Promising Platform For Cancer Therapy Research Articles

Innovative utilization of cell membrane‐coated nanoparticles in precision cancer therapy

AbstractCell membrane‐coated nanoparticles (CMNPs) have recently emerged as a promising platform for cancer therapy. By encapsulating therapeutic agents within a cell membrane‐derived coating, these nanoparticles combine the advantages of synthetic nanoparticles and natural cell membranes. This review provides a comprehensive overview of the recent advancements in utilizing CMNPs as effective drug delivery vehicles for cancer therapy. The synthesis and fabrication methods of CMNPs are comprehensively discussed. Various techniques, such as extrusion, sonication, and self‐assembly, are employed to coat synthetic nanoparticles with cell membranes derived from different cell types. The cell membrane coating enables biocompatibility, reducing the risk of an immune response and enhancing the stability of the nanoparticles in the bloodstream. Moreover, functionalization strategies for CMNPs, primarily chemical modification, genetic engineering, and external stimuli, are highlighted. The presence of specific cell surface markers on the coated membrane allows targeted drug delivery to cancer cells and maximizes therapeutic efficacy. Preclinical studies utilizing CMNPs for cancer therapy demonstrated the successful delivery of various therapeutic agents, such as chemotherapeutic drugs, nucleic acids, and immunotherapeutic agents, using CMNPs. Furthermore, the article explores the future directions and challenges of this technology while offering insights into its clinical potential.

Clostridium Bacteria: Harnessing Tumour Necrosis for Targeted Gene Delivery.

Necrosis is a common feature of solid tumours that offers a unique opportunity for targeted cancer therapy as it is absent from normal healthy tissues. Tumour necrosis provides an ideal environment for germination of the anaerobic bacterium Clostridium from endospores, resulting in tumour-specific colonisation. Two main species, Clostridium novyi-NT and Clostridium sporogenes, are at the forefront of this therapy, showing promise in preclinical models. However, anti-tumour activity is modest when used as a single agent, encouraging development of Clostridium as a tumour-selective gene delivery system. Various methods, such as allele-coupled exchange and CRISPR-cas9 technology, can facilitate the genetic modification of Clostridium, allowing chromosomal integration of transgenes to ensure long-term stability of expression. Strains of Clostridium can be engineered to express prodrug-activating enzymes, resulting in the generation of active drug selectively in the tumour microenvironment (a concept termed Clostridium-directed enzyme prodrug therapy). More recently, Clostridium strains have been investigated in the context of cancer immunotherapy, either in combination with immune checkpoint inhibitors or with engineered strains expressing immunomodulatory molecules such as IL-2 and TNF-α. Localised expression of these molecules using tumour-targeting Clostridium strains has the potential to improve delivery and reduce systemic toxicity. In summary, Clostridium species represent a promising platform for cancer therapy, with potential for localised gene delivery and immunomodulation selectively within the tumour microenvironment. The ongoing clinical progress being made with C. novyi-NT, in addition to developments in genetic modification techniques and non-invasive imaging capabilities, are expected to further progress Clostridium as an option for cancer treatment.

Channeling the Natural Properties of Sindbis Alphavirus for Targeted Tumor Therapy.

Sindbis alphavirus vectors offer a promising platform for cancer therapy, serving as valuable models for alphavirus-based treatment. This review emphasizes key studies that support the targeted delivery of Sindbis vectors to tumor cells, highlighting their effectiveness in expressing tumor-associated antigens and immunomodulating proteins. Among the various alphavirus vectors developed for cancer therapy, Sindbis-vector-based imaging studies have been particularly extensive. Imaging modalities that enable the in vivo localization of Sindbis vectors within lymph nodes and tumors are discussed. The correlation between laminin receptor expression, tumorigenesis, and Sindbis virus infection is examined. Additionally, we present alternative entry receptors for Sindbis and related alphaviruses, such as Semliki Forest virus and Venezuelan equine encephalitis virus. The review also discusses cancer treatments that are based on the alphavirus vector expression of anti-tumor agents, including tumor-associated antigens, cytokines, checkpoint inhibitors, and costimulatory immune molecules.

