Found this on the VLA thread and just goes to show that La Jolla are an investment company that like to get in on the ground floor and are long term investors
goes well for the future of RCP don,t you think
. The convertible note is not an issue. It is from a Californian investment company, La Jolla Cove. They have only converted a relatively small number of shares.(a few million) VLA have only used a small portion of the money and have the option of repaying the loans , plus interest, instead of converting them to shares. When the VLA share price was in the 2.6c to 4.0c range there was a real problem of diluting the share price. But at a share price over 5.0c, this has off-set this problem!!! VLA will also receive $3,000,000 cash from the options on 29/01/2010!!! Cheers PS VLA is in good financial shape, and has a very exclusive superior product. A USA company, using a different and inferior virus are presently in stage 3 trials which are very promising and their product will come to market shortly!!! It has a different cancer killing spectrum, so will not compete with ours. Also our virus is the smallest of all those undergoing research and therefore has significant better mobility, pentration and effectivity!!! Also our virus has a specific unique attraction to certain specific cancer cell receptor sites on the outer cancer cell membrane. Our virus ,will "home in" on all cancer cells with this receptor, leaving normal, healthy cells alone. The virus enters the inner cell and uses it as a reproduction factory, to manufacture new viruses (clones). These new viruses burst out of the cancer cell in their millions, destroying the cancer cell and moving on to do the same thing to other cancer cells nearby and far away!!!
PLEASE READ FURTHER IF YOU ARE INTERESTED!!! THIS IS NOT A "FLY-BY-NIGHT" COMPANY OR A "FLY-BY-NIGHT" INVESTMENT!!! TRY TO BELIEVE ME!!! My name is Deeds, Mr Deeds, even Dirty Deeds!!! but in reallity, I am Dr Deeds, and I have researched all this extensively and it all checks out 100%!!!
Oncolytic Virotherapy of Cancer Erin Haley and Darren Shafren, University of Newcastle, and Viralytics Modern day studies reveal that oncolytic viruses may be an effective therapy for dealing with cancer tumors. Saturday, August 01, 2009 Email This | Printer Friendly ________________________________________ Currently, oncolytic viruses are being evaluated in the pre-clinical and clinical settings. The acceptance of oncolytic viruses in the clinic has increased, following the publication of clinical trial results, reporting safety and efficacy data. Moreover, China has recently granted approval for the clinical use of the oncolytic virus, adenovirus H101, specifically for the treatment of head and neck cancer .
Targeted Destruction Oncolytic viruses are defined as those viruses that are capable of specifically targeting, and subsequently destroying tumor cells without causing excessive damage to surrounding normal tissue. These viruses are able to replicate in the target tumor cells, thereby producing high levels of infectious progeny virus and subsequently enabling the infection of additional malignant cells (Figure 1) . To be employed successfully and safely as an anti-cancer therapeutic, it is desired that an oncolytic virus displays a number of attributes:
i) Relatively low pathogenicity ii) Able to replicate specifically in malignant cells iii) Easily genetically manipulated iv) Relatively well characterized in terms of viral genome and protein function v) Possess a rapid life cycle vi) Well characterized in terms of mechanism of oncolytic action and tumor cell specificity vii) Able to be delivered systemically viii) Display susceptibility to an antiviral drug ix) Not cause serious side effects following administration
Some oncolytic viruses are naturally occurring, whilst others are genetically engineered to reduce pathogenicity, enhance tumour cell selectivity and encode therapeutic genes. Naturally occurring oncolytic viruses include: Newcastle Disease Virus (NDV), Vesicular Stomatitis Virus (VSV), myxoma virus, reovirus, Seneca Valley virus, Coxsackie A viruses and echoviruses. Engineered oncolytic viruses encompass backbones from adenoviruses, vaccinia viruses, Herpes Simplex Virus (HSV) and poliovirus.
Oncolytic virus infections are believed to induce tumor cell death in three main ways. In the first instance (i), viruses infect and replicate in malignant cells, (ii) may induce apoptotic induction, followed by (iii) cell lysis and the expulsion of numerous progeny viral particles. This can subsequently infect additional surrounding malignant cells, thereby enabling further lytic destruction within the tumor micro-environment.
In addition, oncolytic viruses may induce immunotherapy, involving the substantially more complicated mechanism of oncolytic viral killing of malignant cells via the stimulation of the host immune system. In general, the immune system plays the natural role of immune surveillance via the detection of Tumor Associated Antigens (TAAs) and the elimination of neoplastic cells prior to tumor development.
