Encapsulated Cell Technology Research Articles

A First-in-Human Phase I Clinical Study with MVX-ONCO-1, a Personalized Active Immunotherapy, in Patients with Advanced Solid Tumors.

This first-in-human phase I study introduces a groundbreaking approach to personalized cancer immunotherapy, addressing limitations of traditional strategies. By combining autologous irradiated tumor cells as a source of patient-specific antigens and utilizing encapsulated cell technology for localized, sustained delivery of granulocyte-macrophage colony-stimulating factor as an adjuvant, the study shows a very good safety and feasibility profile. This innovative approach holds the promise of addressing tumor heterogeneity by taking advantage of each patient's antigenic repertoire.

Frequency and Pattern of Worldwide Ocular Gene Therapy Clinical Trials up to 2022.

The purpose of this study is to describe worldwide gene therapy clinical trials aimed at treating ophthalmic disorders. Information regarding all worldwide clinical trials was collected through 15 different sources, including ClinicalTrials.gov. There were 159 gene therapy clinical trials on ophthalmic diseases up until 2022. Phase 1/2 trials had the highest frequency (50-32%), followed by phase 2 (33-21%); 107 trials (67%) were conducted in a single country, and 50 trials (31%) were multinational. Overall, the USA was the site of 113 (71%) single or multinational trials. Of the trials, 153 (96%) targeted retina and optic nerve disorders, 3 (2%) glaucoma, 2 (1%) uveitis, and 1 (1%) cornea; 104 trials (65%) employed gene augmentation using viral vectors, and the remaining employed other methods such as inhibitory RNA (18-11%) and cell-based gene therapy using encapsulated cell technology (18-11%). For gene augmentation trials, adeno-associated virus was used for transgene delivery in 87% of cases. The most common conditions targeted by gene augmentation included inherited retinal (74%) and age-related macular degeneration (wet, 14%; dry, 7%). Overall, a large number of gene therapy clinical trials have been conducted in the eye, and so far, one has led to regulatory approval.

762P Personalized immunotherapy with encapsulated cell technology: Feasibility, safety and efficacy results from the first-in-human clinical trial in advanced relapsing solid tumors

Preclinical data shows that sustained, local delivery of low doses of GM-CSF by irradiated, genetically engineered tumor cells at the immunization site leads to specific, long-lasting anti-tumor immunity in several tumor types. Providing sustained levels of GM-CSF SC in a clinical setting remains challenging. Encapsulated Cell Technology enables the sustained and controlled delivery of GM-CSF by allogeneic cells. MVX-ONCO is an active, personalized cancer immunotherapy combining irradiated autologous tumor cells and encapsulated, genetically engineered allogeneic cells producing GM-CSF.

Immortalized human myoblast cell lines for the delivery of therapeutic proteins using encapsulated cell technology

Despite many promising results obtained in previous preclinical studies, the clinical development of encapsulated cell technology (ECT) for the delivery of therapeutic proteins from macrocapsules is still limited, mainly due to the lack of an allogeneic cell line compatible with therapeutic application in humans. In our work, we generated an immortalized human myoblast cell line specifically tailored for macroencapsulation. In the present report, we characterized the immortalized myoblasts and described the engineering process required for the delivery of functional therapeutic proteins including a cytokine, monoclonal antibodies and a viral antigen. We observed that, when encapsulated, the novel myoblast cell line can be efficiently frozen, stored, and thawed, which limits the challenge imposed by the manufacture and supply of encapsulated cell-based therapeutic products. Our results suggest that this versatile allogeneic cell line represents the next step toward a broader development and therapeutic use of ECT.

Emerging Treatment Modalities for Neovascular Age-Related Macular Degeneration: A Systematic Overview.