Phytosomes: A Promising Nanocarrier for Enhanced Delivery of Herbal Compounds in Cancer Therapy

Cancer is a life-threatening disease that remains a global health problem, with millions of people diagnosed yearly. Despite significant progress in cancer treatment, conventional chemotherapy still faces several limitations, including poor solubility, low bioavailability, lack of selectivity, and severe side effects. Therefore, alternative therapeutic strategies are necessary to improve cancer therapy. This review aimed to provide an updated overview of phytosome complexes and their potential application in cancer therapy, including their formulation techniques, transportation mechanism through phytosome, and recent investigations on their efficacy in treating different types of cancers. In recent years, nanotechnology has emerged as a promising approach to cancer therapy, as it enables the delivery of therapeutic agents to the tumor site with higher selectivity and efficiency. Phytosomes are a nanotechnology-based drug delivery system conjugating plant extracts or phytoconstituents with phospholipids. This conjugation results in the formation of a complex with improved solubility, stability, and bioavailability. Phytosomes have been shown to enhance the pharmacokinetic profile of phytoactive compounds, allowing for better targeting and sustained release. Phytosomes of curcumin, resveratrol, and quercetin have demonstrated anticancer properties in various in vitro and in vivo models. Moreover, phytosomes have been used to deliver chemotherapeutic agents, such as paclitaxel, docetaxel, and camptothecin, with improved efficacy and reduced toxicity. Phytosome complexes offer a promising platform for cancer therapy due to their ability to enhance the bioavailability and efficacy of phytoactive compounds. Incorporating phytosomes in cancer therapy could lead to the development of more effective and less toxic treatments for different types of cancers. Further studies are needed to elucidate the mechanism of action of phytosomes and to optimize their formulation for clinical use.

Identifying Potential Tumor Antigens and Antigens-Related Subtypes in Hepatocellular Carcinoma for mRNA Vaccine Development.

Background The mRNA vaccine has become a promising platform for cancer therapy. Lots of studies have been focusing on discovering novel potent cancer-associated antigens to develop mRNA vaccines against cancers. Besides, immunotyping shows the immune status, and immune microenvironment of immunotyping is related with therapeutic reaction. However, potential antigens for mRNA vaccines and immunotyping of liver hepatocellular carcinoma (LIHC) remain far from being understood. Methods In this study, we collected gene expression data and clinical information data from ICGC and TCGA databases. Using GEPIA2, we calculated differential expression genes and prognostic indices. We applied TIMER to calculate the correlation coefficient between immune infiltrating cells and each gene. Consensus cluster was used for immunotyping of LIHC. Results We uncovered four most potential candidates including PES1, MCM3, PPM1G, and KPNA2, which were all related with antigen-presenting cell (APC) infiltration and poor survival in LIHC in two independent datasets. Furthermore, three immune-related subtypes (IS1-IS3) of LIHC were identified. All these results were validated in two independent datasets. Furthermore, we validated our results in vitro. Conclusions The above candidates will be expected to be potential antigen genes for developing anti-LIHC mRNA vaccine, and furthermore, patients with IS2 and IS3 tumors are supposed to be appropriate for mRNA vaccine in LIHC.

Graphene quantum dots-decorated hollow copper sulfide nanoparticles for controlled intracellular drug release and enhanced photothermal-chemotherapy

Graphene quantum dots (GQDs)-decorated hollow copper sulfide nanoparticles (CuS NPs) were developed as a multifunctional platform for controlled intracellular drug release and enhanced photothermal-chemotherapy. The CuS NPs were firstly synthesized to encapsulate anticancer drug doxorubicin (DOX) followed by the GQDs decoration on the surface of CuS NPs. The prepared NPs exhibited good crystal structure, uniform nanosize, excellent colloidal stability, high drug encapsulation and enhanced optical absorbance. Moreover, the drug release was successfully triggered from the DOX-CuS@GQDs NPs under high temperature and (near-infrared) NIR laser irradiation. Encouraged by this result, we moved to investigate the intracellular drug release behavior under NIR laser irradiation on MDA-MB-231 cells. The confocal images and flow cytometry analysis indicated a significant NIR-triggered DOX release within MDA-MB-231 cells after cellular uptake. Furthermore, the CuS NPs could readily convert light energy to heat to photothermally ablate the cancer cells under NIR laser irradiation, and the photothermal ablation effect was further enhanced by the capping of GQDs on CuS NPs. The combined photothermal therapy and chemotherapy of the prepared DOX-CuS@GQDs NPs also enabled a synergistic therapeutic effect on cancer cells. Therefore, the prepared DOX-CuS@GQDs NPs provided a novel promising platform for cancer therapy with controlled intracellular drug release and combined photothermal-chemotherapy.

