TSOI JadiCells for CTE / TBI

trader32176
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TSOI JadiCells for CTE / TBI

Post by trader32176 »

I'm gonna start the information flow on Stem Cells w/ the TSOI licensed JadiCell for CTE /TBI :


Therapeutic Solutions International Signs Agreement for Licensing Jadi Cell's Universal Donor Adult Stem Cell Product for Chronic Traumatic Encephalopathy and Traumatic Brain Injury
Company intends to use Stem Cells under new Right to Try law for CTE


https://www.globenewswire.com/news-rele ... Injur.html

OCEANSIDE, Calif., Dec. 10, 2018 (GLOBE NEWSWIRE) -- via OTC PR WIRE -- Therapeutic Solutions International, Inc., (OTC Markets: TSOI) announced today the signing of an agreement between TSOI and Jadi Cell LLC for licensing of the Jadi Cell universal donor adult stem cell, as covered in US Patent No.: 9,803,176 B2 for use in Chronic Traumatic Encephalopathy (CTE), and Traumatic Brain Injury (TBI).

The Jadi Cell product, which belongs to the mesenchymal stem cell (MSC) family of cells, is a unique adult stem cell, which produces higher levels of therapeutic factors compared to other stem cells. The cells have demonstrated safety in animal models and pilot human trials. The Jadi Cell product is generated from umbilical cords, which are a source of medical waste and available in large quantities at inexpensive prices.

Chronic Traumatic Encephalopathy (CTE) is caused by repetitive concussive/sub-concussive hits to the head sustained over a period of years and is often found in football players. The condition is characterized by memory loss, impulsive/erratic behavior, impaired judgment, aggression, depression, and dementia. In many patients with CTE, it is anatomically characterized by brain atrophy, reduced mass of frontal and temporal cortices, and medial temporal lobe.

Traumatic brain injury (TBI) is an insult to the brain, not of a degenerative or congenital nature, but caused by external physical force that may produce a diminished or altered state of consciousness, which results in an impairment of cognitive abilities or physical functioning.

"The team assembled by Mr. Dixon is not only impressive, but has succeeded in developing, patenting, and commercializing regenerative and immunological based approaches to a variety of chronic conditions1,2," said Dr. Amit Patel. "CTE represents a significant unmet medical need which we believe is amenable to stem cell intervention. We are eager to work with Mr. Dixon and his internationally renowned team in accelerating treatments and potential cures for debilitating conditions such as CTE and traumatic brain injury."

"Many of my colleagues suffer from CTE. At present there are no therapeutic approaches that possess even the potential to reverse this terrible condition. The cells developed by Dr. Amit Patel, for the first time, give me hope that a treatment may be possible," said Wes Chandler, former NFL Player of 11 seasons.

"It is my honor to work with Dr. Amit Patel, who has a track record of successful FDA applications and product development in the area of regenerative medicine, to accelerate clinical translation of this new treatment modality for patients suffering from brain injuries," said Dr. James Veltmeyer, Chief Medical Officer of Therapeutic Solutions International. "We plan to leverage New regulatory pathways such as the recently approved "Right to Try" Law to deliver these medicines as soon as possible to patients which currently have no other options."

"We are especially enthusiastic about clinically developing the Jadi Cell product because of its advanced stage of development," said Timothy Dixon, President and CEO of TSOI. "In contrast to other stem cell types, which require years, if not decades of development before entry into American patients, we believe that we will be treating patients within 12 months. Currently means of isolating, producing, scaling up, and delivery of the cells has all been worked out by Dr. Patel and Collaborators. We are confident that coming from this position of strength, we will be positioned ahead of everyone in the area of regenerative medicine focusing on CTE."
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TimGDixon
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Re: TSOI JadiCells for CTE / TBI

Post by TimGDixon »

This is a good read and background for everyone on the jadi Cell. Get ready to start hearing more about this as we already disclosed we will be filing an IND and soon.

Mesenchymal Stem Cells for use in Chronic Traumatic Encephalopathy (CTE), and Traumatic Brain Injury (TBI).
On December 10, 2018 Therapeutic Solutions International, Inc., announced the signing of an agreement between TSOI and Jadi Cell LLC for licensing of the Jadi Cell universal donor adult stem cell, as covered in US Patent No.: 9,803,176 B2 for use in Chronic Traumatic Encephalopathy (CTE), and Traumatic Brain Injury (TBI).