Neovascular age-related macular degeneration (nAMD) represents a leading cause of irreversible visual loss affecting the quality of life of millions of elderly patients worldwide. Although the introduction of intravitreal injections with anti-vascular endothelial growth factors (anti-VEGF) agents has revolutionized the management of nAMD, their effectiveness and ultimate success are limited by several therapeutic challenges. Consequently, real-world efficacy appears significantly inferior to that reported by randomized controlled trials. Therefore, further innovative, long-term treatment options are essential to improve the prognosis and outcome of nAMD therapy. Emerging pharmacological therapies for nAMD and those currently in clinical trials are reviewed and their mechanism of action, safety, and efficacy are discussed. The evidence presented herein has been collected from online databases PubMed, Cochrane library, and the ClinicalTrials.gov site. A number of promising technologies and novel anti-VEGF therapies are currently being tested and some have already reached phaseIII trials. Anti-VEGF agents with enhanced durability and possibly efficacy, gene therapy, angiogenic targets, alternative drug delivery routes such as sustained delivery implants, drug carriers, and encapsulated cell technology are currently being explored. We briefly discuss the potential value of these options. Several options may optimize future nAMD management. On the basis of current, albeit limited evidence, the most promising technology to reach clinical practice soon appears to be the sustained drug delivery options, which may improve visual outcome and reduce the socioeconomic burden of nAMD.

Looking into the future: Gene and cell therapies for glaucoma.

Glaucoma is a complex group of optic neuropathies that affects both humans and animals. Intraocular pressure (IOP) elevation is a major risk factor that results in the loss of retinal ganglion cells (RGCs) and their axons. Currently, lowering IOP by medical and surgical methods is the only approved treatment for primary glaucoma, but there is no cure, and vision loss often progresses despite therapy. Recent technologic advances provide us with a better understanding of disease mechanisms and risk factors; this will permit earlier diagnosis of glaucoma and initiation of therapy sooner and more effectively. Gene and cell therapies are well suited to target these mechanisms specifically with the potential to achieve a lasting therapeutic effect. Much progress has been made in laboratory settings to develop these novel therapies for the eye. Gene and cell therapies have already been translated into clinical application for some inherited retinal dystrophies and age-related macular degeneration (AMD). Except for the intravitreal application of ciliary neurotrophic factor (CNTF) by encapsulated cell technology for RGC neuroprotection, there has been no other clinical translation of gene and cell therapies for glaucoma so far. Possible application of gene and cell therapies consists of long-term IOP control via increased aqueous humor drainage, including inhibition of fibrosis following filtration surgery, RGC neuroprotection and neuroregeneration, modification of ocular biomechanics for improved IOP tolerance, and inhibition of inflammation and neovascularization to prevent the development of some forms of secondary glaucoma.

Long-term, stable, targeted biodelivery and efficacy of GDNF from encapsulated cells in the rat and Goettingen miniature pig brain

Delivering glial cell line-derived neurotrophic factor (GDNF) to the brain is a potential treatment for Parkinson's Disease (PD). Here we use an implantable encapsulated cell technology that uses modified human clonal ARPE-19 ​cells to deliver of GDNF to the brain. In vivo studies demonstrated sustained delivery of GDNF to the rat striatum over 6 months. Anatomical benefits and behavioral efficacy were shown in 6-OHDA lesioned rats where nigral dopaminergic neurons were preserved in neuroprotection studies and dopaminergic fibers were restored in neurorecovery studies. When larger, clinical-sized devices were implanted for 3 months into the putamen of Göttingen minipigs, GDNF was widely distributed throughout the putamen and caudate producing a significant upregulation of tyrosine hydroxylase immunohistochemistry. These results are the first to provide clear evidence that implantation of encapsulated GDNF-secreting cells deliver efficacious and biologically relevant amounts of GDNF in a sustained and targeted manner that is scalable to treat the large putamen in patients with Parkinson's disease.

Encapsulated Cell Technology for the Delivery of Biologics to the Mouse Eye

Encapsulated Cell Technology for the Delivery of Biologics to the Mouse Eye

Encapsulated Cell Technology for the Delivery of Biologics to the Mouse Eye.

Many current therapeutics under development for diseases of the posterior pole of the eye are biologics. These drugs need to be administered frequently, typically via intravitreal injections. Encapsulated cells expressing the biologic of choice are becoming a tool for local protein production and release (e.g., via long-term drug delivery). In addition, encapsulation systems utilize permeable materials that allow diffusion of nutrients, waste, and therapeutic factors into and out of cells. This occurs while masking the cells from the host immune response, avoiding the need for suppression of the host immune system. This protocol describes the use of alginate as a polymer in microencapsulation coupled with the electrospray method as a microencapsulation technique. ARPE-19 cells, a spontaneously arising human RPE cell line, has been used in long-term cell therapy experiments due to its lifetime functionality, and it is used here for encapsulation and delivery of the capsules to mouse eyes. The manuscript summarizes the steps for cell microencapsulation, quality control, and ocular delivery.