Oncolytic viruses can contribute to this process through the direct lysis of malignant cells and the subsequent presentation of TAAs to the immune system. The viruses themselves are capable of evoking strong immune responses. Such a theory is behind the utilization of oncolysates for therapy. Oncolysates, comprising of tumor cells that have been infected ex vivo, when administered, elicit strong antiviral and anti-tumoral immune responses and have shown promise in both animal models and human clinical trials.
Furthermore, some oncolytic viruses are modified to encode immune-stimulatory cytokines, including interleukin (IL)-12 and granulocyte macrophage-colony stimulating factor (GM-CSF) encoding HSVs (BioVex), adenoviruses (Cell Genesys) and vaccinia viruses (Jennerex Biotherapeutics).
Mechanisms of Oncolytic Virus Tumor Cell Selectivity
(i) Elevated Surface Expression of Viral Receptors Cancer cells undergo clonal evolution and acquire mutations during this process that are beneficial for the growth and invasive capabilities of the tumor. Many of these cancer-specific, beneficial mutations result in the over-expression of molecules on the cell surface, which are expressed at low levels, or absent, on corresponding normal cells. The elevated surface expression of the integrin a2b1 on ovarian and prostate cancer cells is exploited by the naturally occurring human enterovirus, echovirus type 1 (EV1), for cell attachment, internalization and lytic infection.
Another naturally occurring enterovirus, Coxsackievirus A21 (CVA21) utilizes Inter-Cellular Adhesion Molecule 1 (ICAM-1) and/or Decay- Accelerating Factor (DAF), which are over-expressed on the surface of a variety of malignant cells, for cell entry.
The prototype strain of the "common cold" causing, naturally occurring, genetically unmodified, human C-cluster enterovirus, CVA21 (Kuykendall) displays oncolytic activity in multiple malignancies. In particular, CVA21 displays in vitro and in vivo lytic activity in cell cultures derived from melanoma (Figure 2), multiple myeloma, breast cancer and prostate cancer cell lines. The systemic administration of this strain induces efficient tumor regression in immune-compromised melanoma, breast cancer and prostate cancer xenograft models.
Moreover, the intra-tumoral administration of CVA21 in a melanoma xenograft model induced regression of a second noninjected tumor. Its systemic administration in a metastatic breast cancer model, resulted in the elimination of primary tumors and metastases. This indicates that CVA21 is capable of disseminating and targeting secondary tumors (Figure 3).
In addition, preliminary studies suggest that the efficacy of oncolytic CVA21 therapy is enhanced when it is combined with chemotherapeutic agents and radiation therapy. Oncolytic CVA21 therapy is licensed as CAVATAK, and is currently under Phase I clinical evaluation in patients with late stage melanoma, prostate cancer, breast cancer and head/neck cancer .
In a similar fashion to CVA21 and EV1, engineered attenuated and vaccine strains of PV target the Poliovirus Receptor (PVR)/ CD155 on the surface of cancer cells. In addition, the selectivity of Seneca Valley Virus (SVV: Neotropix) is also believed to be via receptor over-expression. Although the specific receptor is yet to be reported, it is postulated to involve interaction with integrin a4b1. Furthermore, the targeting of the high affinity Laminin Receptor (LAMR), which is elevated on tumor cells, is utilized by Sindbis virus vectors for cell entry. Meanwhile, the Edmonston strain of measles virus targets the upregulated molecule, CD46, which is expressed at high density on the surface of malignant cells. Measles virus has also been engineered for enhanced selectivity via the targeting of CD38 and Epidermal Growth Factor Receptor (EGFR).
(ii) Defective Antiviral Pathway The major cellular response to viral infection is mediated via the induction of type I interferons (IFN-a/b). The presence of viral Deoxyribonucleic acid (DNA), single-stranded RNA (ssRNA) or replication intermediates such as double-stranded RNA (dsRNA), are recognized by extra-cytoplasmic Toll-Like Receptors (TLRs) or other cytoplasmic sensors such as the helicases encoded by Retinoic-acid Inducible Gene-I (RIG-I) and Melanoma-Differentiation-Associated gene 5 (MDA-5). These proteins initiate various signaling cascades, stimulate transcription factors and lead to the initial production of IFN-a/b. The IFNs act in a positive feedback loop on the secreting cells, inducing an "antiviral" state in the surrounding cells. Numerous Interferon-Stimulated Genes (ISGs) are transcribed, including the Protein Kinase PKR, Myxomavirus Resistance 1 (MX1), ISG-20, RNAseL and 2'5' Oligoadenylate Synthetase (OAS) genes, which act via various mechanisms to inhibit viral replication and to protect the host.
