN) response and the production of high levels of the transgenes engineered into the viral genome such as tumor antigens to construct cancer vaccines. Although type I IFNs are essential for establishing CD8-mediated antitumor responses, this cytokine family may also give rise to immunosuppressive mechanisms.

Mouse Models of Peritoneal Carcinomatosis to Develop Clinical Applications.

Peritoneal carcinomatosis of primary tumors originating in gastrointestinal (e.g., colorectal cancer, gastric cancer) or gynecologic (e.

Intratumoral virotherapy with 4-1BBL armed modified vaccinia Ankara eradicates solid tumors and promotes protective immune memory.

Human cancers are extraordinarily heterogeneous in terms of tumor antigen expression, immune infiltration and composition. A common feature, however, is the host's inability to mount potent immune responses that prevent tumor growth effectively. Often, naturally primed CD8 T cells against solid tumors lack adequate stimulation and efficient tumor tissue penetration due to an immune hostile tumor microenvironment.

Synergistic cancer immunotherapy combines MVA-CD40L induced innate and adaptive immunity with tumor targeting antibodies.

Virus-based vaccines and appropriate costimulation potently enhance antigen-specific T cell immunity against cancer. Here we report the use of recombinant modified vaccinia virus Ankara (rMVA) encoding costimulatory CD40L against solid tumors. Therapeutic treatment with rMVA-CD40L-expressing tumor-associated antigens results in the control of established tumors.

Distinct Functions of Senescence-Associated Immune Responses in Liver Tumor Surveillance and Tumor Progression.

Oncogene-induced senescence causes hepatocytes to secrete cytokines, which induce their immune-mediated clearance to prevent tumor initiation, a process termed "senescence surveillance." However, senescent hepatocytes give rise to hepatocellular carcinomas (HCCs), if the senescence program is bypassed or if senescent cells are not cleared. Here, we show context-specific roles for CCR2 myeloid cells in liver cancer.

EGFR-targeted therapy results in dramatic early lung tumor regression accompanied by imaging response and immune infiltration in EGFR mutant transgenic mouse models.

Lung adenocarcinoma patients harboring kinase domain mutations in Epidermal growth factor receptor (EGFR) have significant clinical benefit from EGFR-targeted tyrosine kinase inhibitors (TKIs). Although a majority of patients experience clinical symptomatic benefit immediately, an objective response can only be demonstrated after 6-8 weeks of treatment. Evaluation of patient response by imaging shows that 30-40% of patients do not respond due to intrinsic resistance to these TKIs.

Tumor-Produced Interleukin-8 Attracts Human Myeloid-Derived Suppressor Cells and Elicits Extrusion of Neutrophil Extracellular Traps (NETs).

Purpose: Myeloid-derived suppressor cells (MDSC) are considered an important T-cell immunosuppressive component in cancer-bearing hosts. The factors that attract these cells to the tumor microenvironment are poorly understood. IL8 (CXCL8) is a potent chemotactic factor for neutrophils and monocytes.

NAFLD causes selective CD4(+) T lymphocyte loss and promotes hepatocarcinogenesis.

Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related death. Non-alcoholic fatty liver disease (NAFLD) affects a large proportion of the US population and is considered to be a metabolic predisposition to liver cancer. However, the role of adaptive immune responses in NAFLD-promoted HCC is largely unknown.

Hepatic myeloid-derived suppressor cells in cancer.

Myeloid-derived suppressor cells are key components of tumor-induced immune suppression. They are composed of a heterogeneous population of immature myeloid cells that abrogates innate and adaptive immune responses. Myeloid-derived suppressor cells accumulate not only in peripheral blood, secondary lymphoid organs and tumors, but also in the liver in preclinical tumor models and in hepatocellular carcinoma patients.

Overexpression of apolipoprotein A-I fused to an anti-transforming growth factor beta peptide modulates the tumorigenicity and immunogenicity of mouse colon cancer cells.

Transforming growth factor beta (TGF-β) promotes tumor growth, invasion and metastasis in established tumors. In this study, we analyzed the effect of overexpressing an anti-TGF-β peptide fused to apolipoprotein A-I (ApoA-I) as a scaffold molecule. We generated and characterized stable MC38 colon carcinoma clones expressing ApoA-I fused to the anti-TGF-β peptide P144 and ApoA-I as control cells.

The yin and yang of evasion and immune activation in HCC.

Current systemic treatment options for patients with hepatocellular carcinoma (HCC) are limited to sorafenib. With the recent FDA approval of the second PD1-PD-L1 pathway inhibitor, immunotherapy has gained even more interest as a potential novel treatment option for patients with HCC. This is due not only because of the failure of other treatment approaches in the past, but also because immunological mechanisms have been shown to play an important role during tumor development, growth, and treatment.

