A Role for MSC to Treat Coronavirus Patients. Part 2: Fibrosis in Survivors
Author: Frances Verter, PhD
https://celltrials.org/news/role-msc-treat-coronavirus-patients-part-2-fibrosis-survivors
Reports of 83% survival in ventilator-dependent COVID-19 patients following mesenchymal stem cell therapy
Australian stem cell company Mesoblast Ltd. announced an 83% survival rate in ventilator-dependent COVID-19 patients with moderate to severe acute respiratory distress syndrome (ARDS) treated at New York’s Mount Sinai Hospital with allogeneic mesenchymal stem cells.
Nine of the 12 treated patients (75%) have successfully come off ventilator support within 10 days following two infusions of remestemcel-L.
“Once you’re ventilated when you have acute respiratory distress syndrome in the lungs, your likelihood of coming off a ventilator is 9%, and your survival is 12%,” Mesoblast CEO Silviu Itescu told BioWorld.
In contrast, only 9%, or 38 of 445 ventilator-dependent COVID-19 patients at a major hospital network in New York were able to come off ventilator support when treated with standard of care during the same March to April period.
Moreover, there was 88% mortality with only 12% survival (38/320) among ventilator-dependent COVID-19 patients at a second major hospital network in New York during the same period.
Those poor outcomes are consistent with earlier published data from China where mortality rates of over 80% were reported in patients with COVID-19 and moderate to severe ARDS.
At this time, 7 of the 12 treated patients have been discharged from the hospital. Patients received a variety of experimental agents prior to remestemcel-L. All patients were treated under an emergency IND or expanded access protocol at Mount Sinai.
Under the protocol, patients come into intensive care and received standard-of-care treatment. Once they were intubated on a ventilator, they were treated within 72 hours with two infusions of Mesoblast’s remestemcel-L cells within five days.
A bright light among dismal options
“What’s exciting is that our patients in the same epicenter of this disease with the same treatment everyone else is getting, suddenly 75% are coming off of ventilators within 10 days, and we’ve got 83% survival,” Itescu said.
The compassionate use treatment experience has informed the design of the clinical protocol for a randomized, placebo-controlled phase II/III trial of remestemcel-L in ventilator-dependent COVID-19 moderate to severe ARDS patients across North America.
The FDA has approved the same protocol for the phase II/III trial, and it will be powered so that results will be “self-evident,” Itescu said, noting that the trial will begin “imminently” in 20 to 30 sites across the U.S..
“We’ll know very fast if we’re seeing the same survival benefit in a randomized trial,” the CEO said.
“What people are dying of is acute respiratory distress syndrome, which is the body’s immune response to the virus in the lungs, and the immune system goes haywire, and in its battle with the virus it overreacts and causes severe damage to the lungs,” he said.
The stem cell therapy is currently being reviewed by the FDA for potential approval in the treatment of children with steroid-refractory acute graft-vs.-host disease (aGVHD). The clinical data submitted with the BLA showed a survival rate of 79% compared to an expected 30% survival rate in the pediatric phase III trial in aGVHD.
Advanced Therapy Medicinal Products under investigation (n=24) (wording taken from the titles of the registered studies)
10 out of 24 products that have been employeed in clinical trials for the treatment of Covid 19 are from perinatal tissues, mostly from cord tissue.
