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Old 09-05-2010, 10:51 AM   #1
Rich66
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Viral therapies

Oncologist. 2002;7(2):106-19.
Viral oncolysis.

Mullen JT, Tanabe KK.
Division of Surgical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114-2696, USA.


FREE TEXT

Abstract

The concept of using replicating viruses as anticancer agents is not a new one, but the ability to genetically modify these viruses into increasingly potent and tumor-specific vectors is a recent phenomenon. As more is learned about the functions of viral gene products in controlling the mammalian cell cycle and in disabling cellular defense mechanisms, specific viral functions can be augmented or eliminated to enhance antineoplastic efficacy. In this article, general mechanisms by which oncolytic viruses achieve their antitumor efficacy and specificity are reviewed. The paradoxical roles of the immune response are addressed with respect to oncolytic viral therapy, as it, on one hand, impedes the spread of viral infection, and on the other, augments tumor cell destruction through the recruitment of T cells "vaccinated" against tumor antigens. The most commonly used oncolytic viruses are each reviewed in turn, including adenoviruses, herpes simplex viruses, vaccinia viruses, reoviruses, and Newcastle disease viruses. Special attention is focused on the unique biology of each of these viruses as well as the status of several of these mutants in clinical trials.

PMID: 11961194 [PubMed - indexed for MEDLINE]Free Article



Nelfinavir (Viracept): available Anti HIV, anti cancer

http://her2support.org/vbulletin/sho...878#post260878




Clin Cancer Res. 2011 Nov 8. [Epub ahead of print]
A Pilot Study of MUC-1/CEA/TRICOM Poxviral-Based Vaccine in Patients with Metastatic Breast and Ovarian Cancer.

Mohebtash M, Tsang KY, Madan RA, Huen NY, Poole DJ, Jochems C, Jones J, Ferrara T, Heery CR, Arlen PM, Steinberg SM, Pazdur M, Rauckhorst M, Jones EC, Dahut WL, Schlom J, Gulley JL.
Source

Authors' Affiliations: Medical Oncology Branch and Laboratory of Tumor Immunology and Biology, Center for Cancer Research; Biostatistics and Data Management Section, National Cancer Institute; and Radiology and Imaging Sciences, Clinical Center, NIH, Bethesda, Maryland.

Abstract

PURPOSE:

PANVAC is a recombinant poxviral vaccine that contains transgenes for MUC-1, CEA, and 3 T-cell costimulatory molecules. This study was conducted to obtain preliminary evidence of clinical response in metastatic breast and ovarian cancer patients.
Experimental design: Twenty-six patients were enrolled and given monthly vaccinations. Clinical and immune outcomes were evaluated.
RESULTS:

These patients were heavily pretreated, with 21 of 26 patients having 3 or more prior chemotherapy regimens. Side effects were largely limited to mild injection-site reactions. For the 12 breast cancer patients enrolled, median time to progression was 2.5 months (1-37+) and median overall survival was 13.7 months. Four patients had stable disease. One patient had a complete response by RECIST and remained on study for 37 months or more, with a significant drop in serum interleukin (IL)-6 and IL-8 by day 71. Another patient with metastatic disease confined to the mediastinum had a 17% reduction in mediastinal mass and was on study for 10 months. Patients with stable or responding disease had fewer prior therapies and lower tumor marker levels than patients with no evidence of response. For the ovarian cancer patients (n = 14), the median time to progression was 2 months (1-6) and median overall survival was 15.0 months. Updated data are presented here for one patient treated with this vaccine in a previous trial, with a time to progression of 38 months.
CONCLUSIONS:

Some patients who had limited tumor burden with minimal prior chemotherapy seemed to benefit from the vaccine. Further studies to confirm these results are warranted. Clin Cancer Res; 17(22); 1-10. ©2011 AACR.

PMID:
22068656
[PubMed - as supplied by publisher]






Mol Ther. 2009 Jun;17(6):972-9. Epub 2009 Mar 17.
Oncolytic reovirus effectively targets breast cancer stem cells.

Marcato P, Dean CA, Giacomantonio CA, Lee PW.
Department of Microbiology and Immunology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada.