Long-Term, Targeted Delivery of GDNF from Encapsulated Cells Is Neuroprotective and Reduces Seizures in the Pilocarpine Model of Epilepsy

Neurotrophic factors are candidates for treating epilepsy, but their development has been hampered by difficulties in achieving stable and targeted delivery of efficacious concentrations within the desired brain region. We have developed an encapsulated cell technology that overcomes these obstacles by providing a targeted, continuous, de novo synthesized source of high levels of neurotrophic molecules from human clonal ARPE-19 cells encapsulated into hollow fiber membranes. Here we illustrate the potential of this approach for delivering glial cell line-derived neurotrophic factor (GDNF) directly to the hippocampus of epileptic rats. In vivo studies demonstrated that bilateral intrahippocampal implants continued to secrete GDNF that produced high hippocampal GDNF tissue levels in a long-term manner. Identical implants robustly reduced seizure frequency in the pilocarpine model. Seizures were reduced rapidly, and this effect increased in magnitude over 3 months, ultimately leading to a reduction of seizures by 93%. This effect persisted even after device removal, suggesting potential disease-modifying benefits. Importantly, seizure reduction was associated with normalized changes in anxiety and improved cognitive performance. Immunohistochemical analyses revealed that the neurological benefits of GDNF were associated with the normalization of anatomical alterations accompanying chronic epilepsy, including hippocampal atrophy, cell degeneration, loss of parvalbumin-positive interneurons, and abnormal neurogenesis. These effects were associated with the activation of GDNF receptors. All in all, these results support the concept that the implantation of encapsulated GDNF-secreting cells can deliver GDNF in a sustained, targeted, and efficacious manner, paving the way for continuing preclinical evaluation and eventual clinical translation of this approach for epilepsy.SIGNIFICANCE STATEMENT Epilepsy is one of the most common neurological conditions, affecting millions of individuals of all ages. These patients experience debilitating seizures that frequently increase over time and can associate with significant cognitive decline and psychiatric disorders that are generally poorly controlled by pharmacotherapy. We have developed a clinically validated, implantable cell encapsulation system that delivers high and consistent levels of GDNF directly to the brain. In epileptic animals, this system produced a progressive and permanent reduction (>90%) in seizure frequency. These benefits were accompanied by improvements in cognitive and anxiolytic behavior and the normalization of changes in CNS anatomy that underlie chronic epilepsy. Together, these data suggest a novel means of tackling the frequently intractable neurological consequences of this devastating disorder.

Extended Duration Vascular Endothelial Growth Factor Inhibition in the Eye: Failures, Successes, and Future Possibilities.

Vascular endothelial growth factor (VEGF) plays a pivotal role in the development of neovascularization and edema from several common chorioretinal vascular conditions. The intravitreally injected drugs (aflibercept, bevacizumab, conbercept, pegaptanib, and ranibizumab) used to treat these conditions improve the visual acuity and macular morphology in most patients. Monthly or bimonthly injections were administered in the phase III pivotal trials but physicians usually individualize therapy with pro re nata (PRN) or treat and extend regimens. Despite these lower frequency treatment regimens, frequent injections and clinic visits are still needed to produce satisfactory outcomes. Newly developed drugs and refillable reservoirs with favorable pharmacokinetic profiles may extend durations of action and require fewer office visits. However, we have learned from previous experiences that the longer durations of action seen in strategically designed phase III trials often do not translate to less frequent injections in real-life clinical practice. Unfortunately, long-acting therapies that produce soluble VEGF receptors (encapsulated cell technology and adenovirus injected DNA) have failed in phase II trials. The development of longer duration therapies remains a difficult and frustrating process, and frequent drug injections are likely to remain the standard-of-care for years to come.