The Jadi Cell product, which belongs to the mesenchymal stem cell (MSC) family of cells, is a unique adult stem cell, which produces higher levels of therapeutic factors compared to other stem cells. The cells have demonstrated safety in animal models and pilot human trials.

Peer Reviewed Publications:

https://pubmed.ncbi.nlm.nih.gov/20587136/
Cell Transplant. 2010;19(11):1439-49. doi: 10.3727/096368910X514260. Epub 2010 Jun 29.
An efficient approach to isolation and characterization of pre- and postnatal umbilical cord lining stem cells for clinical applications.
Gonzalez R1, Griparic L, Umana M, Burgee K, Vargas V, Nasrallah R, Silva F, Patel A.

Abstract
There have been various forms of mesenchymal stem cell-like (MSC-like) cells isolated from umbilical cords (UCs). The isolation of umbilical cord lining stem cells (ULSCs) may be of great value for those interested in a possible treatment to several disease/disorders. Unlike umbilical cord blood cells, these cells are unique because they can be expanded to therapeutically relevant numbers and cryopreserved for several different uses. Here we efficiently isolate stem cells from a small segment of pre- and postnatal UCs, and obtain therapeutically relevant amounts of ULSCs within 3 weeks. We demonstrate their growth potential and characterize them using immunocytochemistry, flow cytometry, and RT-PCR. In addition, we differentiate ULSCs into multiple lineages. Pre- and postnatal ULSCs are morphologically similar to mesenchymal stem cells (MSCs) and easily expand to greater than 70 population doublings. They express pluripotent markers Oct4 and nanog at the protein and RNA level. Flow cytometry demonstrates that they express markers indicative of MSCs in addition to high SSEA-4 expression. ULSCs are easily differentiated into osteogenic, adipogenic, chondrogenic, cardiogenic, and neurogenic cells. Pre- and postnatal ULSCs are characteristically similar in respect to their growth, marker expression, and plasticity, demonstrating they are highly conserved throughout development. ULSCs have phenotypic and genotypic properties of MSCs. These studies demonstrate the therapeutic potential of an otherwise discarded tissue. They are a perfect HLA match for the donor and an excellent match for immediate family members; therefore, they may serve as a therapeutic cell source.
PMID: 20587136
DOI: 10.3727/096368910X514260

https://journals.sagepub.com/doi/full/1 ... 912X655064
Mesenchymal Stem Cell Population Isolated from the Subepithelial Layer of Umbilical Cord Tissue
Amit N. Patel, M.D., M.S., Vanessa Vargas, Patricia Revello …
First Published March 1, 2013 Research Article
https://doi.org/10.3727/096368912X655064

Article information
The therapeutic use of stem cells to treat diseases and injuries is a promising tool in regenerative medicine. The umbilical cord provides a rich source of stem cells; we have previously reported a population of stem cells isolated from Wharton’s jelly. In this report, we aimed to isolate a novel cell population that was different than those found in Wharton’s jelly. We isolated stem cells from the subepithelial layer of the umbilical cord; the cells could be expanded for greater than 90 population doubling and had mesenchymal stem cell characteristics, expressing CD9, SSEA4, CD44, CD90, CD166, CD73, and CD146 but were negative for STRO-1. The cells can be directionally differentiated and undergo osteo-, chondro-, adipo-, and cardiogenesis. In addition, we have identified for the first time that mesenchymal stem cells isolated from umbilical cord can produce microvesicles, termed exosomes. This is the first report describing a stem cell population isolated from the subepithelial layer of the umbilical cord. Given the growth capacity, multilineage potential, and most importantly the low levels of HLA-ABC, we propose that this novel cell isolated from the subepithelial layer of umbilical cord is an ideal candidate for allogeneic cell-based therapy.

https://patents.google.com/patent/US9803176B2/en
Intellectual Property: US9803176B2
Methods and compositions for the clinical derivation of an allogenic cell and therapeutic uses

Abstract
Various cells, stem cells, and stem cell components, including associated methods of generating and using such cells are provided. In one aspect, for example, an isolated cell that is capable of self-renewal and culture expansion and is obtained from a subepithelial layer of a mammalian umbilical cord tissue. Such an isolated cell expresses at least three cell markers selected from CD29, CD73, CD90, CD166, SSEA4, CD9, CD44, CD146, or CD105, and does not express at least three cell markers selected from CD45, CD34, CD14, CD79, CD106, CD86, CD80, CD19, CD117, Stro-1, or HLA-DR.
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Combating COVID-19 with mesenchymal stem cell therapy

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Combating COVID-19 with mesenchymal stem cell therapy

https://www.sciencedirect.com/science/a ... 7X20303635

Highlights

SARS-CoV-2 (novel coronavirus) and SARS-2003 both have a similar mechanism of infection, i.e, binding the spike protein on the viral surface to the ACE2 receptors on the host cell surface.


