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Illustration “structure”: This is a model of the RNA-binding domain of ADAR1 (green), bound to double-stranded RNA (yellow). Transportin1, which mediates the nuclear transport of ADAR1, is depicted in gray. The structural model reveals that ADAR1 cannot enter the nucleus when bound to RNA, as RNA (yellow) and Transportin1 (gray) clash. Credit: PNAS
Scientists of the Max F. Perutz Laboratories of the University of Vienna and the Medical University of Vienna, together with colleagues of the ETH Zurich, have now shown how double stranded RNA, such as viral genetic information, is prevented from entering the nucleus of a cell. During the immune response against viral infection, the protein ADAR1 moves from the cell nucleus into the surrounding cytoplasm. There it modifies viral RNA to inhibit reproduction of the virus. But how is the human genome protected from inadvertent import of viral RNA into the nucleus? The current study of the research…
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|Transmission electron micrograph of an unmodified herpes simplex virus|
Amgen Presents Interim Overall Survival Data From Phase 3 Study Of Talimogene Laherparepvec In Patients With Metastatic Melanoma
T-VEC was engineered from herpes simplex 1 (HSV-1), a relatively innocuous virus that normally causes cold sores. A number of genetic modifications were made to the virus in order to:
- Attenuate the virus (so it can no longer cause herpes)
- Increase selectivity for cancer cells (so it destroys cancer cells while leaving healthy cells unharmed)
- Secrete the cytokine GM-CSF (a protein naturally secreted in the body to initiate an immune response)
T-VEC has a dual mechanism of action, destroying cancer both by directly attacking cancer cells and also by helping the immune system to recognize and destroy cancer cells. T-VEC is injected directly into a number of a patient’s tumors. The virus invades both cancerous and healthy cells, but it is unable to replicate in healthy cells and thus they remain unharmed. Inside a cancer cell, the virus is able to replicate, secreting GM-CSF in the process. Eventually overwhelmed, the cancer cell lyses (ruptures), destroying the cell and releasing new viruses, GM-CSF, and an array of tumor-specific antigens (pieces of the cancer cell that are small enough to be recognized by the immune system).
The GM-CSF attracts dendritic cells to the site. Dendritic cells are immune cells that process and present antigens to the immune system so that the immune system can then identify and destroy whatever produced the antigen. The dendritic cells pick up the tumor antigens, process them, and then present them on their surface to cytotoxic (killer) T cells. Now the T cells are essentially “programmed” to recognize the cancer as a threat. These T cells lead an immune response that seeks and destroys cancer cells throughout the body (eg, tumors and cancer cells that were not directly injected with T-VEC).
In this way, T-VEC has both a direct effect on injected tumors and a systemic effect throughout the entire body. Because the adaptive immune system “remembers” a target once it has been identified, there is high likelihood that the effect of an oncolytic virus like T-VEC will be durable (eg, prevent relapse). And it is for this reason that T-VEC does not need to be injected into every tumor, just a few in order to start the immune process.
Clinical efficacy in unresectable melanoma has been demonstrated in Phase II and Phase III clinical trials.
The Phase II clinical trial was published in the Journal of Clinical Oncology in 2009. 50 patients with advanced melanoma (most of whom had failed previous treatment) were treated with T-VEC. The overall response rate (patients with a complete or partial response per RECIST criteria) was 26% (16% complete responses, 10% partial responses). Another 4% of patients had a surgical complete response, and another 20% had stable disease for at least 3 months. On an extension protocol, 3 more patients achieved complete responses, and overall survival was 54% at 1 year and 52% at 2 years—demonstrating that responses to T-VEC are quite durable.
Consistent with other immunotherapies, some patients exhibited initial disease progression before responding to therapy because of the time it takes to generate the full immune response. Responses were seen in both injected and uninjected tumors (including those in visceral organs), demonstrating the systemic immunotherapeutic effect of T-VEC. Treatment was extremely well tolerated, with only Grade 1 or 2 drug-related side effects, the most common being mild flu-like symptoms.