Delivery of CR2-fH using AAV vector therapy and encapsulated cell technology as treatment strategies in mouse model of neovascularization

Delivery of CR2-fH using AAV vector therapy and encapsulated cell technology as treatment strategies in mouse model of neovascularization

Delivery of therapeutics to posterior eye segment: cell-encapsulating systems.

Delivery of therapeutics to posterior eye segment: cell-encapsulating systems.

IAP textbook of vaccines

This book is a collection of 15 chapters exploring the applications of stem cell therapy for the treatment of blinding retinal degenerative diseases. Age-related macular degeneration (ARMD) is the most important cause of vision loss in people over 55 years of age all over the world. The initial few chapters highlight the diseases where degeneration of photoreceptors leads to vision loss, followed by the potential uses of stem cells, their production and delivery while the regulatory issues in cell-based therapy are dealt with in the last chapter. The book begins with a comprehensive review of ARMD including epidemiology, clinical features, histopathology and pathogenesis supported with appropriate illustrations. This chapter also includes the latest imaging modalities (adaptive optics scanning laser ophthalmoscopy, near infrared reflectance, etc) with the objective to pick up early ARMD changes. The next chapter on general pathophysiology of retinal degeneration briefly recapitulates the phototransduction cascade and highlights how the destruction of photoreceptors appears to be the final common pathway in a number of degenerative diseases and may thus be targeted for therapeutic purposes. The third chapter introduces juvenile-onset macular degenerative disorders causing central vision loss and discusses their clinical features, inheritance pattern, basic pathology and diagnostic modalities [electroretinogram, electrooculogram, optical coherence tomography (OCT) and fundus autofluorescence] which help clinch their diagnosis. The fifth chapter familiarizes the readers with various stem cells for retinal repair. Stem cells for retinal repair may be derived from pluripotent or retinal pigment epithelium stem cells (RPESCs) which can replace damaged retina and provide trophic support. Alternatively, bone marrow or neural stem cells may also be used, but these only provide trophic support. Other than these, there are also the induced pluripotent stem cells (iPSCs) and the umbilical cord stem cells (UCSCs). This chapter ends with the mention of ongoing phase 2 trial for subretinal injection of UCSCs (www.clinicaltrials.gov No. {"type":"clinical-trial","attrs":{"text":"NCT00458575","term_id":"NCT00458575"}}NCT00458575), however, this study has been terminated. For optimal cell-based ARMD therapy a number of issues need to be addressed like cell survival in vivo, optimal stage of disease for intervention, safe and simple surgical techniques and identification of sources of cells for transplantation. The question raised in the sixth chapter is which source of RPE-like cells is better, iPSCs or human embryonic stem cells (hESCs)? The next question yet unanswered is regarding the mode of transplantation, bolus injection of dissociated RPE cells into subretinal space versus RPE monolayer transplantation. The seventh chapter introduces various ever-changing protocols for generation of RPE cells and photoreceptor (PR)-like cells from iPSCs and hESCs, for example, using stem cells for glaucoma is thought to have a neuroprotective and neuroregenerative role. Another thought is using skin biopsy to reprogramme cells to iPSCs and then differentiate them to retinal ganglion cells (RGCs) that can be used for drug screening for optimum individualized treatment. However, there is no protocol for effective RGC production. Both iPSC and ESC derived cells are immunoreactive after implantations thus need immunosuppression. The reprogramming itself leads to epigenetic effects in the resultant iPSCs rendering them immunogenic. To overcome rejection certain suggested methods are discussed in chapter nine. The tenth chapter deals with the question of RPE-like stem cell survival post-transplantation. It is known that less than one per cent of stem cells injected in the subretinal space eventually survive after 2-4 wk of transplantation due to shearing forces during injection and reflux of cells from injection site. The next chapter brings in the latest in scaffold delivery strategy. Various scaffold substrates can be used to grow RPE monolayer including natural biomaterials like amniotic membrane, lens capsule, explants of Bruch's membrane, etc. or natural polymers like extracellular matrix protein or synthetic polymers, for example, parylene, PLGA [poly(lactic-co-glycolic acid)], hydrogels, etc. The next chapter is dedicated to the use of an ingenious micromachined parylene-C device as an artificial Bruch's membrane for stem cell therapy. The chapter on gene or cell therapy talks about ex vivo gene correction followed by transplantation, which would reduce the risk of immune rejection via autologous cell therapy. However, it would also increase the mutational load of iPSCs. In the end there is mention of encapsulated cell technology for protein therapy thus delivering consistent levels of neurotrophic factors for longer periods and avoiding repeated injections. The book ends with a look into the cellular manufacturing process which ensures safety of the product that is to be administered. This book compiles the latest in stem cell research and the reader will find an introduction to all there is to know about cell therapy. Researchers as well as ophthalmologists will find reading this book an informative experience. The book can be a useful primer for beginners and also serve as a reference guide to investigators in this area as it gives a comprehensive updated review of cell-based therapy for retinal degenerative disorders in all age groups.