The devastating cytokine explosion attributed to the SARS-CoV-2 infection leads to severe shock, oedema and multiple organ failure.


Administering the COVID-19 patients with an infusion of multipotent MSCs can help to combat the COVID-19 as these cells will inhibit the exaggerated immune response and encourage endogenous repair of the lung epithelial cells.


The mesenchymal stem cell therapy does not have any adverse side effects on the patient.


In this review we have highlighted all the implications associated with MSC therapy application in case of COVID-19 and strongly place our argument in support of this.


Abstract
The COVID-19 disease is caused by a positive stranded RNA virus called SARS-CoV-2. The virus mainly targets the pulmonary epithelial cells as it’s initial site of infection by letting its surface spike protein interact and bind to the host ACE2 receptor. The internalization and gradual replication of the virus results in an exaggerated immune response triggering release of many pro-inflammatory cytokines and chemokines. This immune storm is responsible for multiple health hazards in the host ultimately leading to multiple organ failure. Mesenchymal stem cell therapy offers a promising approach towards mitigating the delirious effects of the infection in the COVID-19 patients. This therapy has shown to reduce the expression of pro-inflammatory cytokines as well as repair of damaged tissues in COVID-19 patients. This review has been organized to put forward the positive aruments and implications in support of mesenchymal stem cell therapy as a necessary approach for treating COVID-19 patients.

1. Introduction
The end of the year 2019 marked the beginning of a new challenge for humanity when several cases of severe respiratory ailments were reported in the city of Wuhan, Hubei province, China. The cases were earlier confused with regular flu and thought to be caused by the normal seasonal influenza virus. The accurate prognosis of the illness was very difficult to make in the beginning but was simulataneously identified to be a virus borne disesase. Due to the increasing severity in the following days, on January 1, the virus was declared novel. Upon the complete phylogenetic analysis of the viral genome consisting of 29,903 nucleotides, it was found that this novel coronavirus had 89.1 % similar nucleotides to a class of Severe Acute Respiratory Syndrome (SARS) – like coronavirus. This novel virus belonged to the genus Betacoronavirus having the subgenus Sarbecovirus [1]. The novel coronavirus was earlier known to be found in Chinese bats [2]. WHO has assigned a brief name to the virus, SARS-CoV-2 and COVID-19 is the name assigned to the SARS-CoV-2 associated disease.

Till date no dedicated therapeutic or vaccination strategies have been implemented or confirmed to prevent COVID-19. Accessory therapeutic manueveurs including corticosteroid mediated inflammation reduction, convalescent plasma therapy, antibiotics for treatment of secondary bacterial sepsis and non-specific antivirals, etc., do not show much effectivity in severe cases of COVID-19. The main reason behind the failure of these therapies is the cytokine storm in the lungs generated by the virus. In the computed tomography scans, these cytokine storms (an augmented immune response in the body towards any external stimulus) appear as inflammatory lesions with ground-glass opacity [3,4].

3. Conclusion
SARS-CoV-2 (novel coronavirus) and SARS-2003, both have a similar mechanism of infection, i.e, binding the spike protein on the viral surface to the ACE2 receptors on the host cell surface. Thus all the tissues and organs expressing the ACE2 receptor are susceptible to the SARS-CoV-2 infection. Since the alveolar epithelial cells have a high propensity of ACE2 receptors, they are the most adversely affected during SARS-CoV-2 infection. The devastating cytokine explosion attributed to the SARS-CoV-2 infection leads to severe shock, oedema and multiple organ failure. Administering the COVID-19 patients with an infusion of multipotent MSCs can help to combat the COVID-19 as these cells will inhibit the exaggerated immune response and encourage endogenous repair of the lung epithelial cells by improving the microenvironment. The mesenchymal stem cell therapy has not tey shown any adverse side effects on the patient. In this review we have highlighted all the implications associated with MSC therapy application in case of COVID-19 and strongly place our argument in support of this.
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he pathogenesis and treatment of the ‘Cytokine Storm’ in CO

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https://reader.elsevier.com/reader/sd/p ... 8B5EAFB131