Intracellular Enzyme-Triggered Assembly of Amino Acid-Modified Gold Nanoparticles for Accurate Cancer Therapy with Multimode.

Multiple amino acid (glutamine and lysine)-modified gold nanoparticles a with pH-switchable zwitterionic surface were fabricated through coordination bonds using ferrous iron (Fe2+) as bridge ions, which are able to spontaneously and selectively assemble in tumor cells for accurate tumor therapy combining enzyme-triggered photothermal therapy and H2O2-dependent catalytic medicine. These gold nanoparticles showed electric neutrality at pH 7.4 (hematological system) to prevent endocytosis of normal cells, which could be positively charged at pH 6.8 (tumor microenvironment) to promote the endocytosis of tumor cells to these nanoparticles, performing great tumor selectivity. After cell uptake, the specific enzyme (transglutaminase) in tumor cells would catalyze the polymerization of glutamine and lysine to cause the intracellular assembly of these gold nanoparticles, resulting in an excellent photothermal property for accurate tumor therapy. Moreover, the Fe2+ ion could decompose excess hydrogen peroxide (H2O2) in tumor cells via the Fenton reaction, resulting in a large amount of hydroxyl radicals (·OH). These radicals would also cause tumor cell damage. This synergetic therapy associating with high tumor selectivity generated an 8-fold in vitro cytotoxicity against tumor cells compared with normal cells under 48 h incubation with 10 min NIR irradiation. Moreover, in vivo data from tumor-bearing nude mice models showed that tumors can be completely inhibited and gradually eliminated after multimode treatment combining catalytic medicine and photothermal therapy for 3 weeks. This system takes advantage of three tumor microenvironment conditions (low pH, enzyme, and H2O2) to trigger the therapeutic actions, which is a promising platform for cancer therapy that achieved prolonged circulation time in the blood system, selective cellular uptake, and accurate tumor therapy in multiple models.

Abstract B14: TCR transgenic T cells improve the anticancer potential of oncolytic vesicular stomatitis virus as cell carriers and as synergistic therapeutics

Abstract With the clinical approval of Talimogen laherparepvec (T-VEC), an oncolytic Herpes-simplex-Virus 1, in 2015, oncolytic viruses have gained much attention as a versatile and promising platform for cancer therapy. Vesicular stomatitis virus (VSV) represents an attractive oncolytic agent due to its inherent ability to preferentially infect and kill tumor cells, boost an antitumor immune response, and its flexibility to efficiently express transgenes. In order to overcome potential hurdles for the systemic administration of VSV, which include neutralization and nonspecific uptake, we aim to develop a combination therapy which employs T-cell receptor (TCR) transgenic T cells directed against an epitope of Myeloperoxidase (Klar et al. 2014, Leukemia). As genetically engineered T cells are currently undergoing clinical trials, they have the potential to provide an ideal vehicle for a combination therapy with VSV. In our work, we have shown that human CD8+ central memory T cells (CD8+ Tcm) not only transport and deliver infectious virus to their tumor target while eliciting their own potent cytotoxic effector functions, but they also support viral amplification in the absence of significantly decreased cell viability in culture after 24h of viral infection. Moreover, we demonstrate in coculture assays with ML2 leukemia cells, that TCR transgenic CD8+ Tcm profit from the additional virus-mediated tumor cell killing as compared to a monotherapy with TCR transgenic CD8+ Tcm alone. Although viral titers in coculture assays with TCR transgenic cells were slightly decreased compared to those achieved in cocultures with T cells not expressing the TCR, we consider this to be an additional benefit of the combination therapeutic approach to reduce VSV-mediated off-target side effects, as VSV is known for its neurotoxic and hepatotoxic effects in a dose dependent manner. This is supported by our findings that highly immune-deficient NSG mice tolerate similar amounts of virus better if applied together with CD8+ Tcm. Furthermore, we demonstrate that the combination therapy for tumor-bearing NSG mice leads to enhanced transduction efficiency of VSV compared to that achieved by delivery of naked virus, as well as faster tumor cell killing compared to monotherapies with TCR transgenic CD8+ T cm or VSV alone when applied at the maximum tolerated dose. We therefore conclude that the combination of these monotherapies is a crucial step toward a broader and safer option for cancer treatment, as each offers a complimentary approach to tumor cell killing while simultaneously reducing the weaknesses of the other treatment option. We speculate that immune evasion can be efficiently overcome by application of the combination therapy while providing an efficient targeting and delivery vehicle of systemically applied oncolytic VSV with a concomitant reduction of toxicity. As both, rVSV and transgenic T cells are already undergoing clinical testing, our proposed combination therapy has the potential for a seamless translation to clinical application. Citation Format: Michael Karl Melzer, Lisa Zeitlinger, Sabine Mall, Katja Steiger, Angela Krackhardt, Oliver Ebert, Jennifer Altomonte. TCR transgenic T cells improve the anticancer potential of oncolytic vesicular stomatitis virus as cell carriers and as synergistic therapeutics [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr B14.

