Stem Cell Clinic

Naturally Treat & Heal The Cause of Pain with Regenerative Therapies – The Mountaineer

By Dr. John C. Haasis III, M.D

Daisy Stem Cell Therapy

Your body is an amazing feat of engineering. Many complex physical, chemical, and neurological processes all work together to make you who you are. Too much medicine today focuses on treating a symptom rather than solving a problem. Regenerative therapies are a spectrum of cutting edge therapeutic techniques used to naturally treat and heal the cause of a painful condition rather than masking the symptom. Therapies such as the ones listed below stimulate and accelerate your own bodys natural ability to heal itself.

Stem Cells

Stem cells are undifferentiated cells, which allow them to develop into another type of cell that is required to repair or replace damaged tissue. Stem cell therapy can repair tissues that are too damaged to heal on their own. Stem cells can stimulate the formation of cartilage, tendon, ligaments, bone and fibrous connective tissues.

Allograft Tissues

A purified amniotic source that contains a healing matrix of cytokines, growth factors, and proteins that helps to rejuvenate and heal damaged tissue can be used via injection.

Exosomes

Exosomes are extracellular vesicles which can be used alone or in combination with stem cell therapy to speed up healing. Exosome therapy can be injected into the affected area for orthopedic injuries, used in aesthetic procedures for cosmetic enhancement or given intravenously for anti-aging.

Platelets

Platelet rich plasm (PRP) therapy utilizes platelets taken from the patients own blood to rebuild damaged tendons and cartilage. Platelets normally circulated within the blood stream and are responsible for blood clotting and initiating a healing response in an acute injury. Many acute injuries do not heal adequately and can lead to chronic pain and loss of function of the injured area. Platelet rich plasma (PRP) therapy allows us to harvest the patients own platelets and re-inject those platelets into sites of injury to initiate healing and improvement of function.

Technology

All procedures are performed under the guidance of ultrasound or a fluoroscopy unit to maximize results. We have incorporated the latest innovations in equipment, supplies, and protocols to optimize outcomes. In addition, we have partnered with leaders in the field, with proven track records, to provide the very best stem therapy products to our patients.

Dr. John C. Haasis III, M.D., is Medical Director and Founder of Daisy Stem Cell Therapy and Advanced Regenerative Medicine Centers of the Carolinas. With over 25 years of comprehensive and interventional pain management experience, Dr. Haasis has treated thousands of patients in our region.

Dr. Haasis received his undergraduate degree in Biology from Pennsylvania State University was accepted into a Ph.D. program at Temple University where he studied molecular biology. He received his medical degree from the Medical College of Pennsylvania in 1992, followed by Anesthesia and Pain management training at Duke University Medical Center. He currently enjoys a thriving practice with six office locations in NC and SC. Over the years, he and his staff have made it their mission to help people manage their pain and improve function so that they can enjoy life again.

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Naturally Treat & Heal The Cause of Pain with Regenerative Therapies - The Mountaineer

CAR T-Cell Therapy UCARTCS1A Shows Early Activity in Relapsed/Refractory Myeloma – OncLive

Expansion and persistence of UCARTCS1A was observed and was found to correlate with clinically meaningful antimyeloma activity and serum cytokine changes in very heavily pretreated patients with multiple myeloma. Also, the CAR T-cell product was noted to be detectable in patients, regardless of donor and batch.

These preliminary data validate CS1 as a target for CAR T-cell products in multiple myeloma and that UCARTCS1A is a promising potential therapy for [those with this disease], Krina K. Patel, MD, MSc, an associate professor of the Department of Lymphoma/Myeloma, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, said during a presentation on the results.

One of the benefits that comes with utilizing an allogeneic CAR T-cell approach over an autologous approach is that it affords the opportunity for off-the-shelf product availability, according to Patel. Patients are able to avoid a prolonged wait for the CAR T cells to be manufactured; the cells are able to be administered within a couple of weeks, Patel explained. In contrast, it can take 4 to 5 weeks to bring an autologous product to a treatment center.

Scalable manufacturing is another benefit of allogeneic approaches, and this can reduce costs and yield 100 or more doses from 1 batch of donor cells. Also, for allogeneic approaches, T cells are collected from healthy donors; these patients have not been given many steroids, chemotherapy, or have undergone autologous transplant. As such, their T cells will likely be more potent, Patel explained. Lastly, more flexible dosing is an option with allogeneic approaches; this allows for the possibility of redosing and alternate schedules.

UCARTCS1A is the first allogeneic CAR T-cell product developed to target CS1 and SLAMF7, both of which are highly and consistently expressed in multiple myeloma, according to Patel. The product knocks out the TRAC gene to avoid graft-versus-host disease through disruption of T-cell receptor (TCR) assembly. The product also knocks out CS1 to facilitate robust expansion and yield, while avoiding fratricide. Lastly, UCARTCS1A has a RQR8 safety switch, which is a CD20 mimotope that can use rituximab (Rituxan) to kill the cells, if necessary.