FREE TEXT

Abstract

Recent evidence suggests that cancer stem cells (CSCs) play an important role in cancer, as these cells possess enhanced tumor-forming capabilities and are resistant to current anticancer therapies. Hence, novel cancer therapies will need to be tested for both tumor regression and CSC targeting. Herein we show that oncolytic reovirus that induces regression of human breast cancer primary tumor samples xenografted in immunocompromised mice also effectively targets and kills CSCs in these tumors. CSCs were identified based on CD24(-)CD44(+) cell surface expression and overexpression of aldehyde dehydrogenase. Upon reovirus treatment, the CSC population was reduced at the same rate as non-CSCs within the tumor. Immunofluorescence of breast tumor tissue samples from the reovirus- and mock-treated mice confirmed that both CSCs and non-CSCs were infectible by reovirus, and terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL) assay showed that both populations died by apoptosis. Ras, which has been shown to mediate reovirus oncolysis, was found to be present at similar levels in all cell types, and this is consistent with their comparable sensitivity to reovirus. These experiments indicate that oncolytic reovirus has the potential to induce tumor regression in breast cancer patients. More important, the CSC population was equally reduced and was as susceptible to reovirus treatment as the non-CSC population.

PMID: 19293772 [PubMed - indexed for MEDLINE]PMCID: PMC2835173Free PMC Article





Cytokine Growth Factor Rev. 2010 Apr-Jun;21(2-3):91-8. Epub 2010 Mar 12.
Clinical trials with oncolytic reovirus: moving beyond phase I into combinations with standard therapeutics.

Harrington KJ, Vile RG, Melcher A, Chester J, Pandha HS.
The Institute of Cancer Research, Chester Beatty Laboratories, Targeted Therapy Laboratory, 237 Fulham Road, London SW3 6JB, UK. kevin.harrington@icr.ac.uk


TEXT

Abstract

It is time for those working on oncolytic viruses to take stock of the status of the field. We now have at our disposal an array of potential therapeutic agents, and are beginning to conduct early-phase clinical trials in patients with relapsed/metastatic cancers. By drawing on lessons learned during the development of other biological therapies, such as monoclonal antibodies and targeted small molecule inhibitors, we are now in a position to chart the course of the next wave of trials that will go beyond the phase I studies of safety and feasibility. In this article we review our approach to the development of oncolytic viruses as cancer therapeutics. In doing so, we emphasise the fact that this process is modular and involves multiple iterative steps between the laboratory and the clinic. Ultimately, at least in the medium term, the future of oncolytic virotherapy lies in combination regimens with standard anti-cancer agents such as radiation and chemotherapy.

PMID: 20223697 [PubMed - in process]




19 May 2010
New drug reverses even 'untreatable' cancers

Cancer patients may be offered new hope in the form of a harmless virus which can reverse even apparently untreatable forms of the disease when injected into tumours.



LINK

Quote:
Reovirus, which lives in human respiratory and gastrointestinal tracts without causing any symptoms, can help magnify the effects of radiotherapy in treating even the most advanced cancers, laboratory tests have shown.

Tumours shrank or stopped growing in every patient who underwent radiotherapy coupled with a new drug, Reolysin, which contains particles of reovirus.

Oncolytics Biotech® Inc. Announces Third Quarter 2011 Results

LINK

Quote:
Selected Highlights
Since July 1, 2011, the Company has made a number of significant announcements:
Clinical Trial Results
  • The presentation of interim preliminary results from a Phase 2 clinical trial using intravenous administration of REOLYSIN® in combination with paclitaxel and carboplatin in patients with non-small cell lung cancer (NSCLC) with Kras or EGFR-activated tumours at the International Association for the Study of Lung Cancer World Conference on Lung Cancer. As of the presentation date, response evaluation in 21 patients showed six partial responses (PR) (28.6%), 13 stable disease (SD) (61.9%) and two progressive disease (PD) (9.5%), translating into a clinical benefit rate (complete response (CR) + PR + SD) of 90.5% and a response rate (CR + PR) of 28.6%;
Preclinical Program
  • The posting of a study in the online version of Molecular Therapy, a publication of The American Society of Gene and Cell Therapy, investigating the timing of chemotherapy delivery that optimizes the efficacy of systemic REOLYSIN. The paper, authored by Kottke et al., was entitled "Precise Scheduling of Chemotherapy Primes VEGF-producing Tumors for Successful Systemic Oncolytic Virotherapy." It describes when best to administer taxanes with reovirus to optimize viral delivery to the tumor mass. The researchers demonstrated that this drug combination yielded superior results to either treatment alone. They were able to reproducibly cure nearly half of the treated animals by employing this optimized schedule of paclitaxel/REOLYSIN;

Mol Med. 2010 Jun;88(6):589-96.Antitumor efficacy of viral therapy using genetically engineered Newcastle disease virus [NDV(F3aa)-GFP] for peritoneally disseminated gastric cancer.

Song KY, Wong J, Gonzalez L, Sheng G, Zamarin D, Fong Y.
Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.