Preparation and photothermal therapy of hyaluronic acid–conjugated Au nanoparticle-coated poly (glycidyl methacrylate) nanocomposites

Nanocomposites are fabricated with poly (glycidyl methacrylate) (PGMA) microspheres, Au nanoparticles and hyaluronic acid (HA) for accurate photothermal therapy. PGMA microspheres are synthesized by emulsifier-free emulsion polymerization followed by amination. The adsorption of gold seeds is successfully achieved through chelation. PGMA@Au-4 nanocomposites (abbreviated as PGMA@Au) are obtained after gold seed growth. The temperature of the 0.3 mg mL−1 PGMA@Au dispersion increases by 10.6 °C when irradiated with a near-infrared (NIR) laser for 5 min. In order to reduce side effects in normal cells and achieve a specific targeting property for cancer cells, HA is further conjugated on the surface of PGMA@Au (denoted as PGMA@Au–HA). The PGMA@Au–HA nanocomposites perform highly selective targeting toward cancer cells and have good photothermal properties, leading to threefold therapeutic efficacy against cancer cells in comparison with normal cells. These results indicate that the PGMA@Au–HA construct could be a promising platform for cancer therapy.

Fabrication and characterization of hollow starch nanoparticles by gelation process for drug delivery application

Hollow nanoparticles (HNPs) have been widely regarded as controlled drug carriers owing to their advantages, such as high drug-loading efficiency and superior control over drug delivery and release. In this study, a facile and efficient strategy has been exploited for preparation of hollow starch nanoparticles (HSNPs) via a sacrificial hard-template process using gelled starch as the shell. These nanocapsules have been characterized through various techniques, including transmission electron microscopy, differential scanning calorimetry, X-ray diffraction, and Fourier transform infrared spectroscopy. The HSNPs have diameters ranging from 30nm to 300nm, with shell thickness of 5–10nm. X-ray diffraction analysis has revealed that HSNPs exhibit B+V type diffraction peaks with a relative crystallinity of 34.2%. Doxorubicin hydrochloride (DOX·HCl) was readily encased in the nanocarriers with a high loading efficiency (97.56%) and a high loading content (37.12%). In addition, no cytotoxicity for normal liver cells was found in HSNPs. However, DOX·HCl-loaded HSNPs exhibited clear cytotoxicity for liver hepatocellular cells. Thus, the hollow starch nanoparticles form a highly promising platform for cancer therapy.

Oncolytic efficacy of thymidine kinase-deleted vaccinia virus strain Guang9.

