The development of oncolytic viruses to target solid tumors is an area of intense preclinical and clinical interest. Oncolytic viruses (OVs) are engineered using well studied viruses such as vaccinia, adenovirus and herpes simplex virus as well as lesser-known viruses such as Maraba virus (originally isolated from Brazilian sandflies) and foamy viruses. Viruses are engineered to have specific characteristics including tissue tropism (the ability to naturally infect specific organs), tumor selectivity, immunogenicity and a payload that can stimulate the immune system. GM-CSF is one of the most widely used payloads in OVs as it boosts the immune system and increases the production of T-cells.
OVs kill tumor cells through multiple mechanisms – tumor cells are directly lysed post infection releasing tumor antigens, immune mediators, cytokines etc. which induce an immune response. The payload in the viruses express therapeutic proteins that further activate the immune response and recruit cytotoxic T cells to the tumor to mediate killing. OVs have also been shown to mediate an abscopal effect where distant uninfected tumors regress in response to OV infection of one tumor site. Given the multi-pronged approach to tumor killing, OVs are actively being developed as stand-alone therapies and as combination therapies with immunomodulators and checkpoint therapies.
One challenge with OVs is the balance between the induction of an antiviral response and an antitumor response. An antiviral response typically starts with the synthesis of proinflammatory cytokines including type I interferons, followed by the priming of T-cells by viral antigen presentation leading to viral clearance. In order for OVs to be maximally efficacious, it is important to manage the antiviral response and subsequent viral clearance. Many OV therapies in development are administered directly into the tumor with the intention of triggering direct tumor lysis and stimulating immune cells in the local tumor microenvironment. Systemic administration of OVs is more challenging due to the presence of anti-viral antibodies that reduce viral titer and contribute to viral clearance. Some of the approaches include masking viruses in polymeric materials or in extracellular vesicles as well as using novel viruses that humans have not been exposed to and therefore do not have pre-existing immunity. A good example of a novel OV is the Maraba virus that is being developed by Turnstone Biologics.
To date, Imlygic® (talimogene laherparepvec) is the only OV therapy for recurrent melanomas1 but there are about 100 active or completed clinical trials using OVs either as single agents or in combination with existing chemotherapies, monoclonal antibodies or radiation2. Melanomas, gastrointestinal cancers including pancreatic tumors and brain tumors (glioblastomas, astrocytomas etc.) are the most popular indications in clinical trials but there is increasing interest in other tumor indications that have an unmet clinical need such as triple negative breast cancer. A recent report3showed that the combination of an oncolytic reovirus (pelareorep) combined with either atezolizumab, letrozole or trastuzumab in women with different types of breast cancers showed an increase in tumor infiltrating lymphocytes or TILs across all breast cancer subtypes. This is a favorable result as an increase in TILs correlates to a better response to immune checkpoint inhibitors and is clinical evidence that OVs can prime the immune system to attack tumors.
While there is limited clinical information on OV efficacy as most of the ongoing trials are in phase I or I/II, there is a growing body of preclinical knowledge on OV engineering and its application as a mono or combination therapy in solid tumors. Interested in learning more about OV engineering? Check out our recent webinars on cell and gene therapies.
Levodopa or L-dopa was approved 50 years ago as a treatment for Parkinson’s disease (PD) to replace dopamine in the brain and slow disease progression. Levodopa has been prescribed to millions of PD patients as the first line of treatment. The drug is a modified amino acid (L-dihydroxyphenylalanine) that is able to cross the blood brain barrier where it is metabolized into dopamine and taken up by dopaminergic neurons.
Age-related macular degeneration or AMD presents in two forms – the more prevalent dry AMD and the less prevalent neovascularized or wet AMD (nAMD). Neovascularized AMD develops when abnormal blood vessels grow under the macula and leak blood and fluids that damage photoreceptor cells. This form of AMD represents 10-15% of all AMD patients, but 90% of the patients develop vision loss. Currently, nAMD is treated with anti-VEGF therapies like bevacizumab (Avastin®) and ranibizumab (Lucentis®) that are injected into the eyes every few weeks. While these therapies are effective, they require frequent injections and are expensive. Due to this trend, there is a large clinical need for improved and affordable therapies for nAMD. An interesting retrospective study in 2016 reported that PD patients who were prescribed L-dopa were less likely to develop age-related macular degeneration (AMD), and those who developed AMD had a later onset compared to the mean age of onset for AMD.