The IFN pathway also plays a role in cancer, primarily through the actions of IFNs and IFN stimulated proteins including PKR, Interferon Regulatory Factors (IRFs) and activated Ribonuclease (RNAse) L, having tumor suppressor functions. Some of these factors also contribute to the induction of apoptosis. Additionally, activated Ras signaling inhibits PKR. Predictably, the genes that are directly involved in the IFN pathway are mutated in many neoplastic cells, presumably conferring a selective advantage for tumor development.
Such characteristics of malignant cells are exploited by multiple oncolytic viruses, as cancer cells are permissive to viral infection whilst the surrounding normal cells, boasting intact IFN responses, are protected from infection. This is the major mechanism of selectivity for NDV (Wellstat Biologics), VSV, Myxoma virus, Reovirus (Oncolytics Biotech) and an engineered Influenza A strain.
(iii) Cellular Proliferation State Malignant cells actively divide due to their being self sufficient in growth signals and insensitivity to regulatory anti-proliferation signals - a characteristic that is exploited by a number of oncolytic viruses. A replication-competent retrovirus vector that is based on the Moloney Murine Leukaemia Virus MLV (ACE-CD) can replicate only in actively dividing cells due to the absence of nuclear localization signals in its capsid, and displays a selective effect in studies of glioblastoma and liver metastases.
Rodent parvovirus H1 is able to infect both resting and proliferating cells. However, it requires the entry of the cell into the S-phase and the activation of the P4 promoter for the occurrence of a productive viral cycle, and has therefore been evaluated for its oncolytic potential. An engineered HSV-1, HSV1716, attenuated via the deletion of the neurovirulence gene, g34.5, replicates conditionally in proliferating cells and has demonstrated oncolytic efficacy in murine melanoma brain metastases.
(iv) Cell-Specific Transcriptional Control Neoplastic cells often display differences in the types of active promoters present, compared to non-malignant cells. Oncolytic viruses can be engineered to ensure that viral gene transcription is controlled by cancer cell-specific promoters. Adenoviruses are widely engineered in this way. The adenovirus E1 gene has been placed under the control of multiple cell-specific promoters.
This includes the prostate specific antigen promoter, rendering the virus specific for prostate cancer cells, and the carcinoembryonic antigen promoter, rendering the virus specific for Carcinoembryonic Antigen (CEA) producing cells such as colorectal cancer cells. Oncolytic HSVs are also engineered to be controlled by the CEA promoter and the cell cycle regulated B-myb promoter. The naturally occurring rodent parvovirus H1 is also under the control of the cellular P4 promoter.
Another engineered adenovirus, AdTop-PUMA, is under the control of a b-catenin/ Tcf-responsive promoter, thereby allowing replication to occur only in cells in which the b-catenin/Tcf pathway is activated, such as colorectal cancer, gastric cancer and hepatocellular carcinoma cells. This is also an example of an oncolytic virus that exploits the proliferation state of a cell, as an activated b-catenin/Tcf pathway results in increased cellular proliferation. An additional mechanism of oncolytic virus tumor cell tropism is attributed to the cell type-specific control of viral protein synthesis. The Internal Ribosome Entry Site (IRES) of a picornavirus is used to initiate viral protein translation. An engineered oncolytic PV containing the rhinovirus 2 (RV2) IRES, PV-RIPO, demonstrates inhibited neuropathogenicity due to the inhibition of translation in cells of neuronal origin. This tissue type specific control of IRES function is regulated by viral 3'-terminal sequence elements, with the virus specifically infecting glioma cells.
(v) MicroRNA Regulated Tropism A relatively new mechanism by which oncolytic virus tumor cell selectivity may be regulated, is through viral encoded targets for microRNAs (miRNAs). miRNAs are short (˜ 22 nt) regulatory RNAs that act post-transcriptionally to influence numerous cellular processes. Through complementary base pairing with short sequences, usually located within the 3' Untranslated Region (UTR) in cellular messenger Ribonucleic Acid (mRNA), miRNAs act to suppress mRNA translation, and depending on the degree of complementarity, degrade mRNA. Furthermore, some host-encoded miRNAs target viral RNA , contributing to the host immune response to infection.
As the expression of many miRNAs is highly tissue specific, viruses may be engineered to encode particular miRNA target sequences, thereby regulating tissue tropism and decreasing pathogenicity. An oncolytic adenovirus that is engineered to encode the target sequence for the liver-specific miRNA 122T, markedly reduces viral replication in normal hepatocytes in vitro, thereby potentially reducing the liver toxicity associated with oncolytic adenovirus administration.