Oncolytic virotherapy is being developed as a promising platform for cancer therapy due to its ability to lyse cancer cells in a tumor-specific manner. Vaccinia virus has been used as a live vaccine in the smallpox eradication program and now is being potential in cancer therapy with a great safety profile. Vaccinia strain Guang9 (VG9) is an attenuated Chinese vaccinia virus and its oncolytic efficacy has been evaluated in our previous study. To improve the tumor selectivity and oncolytic efficacy, we here developed a thymidine kinase (TK)-deleted vaccinia virus based on Guang9 strain. The viral replication, marker gene expression and cytotoxicity in various cell lines were evaluated; antitumor effects in vivo were assessed in multiple tumor models. In vitro, the TK-deleted vaccinia virus replicated rapidly, but the cytotoxicity varied in different cell lines. It was notably attenuated in normal cells and resting cells in vitro, while tumor-selectively replicated in vivo. Significant antitumor effects were observed both in murine melanoma tumor model and human hepatoma tumor model. It significantly inhibited the growth of subcutaneously implanted tumors and prolonged the survival of tumor-bearing mice. Collectively, TK-deleted vaccinia strain Guang9 is a promising constructive virus vector for tumor-directed gene therapy and will be a potential therapeutic strategy in cancer treatment.

Hyaluronic acid and carbon dots-gated hollow mesoporous silica for redox and enzyme-triggered targeted drug delivery and bioimaging

In this work, a redox and enzyme dual-stimuli responsive drug delivery system (DDS) with tracking function (HMSN-SS-CDPEI@HA) based on carbon dots capped hollow mesoporous silica nanoparticles (HMSN) has been developed for targeted drug delivery. The positively charged CDPEI nanoparticles prepared by polyethylenimine (PEI) were grafted on the pore openings of HMSN through disulfide bonds and were used as “gatekeepers” to trap the drugs within the hollow cavity. The hyaluronic acid (HA), a natural polysaccharide, was further grafted on the surface of HMSN to realize targeted drug delivery, controlled drug release and improved the stability. Doxorubicin (DOX) was chosen as a model drug due to its wide clinical application. In vitro drug release profiles demonstrated that DOX-loaded HMSN-SS-CDPEI@HA exhibited redox and enzyme dual-responsive drug release property. In addition, the prepared HMSN-SS-CDPEI@HA exhibited excellent fluorescent properties and biocompatibility. Confocal laser scanning microscope (CLSM) and flow cytometry (FCM) illustrated that HMSN-SS-CDPEI@HA exhibited a higher cellular uptake via the CD44 receptor-mediated endocytosis by CD44-receptor over-expressed A549 cells than NIH-3T3 (receptor-negative) cells, leading to higher cytotoxicity against A549 cells than NIH 3T3 cells. This work suggested an exploration of dual-stimuli responsive as well as real-time imaging targeted drug delivery system based on HMSN and the prepared HMSN-SS-CDPEI@HA could be a promising platform for cancer therapy.

Functionalized milk-protein-coated magnetic nanoparticles for MRI-monitored targeted therapy of pancreatic cancer.

Engineered nanocarriers have emerged as a promising platform for cancer therapy. However, the therapeutic efficacy is limited by low drug loading efficiency, poor passive targeting to tumors, and severe systemic side effects. Herein, we report a new class of nanoconstructs based on milk protein (casein)-coated magnetic iron oxide (CNIO) nanoparticles for targeted and image-guided pancreatic cancer treatment. The tumor-targeting amino-terminal fragment (ATF) of urokinase plasminogen activator and the antitumor drug cisplatin (CDDP) were engineered on this nanoplatform. High drug loading (~25 wt%) and sustained release at physiological conditions were achieved through the exchange and encapsulation strategy. These ATF-CNIO-CDDP nanoparticles demonstrated actively targeted delivery of CDDP to orthotopic pancreatic tumors in mice. The effective accumulation and distribution of ATF-CNIO-CDDP was evidenced by magnetic resonance imaging, based on the T2-weighted contrast resulting from the specific accumulation of ATF-CNIO-CDDP in the tumor. Actively targeted delivery of ATF-CNIO-CDDP led to improved therapeutic efficacy in comparison with free CDDP and nontargeted CNIO-CDDP treatment. Meanwhile, less systemic side effects were observed in the nanocarrier-treated groups than that in the group treated with free CDDP. Hematoxylin and Eosin and Sirius Red staining of tumor sections revealed the possible disruption of stroma during the treatment with ATF-CNIO-CDDP. Overall, our results suggest that ATF-CNIO-CDDP can be an effective theranostic platform for active targeting-enhanced and image-guided cancer treatment while simultaneously reducing the systemic toxicity.