Routes for Drug Delivery: Sustained-Release Devices.

Several different technologies exist for sustained-release drug delivery devices, including: (1) nonbiodegradable implants; (2) biodegradable implants; (3) micro- and nanoparticles; (4) liposomes, and (5) encapsulated cell technology (ECT). Currently, the only sustained-release devices approved by the Food and Drug Administration are the ganciclovir implant for the treatment of cytomegalovirus retinitis, the fluocinolone acetonide implant for the treatment of noninfectious posterior uveitis and the dexamethasone implant for the treatment of diabetic macular edema or noninfectious posterior uveitis. The first two implants are nonbiodegradable and require surgical placement, whereas the dexamethasone implant is biodegradable, and can be shaped and injected using a small-gauge needle or applicator into the vitreous. ECT, currently in a phase II clinical trial, utilizes modified retinal pigment epithelium cells to produce protein drug molecules in the vitreous. The microparticle, nanoparticle and liposome technology currently in development may offer the most flexibility for prolonged drug release and combination therapy for retinal diseases.

Advances in drug delivery to the posterior segment.

Emerging developments and research for drug delivery to the posterior segment offer a promising future for the treatment of vitreoretinal disease. As new technologies enter the market, clinicians should be aware of new indications and ongoing clinical trials. This review summarizes the advantages and shortcomings of the most commonly used drug delivery methods, including vitreous dynamics, physician sustainability and patient preferences. Currently available, intravitreal, corticosteroid-release devices offer surgical and in-office management of retinal vascular disease and posterior uveitis. The suprachoroidal space offers a new anatomic location for the delivery of lower dose medications directly to the target tissue. Implantable drug reservoirs would potentially allow for less frequent intravitreal injections reducing treatment burdens and associated risks. Newer innovations in encapsulated cell technology offer promising results in early clinical trials. Although pars plana intravitreal injection remains the mainstay of therapy for many vitreoretinal diseases, targeted delivery and implantable eluting devices are rapidly demonstrating safety and efficacy. These therapeutic modalities offer promising options for the vitreoretinal therapeutic landscape.

Two-Year Intraocular Delivery of Ciliary Neurotrophic Factor by Encapsulated Cell Technology Implants in Patients with Chronic Retinal Degenerative Diseases

To evaluate the pharmacokinetics of ciliary neurotrophic factor (CNTF) delivered over a period of up to 2 years by an intraocular encapsulated cell technology (ECT) implant in patients with retinitis pigmentosa (RP) and geographic atrophy (GA). Patients from phase 1 RP (CNTF1); phase 2 GA (CNTF2); and phase 2 late and early stage RP (CNTF3, and CNTF4) studies received an ECT-CNTF implant, designated as "NT-501," in one eye. Per protocol, all implants (n = 10) were removed at 6 months from the CNTF1 study patients. Explant for the phase 2 studies was optional, but several patients were explanted at 12, 18, and 24 months post implant. A small amount of vitreous sample was collected at the time of explant. The rate of CNTF secretion from the explants and the corresponding vitreous CNTF levels were evaluated for each time point. Serum samples from these patients were evaluated for CNTF, anti-CNTF antibodies, and antibodies to the encapsulated cells. NT-501 implants produced CNTF consistently over a 2-year period. The calculated half-life of CNTF in the vitreous continuously delivered by ECT implants was 51 months, with CNTF levels statistically equivalent between the 6- and 24-month implant period. CNTF, anti-CNTF antibodies, and antibodies to the encapsulated cells were not detected in the serum of patients. This retrospective study demonstrated that the intraocular ECT implant has a favorable pharmacokinetic profile for the treatment of chronic retinal degenerative diseases without systemic exposure. (ClinicalTrials.gov numbers, NCT00063765, NCT00447954, NCT00447980, NCT00447993.).