Stem cell therapy As an important member of the stem cell family, mesenchy- mal stem cells (MSC) not only have the potential of self-renewal and multidirectional differentiation, but also have strong anti- inflammatory and immune regulatory functions. MSC can inhibit the abnormal activation of T lymphocytes and macrophages, and induce their differentiation into regulatory T cell (Treg) subsets and anti-inflammatory macrophages, respectively. It can also inhibit the secretion of pro-inflammatory cytokines, such as, IL-1, TNF- α, IL- 6, IL-12, and IFN- γ, thereby reducing the occurrence of cytokine storms. 87 , 88 At the same time, MSC can secrete IL-10, hepatocyte growth factor, keratinocyte growth factor and VEGF to alleviate ARDS, regenerate and repair damaged lung tissues, and resist fi- brosis. 89 Therefore, many functions of MSC are expected to make it an effective method for the treatment of COVID-19.
curncman
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Mesenchymal Stem Cells: A New Piece in the Puzzle of COVID-19 Treatment

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Mesenchymal Stem Cells: A New Piece in the Puzzle of COVID-19 Treatment

https://www.frontiersin.org/articles/10 ... 01563/full

COVID-19 is a disease characterized by a strong inflammatory response in severe cases, which fails to respond to corticosteroid therapy. In the context of the current COVID-19 outbreak and the critical information gaps regarding the disease, several different therapeutic strategies are under investigation, including the use of stem cells. In the present manuscript, we provide an analysis of the rationale underlying the application of stem cells to manage COVID-19, and also a comprehensive compendium of the 69 clinical trials underway worldwide aiming to investigate the application of stem cells to treat COVID-19. Even though data are still scarce, it is already possible to observe the protagonism of China in testing mesenchymal stem cells (MSCs) for COVID-19. Furthermore, it is possible to determine that current efforts focus on the use of multiple infusions of high numbers of stem cells and derived products, as well as to acknowledge the positive results obtained by independent groups who publicized the therapeutic benefits provided by such therapies in 51 COVID-19 patients. In such a rapid-paced field, up-to-date systematic studies and meta-analysis will aid the scientific community to separate hype from hope and offer an unbiased position to the society and governments.

Covid-19 Pathophysiology and the Rationale for Using Stem Cells
Coronaviruses were first isolated from patients with common cold by Tyrrell and Bynoe in (21). They constitute enveloped, positive-sense RNA viruses, capable of infecting various mammals, including humans (21). The SARS-CoV-2 belongs to the Nidovirales order, Coronaviridae family, Coronavirinae subfamily. The Coronavirinae is further divided into the alpha, beta, gamma, and delta coronaviruses. While coronaviruses alpha and beta seem to have originated from mammals (especially bats), the gamma and delta coronaviruses seem to derive from pigs and birds (22). Prior to the present SARS-CoV-2 outbreak, coronaviruses were only thought to cause mild infections in humans. Now it is considered that among the seven coronaviruses subtypes that are capable of infecting humans, the beta coronaviruses–including SARS-CoV-2 -, may cause severe and fatal diseases. SARS-CoV-2 spreads mainly through the respiratory airways through droplets that are shed from the respiratory secretions of infected persons, but also by direct personal contact (23). Recently, the SARS-Cov-2 has been isolated from fecal samples of severe pneumonia patients, suggesting other transmission routes (24).

It has been shown that SARS-Cov-2 is capable of infecting angiotensin I converting enzyme 2 (ACE-2) receptor-positive cells. Such a receptor is expressed by a wide variety of cell types, including the lung epithelial and capillary endothelial cells, in which it successfully replicates. Inflammatory cells were shown to be potentially infected by SARS-CoV viruses, but only leading to abortive infection (25). Still, viral entry engenders both innate and adaptive immune response, which initiate in loco, but soon are detectable in the serum of COVID-19 patients (26). The local tissue alterations provoked by the virus infection are characterized by intense inflammation, inflammatory cell migration, and edema (Figure 1). The subsequent tissue destruction and dysfunction are proportional to viral load and ACE-2 expression, which is increased in patients under Angiotensin-converting enzyme inhibitors /angiotensin receptor blockers therapy (27–29). Local tissue damage engendered by the viral infection is detectable by radiological analysis, even before the patient presents pneumonia symptoms.



COVID-19 can also affect the heart, liver, kidneys and alter the immune system (30), presenting a wide range of clinical outcomes that range from mild to common, severe, and critically severe states (26). In the latter scenario, patients require advanced life support, which is of great concern to public health systems (31).