Systemic Agonistic Anti-CD40 Treatment of Tumor-Bearing Mice Modulates Hepatic Myeloid-Suppressive Cells and Causes Immune-Mediated Liver Damage.

Immune-stimulatory mAbs are currently being evaluated as antitumor agents. Although overall toxicity from these agents appears to be moderate, liver toxicities have been reported and are not completely understood. We studied the effect of systemic CD40 antibody treatment on myeloid cells in the spleen and liver.

Tumor-induced CD11b(+) Gr-1(+) myeloid-derived suppressor cells exacerbate immune-mediated hepatitis in mice in a CD40-dependent manner.

Immunosuppressive CD11b(+) Gr-1(+) myeloid-derived suppressor cells (MDSCs) accumulate in the livers of tumor-bearing (TB) mice. We studied hepatic MDSCs in two murine models of immune-mediated hepatitis. Unexpectedly, treatment of TB mice with Concanavalin A (Con A) or α-galactosylceramide resulted in increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) serum levels in comparison to tumor-free mice.

Tumor induced hepatic myeloid derived suppressor cells can cause moderate liver damage.

Subcutaneous tumors induce the accumulation of myeloid derived suppressor cells (MDSC) not only in blood and spleens, but also in livers of these animals. Unexpectedly, we observed a moderate increase in serum transaminases in mice with EL4 subcutaneous tumors, which prompted us to study the relationship of hepatic MDSC accumulation and liver injury. MDSC were the predominant immune cell population expanding in livers of all subcutaneous tumor models investigated (RIL175, B16, EL4, CT26 and BNL), while liver injury was only observed in EL4 and B16 tumor-bearing mice.

Intravenous immunoglobulin promotes antitumor responses by modulating macrophage polarization.

Intravenous Igs (IVIg) therapy is widely used as an immunomodulatory strategy in inflammatory pathologies and is suggested to promote cancer regression. Because progression of tumors depends on their ability to redirect the polarization state of tumor-associated macrophages (from M1/immunogenic/proinflammatory to M2/anti-inflammatory), we have evaluated whether IVIg limits tumor progression and dissemination through modulation of macrophage polarization. In vitro, IVIg inhibited proinflammatory cytokine production from M1 macrophages and induced a M2-to-M1 polarization switch on human and murine M2 macrophages.

Myeloid-derived cells are key targets of tumor immunotherapy.

Tumors are composed of heterogeneous cell populations recruited by cancer cells to promote growth and metastasis. Among cells comprising the tumor stroma, myeloid-derived cells play pleiotropic roles in supporting tumorigenesis at distinct stages of tumor development. The tumor-infiltrating myeloid cell contingent is composed of mast cells, neutrophils, dendritic cells, macrophages, and myeloid-derived suppressor cells.

IFN-γ regulates survival and function of tumor-induced CD11b+ Gr-1high myeloid derived suppressor cells by modulating the anti-apoptotic molecule Bcl2a1.

Myeloid derived suppressor cells (MDSCs) play a critical role in suppression of immune responses in cancer and inflammation. Here, we describe how regulation of Bcl2a1 by cytokines controls the suppressor function of CD11b(+) Gr-1(high) granulocytic MDSCs. Coculture of CD11b(+) Gr-1(high) granulocytic MDSCs with antigen-stimulated T cells and simultaneous blockade of IFN-γ by the use of anti-IFN-γ blocking antibody, IFN-γ(-/-) effector T cells, IFN-γR(-/-) MDSCs or STAT1(-/-) MDSCs led to upregulation of Bcl2a1 in CD11b(+) Gr-1(high) cells, improved survival, and enhanced their suppressor function.

Eradication of liver-implanted tumors by Semliki Forest virus expressing IL-12 requires efficient long-term immune responses.

Semliki Forest virus vectors expressing IL-12 (SFV-IL-12) were shown to induce potent antitumor responses against s.c. MC38 colon adenocarcinomas in immunocompetent mice.

Liver gene transfer of interkeukin-15 constructs that become part of circulating high density lipoproteins for immunotherapy.

Apolipoprotein A-I (Apo A-I) is a major component of high density lipoproteins (HDL) that transport cholesterol in circulation. We have constructed an expression plasmid encoding a chimeric molecule encompassing interleukin-15 (IL-15) and Apo A-I (pApo-hIL15) that was tested by hydrodynamic injections into mice and was co-administered with a plasmid encoding the sushi domain of IL-15Rα (pSushi) in order to enhance IL-15 trans-presentation and thereby bioactivity. The pharmacokinetics of the Apo A-I chimeric protein were much longer than non-stabilized IL-15 and its bioactivity was enhanced in combination with IL-15Rα Sushi.