Colloidal stability, surface characterisation and intracellular accumulation of Rhodium(II) citrate coated superparamagnetic iron oxide nanoparticles in breast tumour: a promising platform for cancer therapy

The colloidal stability of a rhodium(II) citrate, Rh2(H2cit)4, coating on the surface of maghemite (γ-Fe2O3) nanoparticles was studied and compared in different dispersion media. The adsorption of Rh2(H2cit)4 at the water-maghemite interface was evaluated as a function of pH and complex concentration. A slight pH-dependent adsorption of the complex was observed with a maximum at pH 3. The colloidal stability of the functionalised nanoparticles with different amounts of Rh2(H2cit)4 as a function of pH was evaluated using dynamic light scattering measurements. The particles have a mean magnetic core size of 5.6 nm and the hydrodynamic diameters are approximately 60 nm, which remained unchanged in the pH range in which the samples were a stable sol. The tolerance to different dispersion media, which were deionised water, saline, phosphate-buffered saline (PBS), foetal bovine serum (FBS) and NaCl solutions with different concentrations, was investigated. At moderate ionic strength, the colloidal stability of the dispersions was similar in saline and in PBS compared to the stability of dispersions diluted in water. Moreover, the intracellular accumulation of nanoparticles in 4T1 breast tumour was examined by ultrastructural analysis performed by transmission electron microscopy. The rhodium(II) citrate-coated nanoparticles were found mostly in the cytoplasm and nucleus. Thus, we suggest that these SPIO nanoparticles functionalized with Rh2(H2Cit)4 can be potential tools for anticancer therapy.

Targeting gold nanocages to cancer cells for photothermal destruction and drug delivery

Importance of the field: Plasmonic nanoparticles provide a new route to treat cancer owing to their ability to convert light into heat effectively for photothermal destruction. Combined with the targeting mechanisms possible with nanoscale materials, this technique has the potential to enable highly targeted therapies to minimize undesirable side effects.Areas covered in this review: This review discusses the use of gold nanocages, a new class of plasmonic nanoparticles, for photothermal applications. Gold nanocages are hollow, porous structures with compact sizes and precisely controlled plasmonic properties and surface chemistry. Also, a recent study of gold nanocages as drug-release carriers by externally controlling the opening and closing of the pores with a smart polymer whose conformation changes at a specific temperature is discussed. Release of the contents can be initiated remotely through near-infrared irradiation. Together, these topics cover the years from 2002 to 2009.What the reader will gain: The reader will be exposed to different aspects of gold nanocages, including synthesis, surface modification, in vitro studies, intial in vivo data and perspectives on future studies.Take home message: Gold nanocages are a promising platform for cancer therapy in terms of both photothermal destruction and drug delivery.

Oncolytic HSV Armed with Platelet Factor 4, an Antiangiogenic Agent, Shows Enhanced Efficacy

Oncolytic herpes simplex viruses (HSV) have emerged as a promising platform for cancer therapy. However, efficacy as single agents has thus far been unsatisfactory. Tumor vasculature is critical in supporting tumor growth, but successful antiangiogenic approaches often require maintaining constant levels of antiangiogenic products. We hypothesized that oncolytic HSV has the potential to destroy tumor vasculature and that this effect can be enhanced by combination with antiangiogenic gene transfer. We examined the strategy of arming oncolytic HSV with an antiangiogenic transgene, platelet factor 4 (PF4). The PF4 transgene was inserted into oncolytic HSV G47Δ utilizing a bacterial artificial chromosome construction system. Whereas bG47Δ-empty showed robust cell killing and migration inhibition of proliferating endothelial cells (HUVEC and Py-4-1), the effect was further enhanced by PF4 expression. Importantly, enhanced potency did not impede viral replication. In vivo, bG47Δ-PF4 was more efficacious than its nonexpressing parent bG47Δ-empty at inhibiting tumor growth and angiogenesis in both human U87 glioma and mouse 37-3-18-4 malignant peripheral nerve sheath tumor models. Enhancing the antiangiogenic properties of oncolytic HSV through the expression of antiangiogenic factors such as PF4 is a powerful new strategy that targets both the tumor cells and tumor vasculature.

