Interferon-expressing oncolytic adenovirus + chemoradiation inhibited pancreatic cancer growth in a hamster model.

Past clinical trials of adjuvant therapy combined with interferon (IFN) alpha, fluorouracil, cisplatin, and radiation improved the 5-year survival rate of pancreatic ductal adenocarcinoma (PDAC). However, these trials also revealed the disadvantages of the systemic toxicity of IFN and insufficient delivery of IFN. To improve efficacy and tolerability, we have developed an oncolytic adenovirus-expressing IFN (IFN-OAd). Here, we evaluated IFN-OAd in combination with chemotherapy (gemcitabine + nab-paclitaxel) + radiation. Combination index (CI) analysis showed that IFN-OAd + chemotherapy + radiation was synergistic (CI <1). Notably, IFN-OAd + chemotherapy + radiation remarkably suppressed tumor growth and induced a higher number of tumor-infiltrating lymphocytes without severe side toxic effects in an immunocompetent and adenovirus replication-permissive hamster PDAC model. This is the first study to report that gemcitabine + nab-paclitaxel, the current first-line chemotherapy for PDAC, did not hamper virus replication in a replication-permissive immunocompetent model. IFN-OAd has the potential to overcome the barriers to clinical application of IFN-based therapy through its tumor-specific expression of IFN, induction of antitumor immunity, and sensitization with chemoradiation. Combining IFN-OAd with gemcitabine + nab-paclitaxel + radiation might be an effective and clinically beneficial treatment for PDAC patients.

Fatty acid binding protein 4 regulates pancreatic cancer cell proliferation via activation of nuclear factor E2-related factor 2.

BACKGROUND: Obesity and diabetes are associated with an increased incidence of pancreatic cancer. Fatty acid binding protein 4 (FABP4), noted to be higher in patients with severe obesity, is linked to the development and progression of several cancers, and its level in the circulation decreases after bariatric surgery. OBJECTIVE: In this paper, we evaluate the role of FABP4 in pancreatic cancer progression. SETTING: University Hospital and Laboratories, United States. METHODS AND RESULTS: When Panc-1 (human) and Pan02 (mouse) pancreatic cancer cells were treated with FABP4 or the-single-point mutant FABP4 (R126Q, fatty acid binding site mutant), only FABP4 stimulated cellular proliferation. The transcriptional activity of nuclear factor E2-related factor 2 (NRF2) was increased in response to FABP4 but not the R126Q. FABP4 treatment also led to downregulation of reactive oxygen species (ROS) activity. Consistent with induced cell propagation by FABP4, the growth of Pan02 tumor was decreased in FABP4-null animals compared with C57BL/6J controls. CONCLUSION: These results suggest that FABP4 increases pancreatic cancer proliferation via activation of NRF2 and downregulation of ROS activity.

Interferon Alpha-Expressing Oncolytic Adenovirus for Treatment of Esophageal Adenocarcinoma.

INTRODUCTION: Esophageal adenocarcinoma (EAC) has increased in incidence in Western countries, and its poor prognosis necessitates the development of novel therapeutics. We previously reported the potential of conditionally replicative adenoviruses (CRAd) as a novel therapeutic treatment for this disease. To further augment the therapeutic effectiveness of our cyclooxygenase-2 (Cox2) controlled CRAd in EAC, we inserted an interferon alpha (IFN) transgene into the viral genome that is expressed upon viral replication. In this manuscript, we analyze the cytotoxic and oncolytic effects of an IFN-expressing oncolytic adenovirus in EAC and the role of the Cox2 promoter in providing for selective replication in human tissues. METHODS: An infectivity-enhanced IFN-expressing CRAd (5/3 Cox2 CRAd ΔE3 ADP IFN) and other control viruses were first tested in vitro with cell lines. For the in vivo study, EAC xenografts in nude mice were treated with a single intratumoral dose of virus. An ex vivo analysis with live tissue slices was conducted using surgically resected EAC patient specimens. RESULTS: Expression of IFN significantly enhanced the cytotoxic and oncolytic effect of a Cox2-promoter controlled CRAd. This virus showed significant tumor growth suppression in a xenograft model. Furthermore, in human EAC samples, the promoter-controlled virus demonstrated selective replication in cancerous tissues, leaving normal esophageal tissue unaffected. CONCLUSION: An IFN-expressing CRAd driven by the Cox2 promoter has strong oncolytic effects as well as cancer-specific replication. Our novel vector possesses critical characteristics that make it a potential candidate for clinical translation to treat EAC.

Mutant myogenin promoter-controlled oncolytic adenovirus selectively kills PAX3-FOXO1-positive rhabdomyosarcoma cells.

The PAX3-FOXO1 fusion gene functions as a transactivator and increases expression of many cancer-related genes. These lead to metastases and other unfavorable outcomes for alveolar rhabdomyosarcoma (ARMS) patients. In order to target ARMS with the PAX3-FOXO1 transactivator, we developed an Oncolytic Adenovirus (OAd) regulated by the myogenin (pMYOG) promoter with a mutation in the Myocyte Enhancer Factor-2 binding site (mMEF2) in this study. The expression of MYOG in the two RMS cell lines (Rh30; PAX3-FOXO1-positive, RD; PAX3-FOXO1-negative) is about 1,000 times higher than normal skeletal muscle cell (SkMC). Ad5/3-pMYOG(S)-mMEF2 (short-length pMYOG-controlled OAd with mMEF2) showed strong replication and cytocidal effect in Rh30, but to a much lesser extent in RD. Ad5/3-pMYOG(S) (pMYOG-controlled OAd with native pMYOG) showed similar effects in RD and Rh30. Neither virus killed SkMC, indicating that Ad5/3-pMYOG(S)-mMEF2 selectively replicates and kills cells with PAX3-FOXO1. Additionally, Ad5/3-pMYOG(S)-mMEF2 showed replication and spread in vitro as well as tumor growth suppression and intratumoral viral spread in vivo, selectively in Rh30 not in RD. Our findings revealed that Ad5/3-pMYOG(S)-mMEF2 shows a promise as a safe and potent therapy to improve treatment in PAX3-FOXO1-positive ARMSs.