The inflammatory response caused by SARS-Cov-2 is both the primary mechanism of viral elimination, but also tissue destruction and dysfunction (Figure 1). The internalization of the virus in tissue and immune cells leads to activation of nuclear factor-kappa B (NF-kB) pathway and secretion of a myriad of inflammatory factors, including IL-1, IL-17, TNF-α, and INF-γ (32–34). Hyperinflammation and cytokine storm, both of which can promote multiple organ failure, have been observed in severe and critically severe patients (35) justifying current efforts to test the therapeutic benefit of anti-inflammatory interventions, including corticosteroids, immunosuppressors, and inhibitors of Janus kinase (36).

Mesenchymal Stem Cells (MSCs) can be obtained from different tissues and are characterized by regenerative and immunomodulatory properties, which render them exciting tools for cell therapy. As reviewed by our group and others (10, 37, 38), MSCs present remarkable angiogenic, healing, antiapoptotic, and immunomodulatory potential. Furthermore, due to the low expression of MHC-I, MHC-II, and costimulatory molecules, they can be generally recognized as immune evasive and safe when used in allogeneic settings (39).

The immunomodulatory mechanisms of MSCs include cell contact-dependent (40) and paracrine processes, including the secretion of TNF-Stimulated Gene-6 (41), IL-10 (42), indoleamine 2,3-dioxygenase (43), adenosine (9), and also extracellular vesicles (7). Such processes lead to lower immune cell maturation and activation, in addition to promoting the differentiation of T-cells into regulatory T-cells (Tregs) (38).

Over 1,000 clinical studies have been performed up to date investigating the therapeutic potential of MSCs for various purposes, including diseases in which the immune system response is exacerbated, such as rheumatoid arthritis (44), Crohn's disease (45), Systemic lupus erythematosus (46–49) and graft- vs. -host disease (50). Despite the fact that many of such trials are still in progress, the available data obtained during the last 30 years clearly show that MSCs constitute promising tools in the treatment of inflammatory diseases. Considering inflammatory diseases, most consistent data relate to the use of MSCs in the treatment of the graft-vs. -host disease, highlighting the potential of MSCs to improve clinical signs of inflammation and favoring patient survival (50–53). Similar observations have been made in the context of other inflammatory disorders. For instance, it has been reported that MSCs infusions promote a reduction of the inflammatory status and ameliorates the clinical signs of patients with rheumatoid arthritis (54, 55). In Crohn's disease patients, several published studies revealed that MSCs induce perianal fistula healing (56–59). In recognition of the cited and other studies, FDA and EMA have conceded commercial approval for some MSC-based products targeting specific indications (e.g., Alofisel and Remestemcel-L, which are indicated to treat anal fistulas in Crohn's disease and graft- vs. -host disease, respectively).

Frequently, the treatment with MSCs follows intravenous administration of the cells. Interestingly, it has been shown that in this scenario a significant percentage of MSCs are rapidly trapped in the lungs upon intravenous injection, and also that lesioned sites increase MSC migration and retention (60). In the lung capillaries, the same occurs: upon injury, the local production of the pro-inflammatory mediator Angiotensin II (Ang II) is increased, and drives MSC migration in vivo through interactions with the Angiotensin II type 2 receptor (61–63). When trapped in the lungs, MSCs show the same immunomodulatory behavior as described in other body sites, such as the capacity of releasing anti-inflammatory cytokines (64), and antimicrobial peptides (65) (Figure 1).

As revised by Khoury et al. (66), at least 6 preclinical studies have been executed in order to investigate the therapeutic effects of MSCs in rodent (5 studies) and porcine (1 study) models of influenza virus infection. Two out of six studies described a lack of efficacy of MSC treatment in such models, but the most recent investigations (4 out of 6) have revealed positive outcomes, such as survival rate and decreased virus-induced inflammation. The capacity of influenza viruses to infect MSCs (which has not been assessed in vivo), host age, the varied MSC sources (umbilical cord and bone marrow), the different cell doses and administration routes involved in the studies may all help explaining the dissonant observations among research groups.

Clinically, the anti-inflammatory effects of MSCs have also been investigated in the context of Acute Respiratory Distress Syndrome (ARDS) with different etiologies (67–69). In a more recent study, perhaps as a hint for the application of MSCs for COVID-19 management, Chen et al. have infused MSCs into influenza A (H7N9) patients and obtained a significant reduction in mortality, compared to control group (70). In the cited study, 17 patients with ARDS caused by H7N9 infection were treated with menstrual blood-derived MSCs. While the control group (treated with antiviral agents, oxygen inhalation, etc) presented 54.5% mortality, only 17.6% of MSC-treated patients expired. Interestingly, 4 patients were followed during 5 years, with no harmful effects during this period.