Furthermore, the virus (VSV let-7wt) was engineered to encode the target sequence for the let-7 tumor suppressor miRNA, which is often expressed at low levels in tumor cells, thereby eliminating replication in normal cells whilst retaining oncolytic activity in tumor cells in vivo.
Current Clinical Evaluation of Oncolytic Viruses The genetic modifications and pre-clinical studies of oncolytic viruses outlined above have enabled the initiation of the clinical evaluation of an array of oncolytic viruses throughout the world. There are currently more than 10 different oncolytic viruses in various Phase I and II clinical evaluation studies. Comprising this panel of oncolytic viruses are both naturally occurring and genetically altered viruses, with routes of viral delivery including single/multiintravenous and intra-lesional injections.
In some clinical evaluation programs, oncolytic viruses are administered in combination with standard chemotherapeutic regimes and immune-suppressive agents. The tolerance profiles of cancer patients to oncolytic virotherapy are quite impressive when compared to those of cyto-toxic chemotherapeutics and some targeted monoclonal antibody therapies - with toxicity being limited to reports of "flu-like" symptoms following viral administration. The lack of statistical significant data from randomized clinical trials of oncolytic viruses against standard care agents, has historically cast a shadow as to the clinical future of this biologically targeted therapy.
In this environment however, two oncolytic virus companies, BioVex and Oncolytics Biotech have recently announced that they are undertaking pivotal randomized Phase III clinical trials with their lead candidates in late stage melanoma (OncoVexGM-CSF) and refractory head and neck cancers (Reolysin), respectively. Favorable outcomes from these trials should establish oncolytic virotherapy as an accepted targeted anti-cancer therapy, open the regulatory door for further pivotal oncolytic virus trials and finally, attract interest from pharmaceutical companies.
Looking Back ... Virotherapy is the therapeutic use of viruses, both naturally occurring and genetically altered for the selective destruction of cancerous cells.
For many years it has been hypothesized that the declining environmental exposure to bacterial and viral pathogens in the community, due to the increasing availability of immunizations and improved health care, may be contributing to a rising incidence of cancer. Circumstantial evidence contributing to this hypothesis is the numerous cases of spontaneous tumor regression that have been documented throughout history. Many of these cases occurred subsequent to viral or bacterial infections or following an episode of fever, a symptom often indicative of infection.
In 1904, a case was reported of a woman with leukemia that was dramatically reduced following an episode of presumed, but never proven, influenza. In 1912, the regression of uterine cervical carcinoma following the inoculation of an attenuated rabies vaccine was reported. Measles virus infections have appeared in a number of reports, causing the regression of lymphoblastic leukemia and Burkitt's lymphoma. More recently, cases of spontaneous remission of chronic lymphatic leukemia were documented, following virus infection in some instances. The remission of chronic lymphocytic leukaemia following small pox vaccinationhas also been described.
In addition, acquired infections may have a protective effect against the occurrence of cancer later in life. A number of studies have been carried out, in which viral infection and/or the presence of fever early in life, have been correlated with the occurrence of cancer. Early studies on the protective effects of colds and the occurrence of cancer later in life offered conflicting results. A number of larger studies however, have since shown that a protective effect of common cold/ influenza infections is conferred against the development of cancer.
A study in 1991 showed that a history of common colds or gastro-enteric influenza was associated with a decreased risk of cancer, and a specific association was found between febrile abdominal influenzas and a decreased risk of carcinomas of the colon and rectum. In this study, it was also noted that chicken pox infections during childhood were significantly related to a decreased risk of breast cancer later in life.
Meanwhile, Herpes Simplex Virus (HSV) infections and cases of influenza/ common cold during life substantially reduced the risk of melanoma. Although not documented, this phenomenon is possibly attributed to the stimulation of antitumor immune responses following the immune surveillance and early detection and destruction of neoplastic cells.
Early Clinical Evaluations of Oncolytic Viruses The oncolytic activity of a number of viruses was investigated in humans during the first half of the 20th century. In 1940, an attenuated rabies vaccine was used in humans as a treatment for melanoma. By the middle of the century, large numbers of patients were being treated for a variety of cancers with various, and in some cases multiple viruses including; myxovirus, paramyxovirus and arbovirus. During this time, oncolytic virus research grew in popularity. However, towards the end of the century, oncolytic virotherapy trials in humans waned, most likely due to ethical and safety issues.
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