Dominant-Negative Fibroblast Growth Factor Receptor Expression Enhances Antitumoral Potency of Oncolytic Herpes Simplex Virus in Neural Tumors

Oncolytic herpes simplex viruses (HSV) appear to be a promising platform for cancer therapy. However, efficacy as single agents has thus far been unsatisfactory. Fibroblast growth factor (FGF) signaling is important for the growth and migration of endothelial and tumor cells. Here, we examine the strategy of arming oncolytic HSV with a dominant-negative FGF receptor (dnFGFR) that targets the FGF signaling pathway. A mouse Nf1:p53 malignant peripheral nerve sheath tumor (MPNST) cell line expressing dnFGFR was generated by transfection. The effects of dnFGFR expression on cell growth and migration in vitro and tumor formation in vivo were determined. The dnFGFR transgene was then inserted into oncolytic HSV G47Delta using a bacterial artificial chromosome construction system. Antitumoral and antiangiogenic activities of bG47Delta-dnFGFR were examined. MPNST 61E4 cells expressing dnFGFR grew less well than parental control cells. bG47Delta-dnFGFR showed enhanced killing of both tumor (human U87 glioma and F5 malignant meningioma cells and murine MPNST 61E4 and 37-3-18-4 cells) and proliferating endothelial cells (human umbilical vascular endothelial cell and Py-4-1) in vitro compared with the control vector bG47Delta-empty without inhibiting viral replication. In vivo, bG47Delta-dnFGFR was more efficacious than its nonexpressing parent bG47Delta-empty at inhibiting tumor growth and angiogenesis in both human U87 glioma and mouse 37-3-18-4 MPNST tumors in nude mice. By using multiple therapeutic mechanisms, including destruction of both tumor cells and tumor endothelial cells, an oncolytic HSV encoding dnFGFR enhances antitumor efficacy. This strategy can be applied to other oncolytic viruses and for clinical translation.

159. Novel Oncolytic HSV Armed with Platelet Factor 4, an Antiangiogenic Agent, Shows Enhanced Efficacy

Oncolytic herpes simplex viruses (HSV) have emerged as a promising platform for cancer therapy. However, efficacy as single agents has thus far been unsatisfactory. Tumor vasculature is critical in supporting tumor growth, but successful antiangiogenic approaches often require maintaining constant levels of antiangiogenic products. We hypothesized that oncolytic HSV has the potential to destroy tumor vasculature, and that this effect can be enhanced by combination with antiangiogenic gene transfer.

761. Dominant-Negative FGF Receptor Expression by Oncolytic HSV Vector for the Treatment of Malignant Peripheral Nerve Sheath Tumors

Top of pageAbstract Oncolytic herpes simplex viruses (HSV) have emerged as a promising platform for cancer therapy. Their large size permits insertion of therapeutic transgenes to augment the cytotoxicity of the backbone vector. Here we examine the activity of a dominant-negative FGF receptor (dnFGFR). Fibroblast growth factor (FGF) has been shown to stimulate the proliferation of Schwann cells in vitro, in addition to its mitogenic activity in endothelial cells, indicating its importance in malignant peripheral nerve sheath tumors (MPNST). We established MPNST cell lines transformed with dnFGFR or the control plasmid and showed that dnFGFR decreased cell proliferation and migration in vitro and reduced vascularity and delayed tumor growth in vivo. The dnFGFR transgene was inserted into oncolytic HSV G47|[Delta]| (deleted in |[aacute]|47/Us11 promotor, |[gamma]|34.5, and a LacZ insertion inactivating ICP6), using the G47|[Delta]|-BAC (bacterial artificial chromosome) system. G47|[Delta]|-dnFGFR showed enhanced killing of both tumor and proliferating endothelial cells in vitro compared to the G47|[Delta]|-empty control vector. In vivo, G47|[Delta]|-dnFGFR was more efficacious than it's non-expressing parent G47|[Delta]|-empty at inhibiting MPNST growth. Therefore oncolytic HSV encoding antiangiogenic dominant-negative FGFR transgene is a new strategy for tumor treatment.