· Aerosol inhalation of vMIP: viral macrophage inflammatory protein
· Ankylosaurus; M1 macrophages target
· Anti-2019-nCoV inactivated convalescent plasma
· Anti-SARS-CoV-2 inactivated convalescent plasma
· Biological preparation of human placenta
· Convalescent plasma treatment
· Cord blood mesenchymal stem cells
· Human menstrual blood-derived stem cells
· Immunoglobulin from cured patients
· Inactivated Mycobacterium vaccine
· Infusion of convalescent plasma
· Mesenchymal stem cells
· Mesenchymal stem cells exosomes atomization
· mRNA-1273
· NK cells
· Plasma treatment
· Recombinant cytokine gene-derived protein injection
· Regulating intestinal flora
· Therapeutic antibody from recovered novel coronavirus pneumonia patients
· Umbilical cord blood mononuclear cells
· Umbilical cord mesenchymal stem cells (hucMSCs)
· Umbilical cord Wharton’s Jelly derived mesenchymal stem cells
· Umbilical Cord(UC)-derived mesenchymal stem cells
· Washed microbiota transplantation
Carl Heneghan is the Editor in Chief BMJ EBM and Professor of EBM, Centre for Evidence-Based Medicine in the Nuffield Department of Primary Care Health Sciences, University of Oxford Oxford https://www.cebm.net/covid-19/registered-trials-and-analysis/
FDA Green-Lights Clinical Trial For COVID-19 Coronavirus Treatment That ‘Flattens The Curve’ In Patients
Celularity founder Robert Hariri
CELULARITY
Therapeutics startup Celularity announced Thursday morning that it has received FDA clearance to begin a clinical trial of a proposed stem-cell treatment for COVID-19. The approval of the New Jersey-based company’s IND application enables the company to begin a clinical trial with patients who have the disease. The company’s therapy, called CYNK-001 for now, uses “Natural Killer” (NK) cells, a form of white blood cells that wage war against cancer and viral infection, derived from placental stem cells. The company’s been developing similar treatments for several years against cancer and Crohn’s disease, several of which are being tested as well.
The idea behind the therapy is that for patients who are starting to show symptoms, or who may be at risk for a more severe form of the disease, can receive an intravenous infusion of NK cells to bolster their immune response to the virus, says founder and CEO Robert Hariri. That’s because the additional NK cells help slow down the viruses’ ability to replicate within the body. It’s an approach he likens to social distancing—slowing the spread of COVID-19 so hospitals don’t get even more overwhelmed—within patients themselves.‘’By administering our NK cells to patients, we are acting to ‘flatten the viral titer curve,’ so the patient’s adaptive immune system can get in gear and do the job of clearing the virus,” he says.Celularity was cofounded by Hariri and X Prize Foundation chair Peter Diamandis in 2016 as a spinout of pharmaceutical company Celgene. About a decade before, the company had found itself in the business of collecting and storing umbilical cord blood from placentas after birth. The undifferentiated stem cells found in that blood offer a universal way to generate NK cells that potentially reduce risk of rejection or other complications.It’s a strategy that’s earned the company support from investors like Bill Maris at Section 32, Sorrento Therapeutics, and former Apple CEO John Sculley. According to Pitchbook, the company has raised over $327 million in backing to date. The primary thrust of the company’s therapeutic efforts have been to leverage these treatments against forms of cancer such as myelomas and leukemia. But because NK cells are often involved in protecting the body against viruses, Hariri says he’s always looked to the company one day going after infectious disease.According to Hariri, it may take only a matter of days to see results from the first clinical trial of COVID-19 patients. That test will involve use of the treatment in a patient group of up to 86 people. If that’s successful, Hariri hopes those results will mean accelerating to a larger trial, and then, if all goes well, out to market.
“This is a very easy product to deploy,” says Hariri. “We’re hopeful that if we get compelling enough data, the agency and the CDC and the NIH will work with us to scale up production.”