TEXT

Abstract

Peritoneal dissemination is a common and fatal clinical manifestation of gastric cancer with few effective therapies available. Natural Newcastle disease virus (NDV) has been shown to be an effective oncolytic agent, and recent advances now allow genetic manipulation of this virus to improve cancer killing and safety. This study was designed to investigate the effectiveness of a genetically engineered NDV in the treatment of peritoneally disseminated gastric carcinoma. NDV mutant virus containing a modified F cleavage site and insertion of enhanced green fluorescent protein (GFP), NDV(F3aa)-GFP, was tested in vitro against human gastric cancer cells by standard cytotoxicity at different multiplicities of infection. To test NDV(F3aa)-GFP in vivo in a peritoneal carcinomatosis gastric tumor model, MKN-74 human gastric cancer cells were injected intraperitoneally (IP) in severe combined immunodeficient mice. Mice were treated with NDV(F3aa)-GFP either once or multiple times after tumor challenge. Effective killing of MKN-74 cells by NDV(F3aa)-GFP was found in vitro. This cancer killing was dose-related and correlated with viral replication. GFP expression was a good marker of infection. The virus was also effective as an antitumor therapy in a peritoneal cancer model that simulates clinical disease. Half the animals treated with virus had no evidence of disease. Genetically engineered NDV [NDV(F3aa)-GFP] administered IP is an effective antitumor therapy against peritoneal carcinomatosis from human gastric cancer in a xenograft model, without significant toxicity. These data provide further rationale for clinical trials involving NDV for peritoneal carcinomatosis from gastric cancer.

PMID: 20393691 [PubMed - indexed for MEDLINE]


Commentary on above:


http://www.cancerdecisions.com/conte.../lang,english/

Quote:
The results were dramatic. While all the control animals developed innumerable tumor nodules in the peritoneal cavity, as large as 3.5 centimeters, there was no gross tumor in 6 (or 40 percent) of the NDV-treated mice and in 50 percent of the multiple treatment group. Even in the animals that were treated but still developed tumors, the Sloan-Kettering authors report that "the nodules were significantly smaller, the largest being 1.5 centimeters" (Song 2010). The presence of NDV in tumor specimens of these treated animals was subsequently confirmed by immunofluorescence staining.
I first learned about NDV on a trip to Hungary 20 years ago. Upon my return, I contacted Dr. Laszlo Csatary, and his wife, Eva, and wrote about them in my book, Cancer Therapy. Over the years, I have observed positive clinical effects of this less-toxic viral treatment in patients, even in some with brain tumors. I recently had the pleasure of discussing this issue with pediatric oncologists at Hadassah Hospital in Jerusalem, where work on NDV progresses, albeit slowly. In the meantime, NDV treatment continues to be offered at a few clinics around the world. I welcome this new development at MSKCC, and hope it will result in clinical trials and a greater acceptance of such methods very soon.



Mol Ther. 2008 Nov;16(11):1883-90. Epub 2008 Aug 19.
Recombinant Newcastle disease virus as a vaccine vector for cancer therapy.

Vigil A, Martinez O, Chua MA, GarcÃ*a-Sastre A.
Department of Microbiology, Mount Sinai School of Medicine, New York, New York 10029, USA.


FREE TEXT

Abstract

Naturally occurring strains of Newcastle disease virus (NDV) are currently being investigated in multiple clinical trials for oncolytic cancer therapy in the United States and abroad. We have previously reported, for the first time, the development of recombinant NDVs designed for enhanced cancer therapeutic efficacy. Specifically, we have shown that NDV engineered to express interleukin-2 (IL-2) generates a robust therapeutic response associated with increased tumor-specific T-cell infiltration after intratumoral administration in mice. We have now demonstrated that this therapeutic response is dependent on T cells and we have investigated the potential to focus the NDV-induced immune response toward a tumor-associated antigen (TAA) to enhance the inherent therapeutic efficacy of NDV further. We found that intratumoral treatments of tumor-bearing mice with recombinant NDV expressing a model TAA elicited an enhanced tumor-specific response, resulting in a significant increase in the number of complete tumor regressions compared with control NDV. Additionally, coadministration of NDV expressing a model TAA with NDV expressing IL-2 enhanced the TAA-directed response and led to more complete tumor regressions. Our results show that TAA-directed immunotherapy by oncolytic recombinant NDV alone or in combination with IL-2 results in an enhanced therapeutic efficacy and warrant consideration in the development of cancer therapies based on the use of oncolytic NDV.

PMID: 18714310 [PubMed - indexed for MEDLINE]PMCID: PMC2878970Free PMC Article
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Old 09-05-2010, 10:51 AM   #2
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Old 09-05-2010, 10:52 AM   #3
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