Neuroprotection of retinal degenerative disease by ciliary neurotrophic factor

Ciliary neurotrophic factor (CNTF) has been showing neuroprotective effects on photoreceptors in a variety of in vivo and in vitro experiments and clinical trials. CNTF causes morphological and functional alterations in various retinal nerve cells. The neuroprotection mechanism of CNTF involves STAT-dependent, ERK-dependent, and Akt-dependent signaling pathways, in which Müller cells play an important role. Encapsulated cell technology (ECT) device is an efficient administration approach to deliver CNTF into the eyes, which is effective in retarding photoreceptor degeneration in several animal models with retinal degenerative diseases. The safety and efficiency of the device in clinical trials are also being evaluated currently for further clinical use in human eyes as a potential treatment.

Longitudinal Study of Cone Photoreceptors during Retinal Degeneration and in Response to Ciliary Neurotrophic Factor Treatment

To study cone photoreceptor structure and function in patients with inherited retinal degenerations treated with sustained-release ciliary neurotrophic factor (CNTF). Two patients with retinitis pigmentosa and one with Usher syndrome type 2 who participated in a phase 2 clinical trial received CNTF delivered by an encapsulated cell technology implant in one eye and sham surgery in the contralateral eye. Patients were followed longitudinally over 30 to 35 months. Adaptive optics scanning laser ophthalmoscopy (AOSLO) provided high-resolution images at baseline and at 3, 6, 12, 18, and 24 months. AOSLO measures of cone spacing and density and optical coherence tomography measures of retinal thickness were correlated with visual function, including visual acuity (VA), visual field sensitivity, and full-field electroretinography (ERG). No significant changes in VA, visual field sensitivity, or ERG responses were observed in either eye of the three patients over 24 months. Outer retinal layers were significantly thicker in CNTF-treated eyes than in sham-treated eyes (P < 0.005). Cone spacing increased by 2.9% more per year in sham-treated eyes than in CNTF-treated eyes (P < 0.001, linear mixed model), and cone density decreased by 9.1%, or 223 cones/degree(2) more per year in sham-treated than in CNTF-treated eyes (P = 0.002, linear mixed model). AOSLO images provided a sensitive measure of disease progression and treatment response in patients with inherited retinal degenerations. Larger studies of cone structure using high-resolution imaging techniques are urgently needed to evaluate the effect of CNTF treatment in patients with inherited retinal degenerations.

Ciliary neurotrophic factor delivered by encapsulated cell intraocular implants for treatment of geographic atrophy in age-related macular degeneration

There is no treatment available for vision loss associated with advanced dry age-related macular degeneration (AMD) or geographic atrophy (GA). In a pilot, proof of concept phase 2 study, we evaluated ciliary neurotrophic factor (CNTF) delivered via an intraocular encapsulated cell technology implant for the treatment of GA. We designed a multicenter, 1-y, double-masked, sham-controlled dose-ranging study. Patients with GA were randomly assigned to receive a high-or low-dose implant or sham surgery. The primary endpoint was the change in best corrected visual acuity (BCVA) at 12 mo. CNTF treatment resulted in a dose-dependent increase in retinal thickness. This change was followed by visual acuity stabilization (loss of less than 15 letters) in the high-dose group (96.3%) compared with low-dose (83.3%) and sham (75%) group. A subgroup analysis of those with baseline BCVA at 20/63 or better revealed that 100% of patients in the high-dose group lost <15 letters compared with 55.6% in the combined low-dose/sham group (P = 0.033). There was a 0.8 mean letter gain in the high-dose group compared with a 9.7 mean letter loss in the combined low-dose/sham group (P = 0.0315). Both the implant and the implant procedure were well-tolerated. These findings suggest that CNTF delivered by the encapsulated cell technology implant appears to slow the progression of vision loss in GA, especially in eyes with 20/63 or better vision at baseline.