Transplantation of ACE2- Mesenchymal Stem Cells Improves the Outcome of Patients with COVID-19 Pneumonia
Zikuan Leng1,5,#, Rongjia Zhu2,#, Wei Hou3,#, Yingmei Feng3,#, Yanlei Yang4, Qin Han2, Guangliang Shan2, Fanyan Meng1, Dongshu Du1, Shihua Wang2, Junfen Fan2, Wenjing Wang3, Luchan Deng2, Hongbo Shi3, Hongjun Li3, Zhongjie Hu3, Fengchun Zhang4, Jinming Gao4, Hongjian Liu5*, Xiaoxia Li6, Yangyang Zhao2, Kan Yin6, Xijing He7, Zhengchao Gao7, Yibin Wang7, Bo Yang8, Ronghua Jin3*, Ilia Stambler9,10,11, Lee Wei Lim9,10,12, Huanxing Su9,10,13, Alexey Moskalev9,10,14, Antonio Cano9,10,15, Sasanka Chakrabarti16, Kyung-Jin Min9,10,17, Georgina Ellison-Hughes9,10,18, Calogero Caruso9,10,19, Kunlin Jin9,10,20*, Robert Chunhua Zhao1,2,9,10* 1School of Life Sciences, Shanghai University, Shanghai, China. 2Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China. 3Beijing YouAn Hospital, Capital Medical University, Beijing, China. 4Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. 5Department of Orthopaedics, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. 6Institute of Stem Cell and Regeneration Medicine, School of Basic Medicine, Qingdao University, Shandong, China. 7Department of Orthopaedics, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China. 8Department of Neurosurgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. 9The Executive Committee on Anti-aging and Disease Prevention in the framework of Science and Technology, Pharmacology and Medicine Themes under an Interactive Atlas along the Silk Roads, UNESCO, Paris, France. 10International Society on Aging and Disease, Fort Worth, Texas, USA. 11The Geriatric Medical Center "Shmuel Harofe", Beer Yaakov, affiliated to Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel. 12School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China. 13Institute of Chinese Medical Science, University of Macau, Taipa, Macau, China. 14Institute of Biology, Komi Science Center of Russian Academy of Sciences, Syktyvkar, Russia. 15Department of Pediatrics, Obstetrics and Gynecology, University of Valencia, Valencia, Spain. 16Maharishi Markandeshwar Deemed University, Mullana-Ambala, India. 17Department of Biological Sciences, Inha University, Incheon, South Korea. 18Faculty of Life Sciences & Medicine, King's College London, London, UK. 19Department of Biomedicine, Neuroscience and Advanced Diagnostics, University of Palermo, Palermo, Italy. 20University of North Texas Health Science Center, Fort Worth, TX76107, USA.
[Received February 25, 2020; Revised February 28, 2020; Accepted February 28, 2020] Aging and Disease Vol 11,N02; 216-228
ABSTRACT: A coronavirus (HCoV-19) has caused the novel coronavirus disease (COVID-19) outbreak in Wuhan, China. Preventing and reversing the cytokine storm may be the key to save the patients with severe COVID-19 pneumonia. Mesenchymal stem cells (MSCs) have been shown to possess a comprehensive powerful immunomodulatory function. This study aims to investigate whether MSC transplantation improves the outcome of 7 enrolled patients with COVID-19 pneumonia in Beijing YouAn Hospital, China, from Jan 23, 2020 to Feb 16, 2020. The clinical outcomes, as well as changes of inflammatory and immune function levels and adverse effects of 7 enrolled patients were assessed for 14 days after MSC injection. MSCs could cure or significantly improve the functional outcomes of seven patients without observed adverse effects. The pulmonary function and symptoms of these seven patients were significantly improved in 2 days after MSC transplantation. Among them, two common and one severe patient were recovered and discharged in 10 days after treatment. After treatment, the peripheral lymphocytes were increased, the C-reactive protein decreased, and the overactivated cytokine-secreting immune cells CXCR3+CD4+ T cells, CXCR3+CD8+ T cells, and CXCR3+ NK cells disappeared in 3-6 days. In addition, a group of CD14+CD11c+CD11bmid regulatory DC cell population dramatically increased. Meanwhile, the level of TNF-α was significantly decreased, while IL-10 increased in MSC treatment group compared to the placebo control group. Furthermore, the gene expression profile showed MSCs were ACE2- and TMPRSS2- which indicated MSCs are free from COVID-19 infection. Thus, the intravenous transplantation of MSCs was safe and effective for treatment in patients with COVID-19 pneumonia, especially for the patients in critically severe condition.
Key words: COVID-19, ACE2 negative, mesenchymal stem cells, cell transplantation, immunomodulation, function recovery
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