The Role of Adenovirus in Cancer Therapy.

This series of 13 articles (7 original articles, 6 reviews) is presented by international leaders in adenovirus-based cancer therapy [...].

Adenovirus and Immunotherapy: Advancing Cancer Treatment by Combination.

Gene therapy with viral vectors has significantly advanced in the past few decades, with adenovirus being one of the most commonly employed vectors for cancer gene therapy. Adenovirus vectors can be divided into 2 groups: (1) replication-deficient viruses; and (2) replication-competent, oncolytic (OVs) viruses. Replication-deficient adenoviruses have been explored as vaccine carriers and gene therapy vectors. Oncolytic adenoviruses are designed to selectively target, replicate, and directly destroy cancer cells. Additionally, virus-mediated cell lysis releases tumor antigens and induces local inflammation (e.g., immunogenic cell death), which contributes significantly to the reversal of local immune suppression and development of antitumor immune responses ("cold" tumor into "hot" tumor). There is a growing body of evidence suggesting that the host immune response may provide a critical boost for the efficacy of oncolytic virotherapy. Additionally, genetic engineering of oncolytic viruses allows local expression of immune therapeutics, thereby reducing related toxicities. Therefore, the combination of oncolytic virus and immunotherapy is an attractive therapeutic strategy for cancer treatment. In this review, we focus on adenovirus-based vectors and discuss recent progress in combination therapy of adenoviruses with immunotherapy in preclinical and clinical studies.

Role of Gene Therapy in Pancreatic Cancer-A Review.

Mortality from pancreatic ductal adenocarcinoma (PDAC) has remained essentially unchanged for decades and its relative contribution to overall cancer death is projected to only increase in the coming years. Current treatment for PDAC includes aggressive chemotherapy and surgical resection in a limited number of patients, with median survival of optimal treatment rather dismal. Recent advances in gene therapies offer novel opportunities for treatment, even in those with locally advanced disease. In this review, we summarize emerging techniques to the design and administration of virotherapy, synthetic vectors, and gene-editing technology. Despite these promising advances, shortcomings continue to exist and here will also be highlighted those approaches to overcoming obstacles in current laboratory and clinical research.

The Development of Oncolytic Adenovirus Therapy in the Past and Future - For the Case of Pancreatic Cancer

Pancreatic cancer is an aggressive malignant disease and the efficacy of current treatments for unresectable diseases is quite limited despite recent advances. Gene therapy /virotherapy strategies may provide new options for the treatment of various cancers including pancreatic cancer. Oncolytic adenovirus shows an antitumoral effect via its intratumoral amplification and strong cytocidal effect in a variety of cancers and it has been employed for the development of potent oncolytic virotherapy agents for pancreatic cancer. Our ultimate goal is to develop an oncolytic adenovirus enabling the treatment of patients with advanced or spread diseases by systemic injection. Systemic application of oncolytic therapy mandates more efficient and selective gene delivery and needs to embody sufficient antitumor effect even with limited initial delivery to the tumor location. In this review, the current status of oncolytic adenoviruses from the viewpoints of vector design and potential strategies to overcome current obstacles for its clinical application will be described. We will also discuss the efforts to improve the antitumor activity of oncolytic adenovirus, in in vivo animal models, and the combination therapy of oncolytic adenovirus with radiation and chemotherapy.

CD133-targeted oncolytic adenovirus demonstrates anti-tumor effect in colorectal cancer.

Oncolytic Adenoviruses (OAds) are one of the most promising anti-cancer agents that can induce cancer specific cell death. Recently, we generated infectivity-selective OAd, and the resultant OAd tumor-specific binding shows strong efficacy and mitigates toxicity. In this study, we applied this strategy based on adenovirus library screening system for generation of CD133-targeted OAd, and examined their oncolytic activity against colorectal cancer (CRC) in vitro and in vivo. CD133 (Prominin-1) is an important cell surface marker of cancer stem (like) cells (CSCs) in various cancers, including CRC. Elimination of CSCs has a high likelihood to improve CRC treatment because CSCs population in the tumor contributes to recurrence, metastases, chemotherapy resistance, and poor survival. The OAd with CD133-targeting motif (AdML-TYML) selectively infected CD133+ cultured cells and lysed them efficiently. Treatment with AdML-TYML prior to tumor inoculation inhibited the establishment of tumor of CD133+ CRC cell lines in nude mice. AdML-TYML also showed strong antitumor effect after intratumoral injections in already established CD133+ CRC subcutaneous xenografts. Our results indicate that CD133-targeted OAd selectively infected CD133+ CRC, and exhibited anti-tumorigenicity and therapeutic effect in established tumors. This novel infectivity selective virus could be a potent tool for the prevention of metastases and relapses in CRC.