What if levodopa, which is a safe and well tolerated therapy, could help delay the need or frequency of anti-VEGF injections? To answer this question, two proof of concept studies were performed in Tucson, Arizona. In the first study, 20 newly diagnosed nAMD patients were dosed with Levodopa and then tested for visual improvement and acuity over 32 days. The second study was a dose range study with 35 patients. Both studies showed that levodopa induced significant improvement in vision and retinal anatomy including central retinal thickness and retinal fluid. The dose ranging study reported limited adverse events suggesting that levodopa is well tolerated and a viable option for advanced AMD patients.
How does levodopa work in the retinal pigment epithelia? A G-protein coupled receptor (GPCR) called GPR143 is expressed in retinal pigment epithelial cells and the ligand for this GPCR is levodopa. GPR143 is involved in melanin synthesis via the biogenesis, organization and transport of melanosomes in pigment epithelial cells. One of the signaling factors that is expressed in retinal epithelial cells is PEDF (pigment epithelium-derived factor), an anti-angiogenic factor that is downregulated along with melanin in aged populations. nAMD patients tend to be older so the downregulation of PEDF and upregulation of VEGF induces the formation of abnormal blood vessels in nAMD patients. Levodopa acts by flipping the angiogenesis balance – PEDF expression is upregulated and VEGF expression is downregulated.
It’s important to note that levodopa is likely not a replacement for anti-VEGF therapies and more work needs to be done including expanded clinical trials that include a control arm, and segmentation of the results by racial diversity and other known factors that contribute to nAMD development. These studies show that levodopa has the potential to be a safe and effective adjunct therapy to help manage the use of anti-VEGF injections in the treatment of neovascularized AMD. Interested in learning more about the clinical results? Check out the paper published in July 2020 and the proof of concept clinical trial 1 and clinical trial 2.
20 | Jan | 2021
CROs are not the engines that drive innovation. Instead, they serve as an integral part of a large and complex machine that must, even under the most trying of times, function flawlessly. Last year was as trying as it gets (hopefully) and 2021 is setting up to be equally as challenging. Challenging times provide for unique opportunities for those best prepared. While I do not pretend to be any more of a clairvoyant than the next person, an obvious key to success in 2021 starts with doing everything possible to keep employees safe while maintaining operations at full capacity. These are not mutually exclusive and must happen in parallel, one without the other leads to a failed year and wasted opportunity.
As a service provider to the bio-pharmaceutical industry, it is critical that a lab be able to meet the demands of its clients both from a capabilities and scheduling perspective. The current global pandemic should remind us all that we cannot become complacent when it comes to the discovery and development of new therapies, not just for the treatment of a virus but all diseases. Those that truly embrace a sense of urgency in their missions will be the ones that thrive during 2021 and beyond. In order to reduce this to practice, it will be important that CROs have relationships with key vendors that allow for access to important resources such as animals. COVID-19 caused travel restrictions and importation bans in 2020 that will continue into 2021. These produced a choke hold on a critical component in the preclinical supply chain leading to an industry-wide shortage of supplies that will favor those that can find solutions. This will benefit certain global companies that have strategic locations and relationships in place that provide access and availability of critical supplies.
With much of the industry’s focus on a virus and the development of a vaccine, manipulation/modulation of the immune system will dominate the science we support. Not just for the treatment of a virus but as a means for treating a wide array of conditions ranging from and beyond neurology, nephrology, gastroenterology, dermatology, rheumatology, and xenotransplantation. For new viruses or early phase work, labs with virology experience and expertise will have competitive advantages. Gene therapy will also continue to be a major driver of demand for CROs. Since much of this work requires the use and availability of non-human primates, the importance of availability and access to this resource will be paramount in 2021.