Amgen announced the initial results of the Phase III OPTiM trial on Mar. 19, 2013. This global, randomized, open-label trial compared T-VEC with subcutaneously administered GM-CSF (2:1 randomization) in 430 patients with unresectable stage IIIB, IIIC or IV melanoma. The primary endpoint was durable response rate (DRR), defined as a complete or partial tumor response lasting at least 6 months and starting within 12 months of treatment.
T-VEC was proven to offer superior benefits in metastatic melanoma. DRR was achieved in 16% of patients receiving T-VEC compared with only 2% in the GM-CSF control group (P<.0001). The greatest benefit was seen in patient with stage IIIB or IIIC melanoma, with a 33% DRR vs 0% with GM-CSF. The objective response rate (any response) with T-VEC was 26%, with an impressive 11% of patients experiencing a complete response (complete disappearance of melanoma throughout the body). This demonstrated once again that T-VEC has a systemic immune effect that destroys distant, uninjected tumors. According to Financial Times one of the investigators involved questioned the ethics of the trial design, as the control arm received subcutaneous GM-CSF instead of standard care
A trend toward improved survival with T-VEC was observed in a pre-specified interim analysis of this endpoint, with the final survival data (event-driven) expected in late 2013. At the interim analysis, T-VEC was associated with a 21% reduced risk of death. The most common side effects with T-VEC were fatigue, chills, and fever. No serious side effect occurred in more than 3% of patients in either arm of the study.
The investigators concluded that “T-VEC represents a novel potential [treatment] option for melanoma with regional or distant metastases.” The success of T-VEC in the OPTiM trial represents the first Phase III proof of efficacy for a virus-based oncolytic immunotherapy.
Peregrine Pharmaceuticals Announces Results From Phase II Clinical Trial of Bavituximab in Stage IV Pancreatic Cancer
TUSTIN, CA 02/13/13 — Peregrine Pharmaceuticals announced results from its 70 patient open-label, randomized Phase II clinical trial of bavituximab used in combination with gemcitabine in patients with previously untreated, advanced Stage IV pancreatic cancer. The trial included the enrollment of patients with advanced metastatic disease including significant liver involvement and poor performance status associated with rapid disease progression. Results showed that the combination of bavituximab and gemcitabine resulted in more than a doubling of overall response rates (ORR) and an improvement in overall survival (OS) when compared with gemcitabine alone (control arm). In the trial, patients treated with a combination of bavituximab and gemcitabine had a 28% tumor response rate as compared to 13% in the control arm. Median OS, the primary endpoint of the trial, was 5.6 months for the bavituximab plus gemcitabine arm and 5.2 months for the control arm (hazard ratio = 0.75).
Bavituximab binds to phosphatidylserine which is exposed on the surface of certain atypical animal cells, including tumour cells and cells infected with any of six different families of virus. These viral families contain the viruses hepatitis C, influenza A and B, HIV 1 and 2, measles, respiratory syncytial virus and pichinde virus, which is a model for the deadly Lassa virus. Other cells are not affected since phosphatidylserine normally is only intracellular.
These target aminophospholipids, usually residing only on the inner leaflet of the plasma membrane of cells, become exposed in virally infected, damaged or malignant cells, and more generally in most cells undergoing the process of apoptosis.
The antibody’s binding to phospholipids alerts the body’s immune system to attack the tumor endothelial cells, thrombosing the tumor’s vascular network and/or attacking free floating virally infected and metastatic cells while potentially minimizing side effects in healthy tissues.
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- New Progression-Free Survival Data From Peregrine’s Bavituximab in Phase II Refractory Breast Cancer
- Phase II Advanced Breast Cancer Data to Be Presented at ASCO Highlight Promising Tumor Response and Progression-Free Survival Data With Peregrine’s Bavituximab
- Pharma company completes humanization of 3G4 antibody
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