Overall, the achieved results of MSC therapy for ARDS are promising, but important information is lacking in the literature, such as details on the management of control subjects, the time between MSC infusions, details regarding registered deaths, as well as other outcomes of interest, such as ventilator-free days and ICU stay.

Therefore, considering the acquired experience of the scientific and medical communities regarding the clinical application of MSCs to modulate the immune response, as well as the limited–but existent–pieces of evidence regarding the safety and efficacy of MSC therapy for viral respiratory infections, MSCs have entered clinical investigation for COVID-19 treatment. The current state of the art is reviewed below.

Current Efforts to Treat Covid-19 Based on Stem Cell Products
Using the terms “COVID-19” and “stem cells” we found studies in the ClinicalTrials.gov database (June, 2020). We complemented our search by assessing the complete list of COVID-19 clinical trials registered in the World Health Organization International Clinical Trials Registry Platform, and searching for studies which included the term “stem cells.” We finalized our search by accessing the European Union Clinical Trials Register (https://www.clinicaltrialsregister.eu). Studies that were withdrawn will not be mentioned in the present manuscript. Two observational studies were also removed from the list. We ended up with 69 clinical studies, 60 of which aim to investigate the therapeutic efficacy of MSCs to treat COVID-19. One trial aims to investigate the use of mononuclear cells, one trial investigates PRP in addition to stem cells, and six trials focus on the use of MSC-derived exosomes/conditioned media. One study aims to investigate the therapeutic benefits promoted by the combination of MSCs with ruxolitinib (Supplementary Table 1). One trial proposes the use of human Embryonic Stem Cells to produce “Immunity- and matrix-regulatory cells (NCT04331613). One trial focuses on using MSCs as “educators” of patients' mononuclear cells. By educated cells, researchers refer to mononuclear cells briefly co-cultured with MSCs ex vivo. As revised by Zhao (71), such a co-culture procedure leads to decreased expression of costimulatory molecules by T cells, increased Treg generation, and TGF-b1 synthesis. Educated cells have shown to be safe in clinical studies and to impose effective anti-inflammatory effects. The strategies under investigation based on Mesenchymal Stem Cells are illustrated in Figure 2, and involve different routes of administration, as well as the use of both MSCs, as well as their products, such as exosomes.

More recently, in a company announcement, Mesoblast described no adverse effects and positive clinical data obtained in march-april 2020 regarding 12 ventilator-dependent COVID-19 patients who received two MSC infusions 4 days apart from each other (81). Among treated subjects, 10 (83%) survived and 9 (75%) came off ventilator during the period of observation. In the document, the company mentions two studies which describe contemporaneous data of 12% survival among ventilator-dependent COVID-19. Since the clinical study is still ongoing, it will be important to see the final results of the study, which includes a placebo control group and will, therefore, be able to provide more reliable control data.

Concluding Remarks
Taken together, the present data reveal that stem cells and stem cell-derived strategies are currently under investigation as therapeutic tools to manage COVID-19, and also that the limited observations published so far point to the safety and efficacy of such therapies in the short-term, at least in severe and critically severe patients. The replication of the positive outcomes by independent groups was an important milestone recently achieved in the field. The current data, albeit preliminary and descriptive in nature, are promising. Nevertheless, the comparison between different therapeutic regimens, including various doses, MSC sources, and injection routes in the short-term, as well as in long-term, will provide valuable information about how to potentialize therapeutic outcomes. In the safety assessment side, patients need to be followed for long periods after stem cell therapy, since the angiogenic and immunomodulatory effects of MSCs could influence other outcomes, such as cancer progression (87).

Drawing any major conclusions regarding the use of stem cells and stem cell-derived products at this point is impossible, due to the small evidence accumulated so far. Moreover, the lack of full detailed data of published studies may compromise future analysis as well. In this sense, the fact that a few studies cited here present incomplete data regarding patients, clinical outcomes, and other parameters is an important limitation of our study. Nevertheless, such a limitation has also been detected as an issue in previous works in the theme (66, 88, 89).

Cell therapies are complex and present high costs; therefore, it will be paramount to carefully analyze the effect of such a therapeutic strategy according to sensitive parameters, such as time in ICU, time to recovery and duration of hospitalization. Still, advanced therapies are hardly seen as a unique alternative to manage a pandemic, but rather as an alternative to possibly save patients in severe or critically-severe conditions. Cell-free strategies under investigation are more easily scaled-up, and may simplify the logistics and regulatory path for commercial registration.