04 | Jan | 2021
Vedere Bio was founded in June 2019 with $21 million series A funding and was acquired by Novartis in a lucrative deal valued at up to $280 million ($150 million upfront)1 18 months later. This is exceptional even in the fast-paced M&A world and one contributing factor may be that Vedere’s technology has the potential to be a game changer in gene therapy. Vedere’s novel optogenetics platform could be used to develop novel gene therapies for retinal disorders like age-related macular degeneration (AMD) and retinitis pigmentosa that can lead to blindness. It’s well known that cataracts and retinal eye diseases are the most common causes of permanent blindness, and while cataracts are treated surgically, retinal eye diseases typically do not have a standard treatment regimen. In developed countries, retinal diseases are the most common cause of irreversible blindness and AMD is the most common retinal eye disease in older people. AMD does have a few therapeutic options such as laser photocoagulation and anti-angiogenic therapies (for wet AMD) but there is an unmet clinical need for long-term therapies and the more prevalent dry form of AMD has very limited therapeutic options. Gene therapies are being actively investigated but one of the complications is the fact that there are several therapeutic targets for retinal disease – more than 250 different genetic mutations have been reported for retinitis pigmentosa alone. Gene therapy that targets a specific disease driver gene would be beneficial only to the patients with that mutation, thus limiting the addressable patient population.
Vedere Bio’s technology is unique in that it does not depend on the presence of specific genetic mutations and can address a broader patient population. Some retinal diseases like AMD and retinitis pigmentosa can cause widespread death of photoreceptor cells (rods and cones) resulting in vision loss. Vedere’s strategy is to target retinal cells that are not destroyed during the disease process. The technology was originally developed at UC Berkeley in the labs of Ehud Isacoff and John Flannery and focuses on the development of adeno-associated virus (AAV) vectors that express light sensing opsin proteins and can be directly injected into the vitreous space. The goal of this approach is to reverse blindness by using an AAV expressing green cone opsin targeted to retinal ganglion cells in the inner retina. Normally, these cells are not sensitive to light but the presence of the green cone opsin protein makes them light sensitive, so they are able to function as surrogates for photoreceptor cells and generate electrical signals for the brain to interpret as vision.
Another unique feature is the AAV vector that was engineered to specifically infect cells in the inner retina. The AAV serotype 2 viruses with tissue specific opsin expression infect the retinal ganglion cells in the inner retina– the tissue specific expression simplifies the delivery method as the virus can be directly injected into the vitreous space instead of the subretinal area, which is a more complicated process. The use of the green cone opsin is a technological innovation as optogenetic methods have used microbial opsins that have high response rates but need a strong light stimulus which could damage the retina. Conversely, rhodopsin and melanopsin from retinal ganglion cells are sensitive but have a slow response to light. The medium wavelength green cone opsin solves both challenges as it is sensitive to dim light and has a fast response rate. An added benefit is that the green cone opsin protein allows visual adaptation in normal light for 3D object visualization.
This opens up the possibility that people with advanced retinal disease may be able to see again and regain a better quality of life so Vedere’s innovative technology could be a true game changer in ocular gene therapy.
Interested in reading more about the development and testing of the AAV in the rd1 mouse model of blindness? Check out the original paper from March 2019.
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30 | Sep | 2020
One thing we all experience is the increasing level of complex science that is needed to get a drug to market. In the rush to get new therapies into the clinic, the experience of sharing and collaboration within the scientific community are becoming increasingly challenging and to a great extent impersonal.
It’s Personal. This simple phrase can be interpreted in many ways. What does this mean to us? It means that we know how much your drug discovery program means to you, your colleagues and your organization. We know that success means lives saved, families achieving life’s milestones. We are invested in moving your drug development program into the clinic to benefit patients and working with you is personal to all of us at Biomere. We define “personal” as building a community with scientists to access meaningful science and learn about new technologies. Biomere strives to build this community in ways that encourage discussions and collaborations to inspire exploration and discovery. In our online Concourse, we are committed to providing science-rich content on an ongoing basis. The content is designed to dive deep into basic and translational research on key disease areas and therapeutic modalities and our aim is to showcase cutting-edge science in accessible and easily consumable formats.
In the coming weeks, we invite you to engage with our blog posts, share your thoughts and participate in this free exchange of collaborative information.
Because, making what we do personal means that it is relevant to you and your voice is an important part of this experience.