Preliminary data regarding the safety and efficacy of MSC therapy for COVID-19 is positive and has been obtained by independent groups. A second generation of trials adhering to rigorously designed blind, randomized, placebo-controlled protocols must now be pursued, with the aid of experienced clinical and basic science investigators.

The stem cell sector suffers from much hype and, unfortunately, unproven stem cell therapies for COVID-19 (and other disorders) are being offered worldwide, as alerted by the International Society for Cell & Gene Therapy (90), and more thoroughly reviewed by Turner (91). In such a rapid-paced field, systematic studies and meta-analysis will aid the scientific community to separate hype from hope and offer an unbiased position to the society.
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Re: TSOI JadiCells for CTE / TBI

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A I understand STEMVACS 2 is loading dendritic cells with protiens expressed in cancer cells, to get our immune system super charged to attack COVID-19.
STEMVACS2 is an allogeneic, or non-patient specific, COVD-19 vaccine candidate designed to stimulate patient immune responses against COVID-19. STEMVACS2, which is produced from our pluripotent cell technology using a directed differentiation method, is comprised of a population of mature dendritic cells. As the most potent type of antigen presenting cell in the body, dendritic cells instruct our body’s immune system to attack and eliminate harmful pathogens and unwanted cells. Because the tumor antigen is loaded exogenously into the dendritic cells prior to administration, STEMVACS2 is a platform technology that can be modified to carry any antigen, including patient-specific tumor neo-antigens.
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TimGDixon
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Re: TSOI JadiCells for CTE / TBI

Post by TimGDixon »

Yes that is true - it is also true that non-antigen specific activation can be used too and that makes it even more universal.
curncman
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Re: TSOI JadiCells for CTE / TBI

Post by curncman »

Thanks Tim for your approach to come up with allogeneic dendritic cells and supercharge th to fight all types of pathogens associated with Covid19, Cancers....the big Pharoah is looking with horoscope to scoop up allogeneic technology. Hope they are found us already and hunting us down 😀🤣😀
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Transforming Personalized Medicine into Off-the-Shelf Cell Therapies

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Transforming Personalized Medicine into Off-the-Shelf Cell Therapies

https://bioprocessintl.com/sponsored-co ... therapies/

Initial progress in cell and gene therapy has seen 12 advanced therapeutic medicinal products (ATMPs) become available on the market in 2019 for a range of conditions, from monogenic diseases to cancer. Despite such progress, development of clinically and commercially successful cell therapies presents manufacturability challenges and questions about bypassing patients’ immune systems. The availability of rapid sequencing and next-generation bioinformatics has made it possible to understand the mechanisms of disease better and accelerate development of therapeutic responses. The same toolbox will enable our fight against cancer (with advanced immunotherapies) and other conditions.

The Autologous Approach
In cell therapy for immunooncology, often the medicinal product is a cell that has acquired a therapeutic function through genetic modification induced by a virus. That is achieved by collecting relevant cells from donors, then genetically modifying and expanding them in culture to obtain the numbers required for infusion into a recipient. Most often, that has been an autologous strategy in which donor and recipient would be the same person — a patient (Figure 1, left). Such a vein-to-vein approach presents some difficulties because chemistry, manufacturing, and control (CMC) activities all have to be completed under extremely aggressive timelines (e.g., two to three weeks) dictated by protocols that patients undertake as part of their therapy. Those protocols are designed both to maximize collection of starting material that will become the medicinal product and to provide the best engrafting conditions at the time of infusion.

Autologous therapies are prime examples of personalized medicine. Making one medicine for treating one person’s condition builds on decades of experience gained in the field of bone marrow transplantation and has been adopted in the field of immuno-oncology. Two autologous products — Yescarta (axicabtagene ciloleucel) from Kite Pharma and Gilead Sciences and Kymriah (tisagenlecleucel) from Novartis — have been approved for commercialization and are now on the market. Both products are designed to empower T-cells with a chimeric antigen receptor (CAR) to recognize and kill cells that express the cluster of differentiation (CD)19 protein on their surfaces. CD19 is found on B cells, particularly malignant B cells in some forms of hematological malignancies. Both of those products have elicited good overall responses followed by durable results in many patients.

Even though autologous therapies have the advantage of eliminating concerns related to graft-versus-host disease, they are inherently expensive. They carry high costs and variability associated with an ad-hoc manufactured product. For each single-dose batch, not only will the quality and quantity of the starting material be different — thus requiring adjustments to downstream processing each time — but the final product itself also will be different depending on efficiency of viral transduction as well as purities and potencies achieved. Each such batch released will have to be qualified by a certificate of analysis (CoA), often comprising a matrix of analytical test results to ensure safety, identity, and potency of the product.

Those are nontrivial tasks for companies trying to turn around hundreds to thousands of batches per year, and as such, they have resulted in substantial costs per treatment. Because cell therapy is a technology that is still in its infancy, we can expect associated costs to drop over time, even when providing required manufacturing “at the bedside.” To that end, combining the scaling-out of manufacturing with closed systems, automation, and process simplification with increased accessibility and affordability of manufacturing suites (already available at several hospital sites) will reduce the costs of autologous products provided in a distributed strategy, as required.

The Allogeneic Approach
That raises the question of whether an alternative approach can be considered. The body of knowledge developed so far from current autologous cell therapies could represent a solid basis on which to build the next range of products. These new products could advance the concept of personalized medicine by optimizing and hybridizing the autologous model or offering a single allogeneic cell therapy product for all patients.

From a manufacturing perspective, such products will share many of the challenges with traditional biologics: efficacy, safety, and scalability. The ultimate goal would be to scale up manufacturing based on a centralized model to produce affordable batches for hundreds of patients — all quality controlled, stored, and ready for use — and thus generate “off-the-shelf” products.

To achieve that, the scientific community has focused attention on identifying the best allogeneic cell therapy system, in which cell donors and recipients are not the same people (Figure 1, right) This should provide unlimited amounts of identical starting materials that, after genetic modification, will engraft safely in all patients to exert expected functions. But do such donors exist? In cell therapy products for immunooncology — e.g., CAR T-cells — it is likely that recruiting healthy individuals as donors will provide higher yields and perhaps better-quality starting materials than are possible in an autologous strategy.

Using T cells obtained by leukapheresis as a starting material probably will be sufficient to manufacture enough finished product for a few histocompatible patients at least. That is a step toward development of more affordable products, but it remains a laborious manufacturing process for a limited number of patients.

An alternative to obtaining cells by leukapheresis is using well-characterized induced pluripotent stem cells (iPSCs). Through systematic optimization of a dedifferentiation protocol to eliminate product-related and process-related impurities while reducing the timelines, generation of iPSCs can be scaled up to provide large amounts of starting material for thousands of patients. In turn, that could enable large, fully characterized and validated cell banks for the most common haplotypes to be generated, then subsequently used to manufacture different cells of interest in fully automated and cost-effective processes. Establishing and banking a “universal” iPSC line, offering compatibility to all haplotypes, could bring the goal of developing a true “off-the-shelf” cell therapy product a step closer to reality. Several attempts to do so are under way and have generated great interest in immunooncology. A further scalable source of starting material could be generated through cell transdifferentiation and systematic, data-led conversion technologies to enable considering any cell type as a source of starting material for downstream cell-therapy processing.

The Next Step
Optimizing and scaling up good manufacturing practice (GMP)-compliant differentiation protocols will be vital to creating safe and efficacious cell therapeutic products from iPSCs. Streamlining those processes undoubtedly will be guided by data-driven computational approaches and manipulation of large-scale data. Mogrify Ltd. has developed a data-driven bioinformatic approach that will play a key role in the future of cell therapy development and manufacturing. Using next-generation sequencing and gene-regulatory information to identify how to convert any human cell into any other with transcription factors (TFs) or small molecules, this technology provides an elegant method for systematic cell programming and reprogramming. Although their differentiation capacity has made iPSCs many scientists’ starting cell type of choice, Mogrify technology allows researchers to start with any cell type and induce transdifferentiation into immune cells needed for therapy. A propriety algorithm identifies an optimal set of TFs and culture conditions for doing so. Those are delivered by existing methods (e.g., retroviruses and adenoassociated viruses) to differentiate large quantities of a desired cell type with high specificity, shorter timelines, and lower costs. Therefore, the technology could be used to generate large GMP-compliant cell banks ready for further downstream manipulation (Figure 2).

In recent years, cell therapies finally have entered the healthcare market, generating a first wave of immunooncology products that offer new hope for patients. A revolution in cell therapy is upon us now, with laboratories across the world already designing the next generation of products. That new generation will have increased efficacy, improved safety, and expanded scalability — allowing for affordable cell therapy products to treat new indications such as autoimmune and infectious diseases.
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