Previously, the CAR T-cell product demonstrated durable in vivo efficacy against MM1S tumors. Here, NSG mice were given a 5 x 105 MM1S myeloma cell line, which is known to be pretty aggressive, Patel noted; this was labeled with GFP and was given for 10 days. Subsequently, the mice received the CAR T cells. Investigators observed CAR-positive cells at day 4 and M protein, which is a surrogate marker for multiple myeloma in mice and patients.

We were able to see an early response, as well. However, eventually, the T cells went down, and the myeloma started to go back up, Patel added. Looking at the imaging, mice who [received] CAR T cells obviously did much better and lived longer and there was a dose-dependent response where the mice that got the higher dose did better, with a much longer survival. Investigators were also able to demonstrate that the mice that received the CAR T-cell therapy experienced improvement in lytic lesions over time.

MELANI-01 enrolled patients with confirmed multiple myeloma per International Myeloma Working Group criteria who relapsed following previous therapy for their disease. To be eligible for enrollment, patients needed to have an ECOG performance status of 0 to 2 and acceptable organ function. They could have not previously received an investigational drug or cell/gene therapy targeting CS1.

The key eligibility [for this trial] is similar to most cell therapy trials [that are done in] myeloma. However, for most of those trials, patients are not able to have previously received CAR T cells or BCMA-directed therapies, Patel said. In this trial, [those are not] ineligibility [criteria]. Our patients had really relapsed/refractory [disease.]

After going through screening, patients received lymphodepletion chemotherapy that was comprised of fludarabine at a daily dose of 30 mg/m2 for 3 days followed by cyclophosphamide at a daily dose of 1 g/m2, also for 3 days. The [cyclophosphamide] dose was 2 to 3 times higher than what [has been] used in most other trials, Patel noted.

Patients then received treatment with UCARTCS1A. Patients were started at dose level 1, where they received 1 x 106/kg. One patient went on to dose level 2, which was 3 x 106/kg. Patients underwent their first disease evaluation at day 28.

The primary and secondary objectives of the study included safety and tolerability of UCARTCS1A, as well as determining the maximum-tolerated dose and efficacy of the product. Exploratory end points are examining expression of CS1 on multiple myeloma cells, UCARTCS1A expansion and persistence, and changes in serum biomarkers or immune cell reconstitution.

Patel shared information on 5 patients who received treatment with UCARTCS1A to date; 4 of the patients received dose level 1 (102-101, 102-109, 102-107, and 102-111) and 1 patient (102-113) received dose level 2.

Four of the 5 patients (102-101, 102-109, 102-107, and 102-113) had previously received over 11 lines of therapy and had most had previously received a BCMA-directed therapy. Just to put this into context, most of the autologous CAR T-cell trials that are done have patients who had a median of 5 to 6 prior lines of treatment, Patel noted.

One patient (102-111) had received only 4 prior lines of therapy and was the only patient who had cells expand and responded on dose level 1. However, the patient had very high-risk disease with 90% plasma cells. He had the most myeloma going into the trial, Patel said.

Notably, patient 102-113 who had received dose level 2 and also experienced an expansion of cells at day 7 had received 13 prior lines of therapy, including 2 prior BCMA-targeted CAR T-cell therapies, the last of which was administered just 5 months prior to the study.

Patient 102-111 was 55 years of age, had 4 prior lines of therapy and 90% of bone marrow involvement. He had relapsed within 6 months of every prior line of therapy and he never experienced more than a partial response (PR) to any of his prior treatments, according to Patel. When looking at his peripheral blood at day 28, investigators noted that the CD45+ CAR-positive lymphocytes was almost 72% and a subgroup of CD8+ effector cells that are TCRnegative CAR-positive cells, were about 46%.

[Some might] think that allogenic cells would not last very long, but for this patient, we definitely saw the majority of T cells still there that were CAR positive, Patel said. For him, we were able to get a bone marrow [sample] at month 3, where we could also see CD45+ CAR-positive cells at 60% in the bone marrow of all CD45+ cells. The CD8+ effector [cells] were at 92%.

Moreover, CAR-positive cells were observed in the patients peripheral blood starting at day 14; they peaked at day 21, and then started to decrease. However, some of these cells were still observed at day 80 to 86, according to Patel. The patients white blood cell count was low, while peripheral blood was high, until approximately day 28, before it started decreasing. However, the patients bone marrow remained high, even at day 77, in terms of the vector copy number of the CAR T cells.

This patient experienced grade 2 cytokine release syndrome (CRS) within the first week of cell infusion. The patient also developed hemophagocytic lymphohistiocytosis (HLH), which has previously been observed with other autologous CAR T-cell products in multiple myeloma. Investigators treated the patients with anakinra (Kineret), dexamethasone, etoposide, and the rituximab kill switch. The rationale for triggering the kill switch was because the patient had reactivation of HHV6, which developed into HHV6 encephalitis.

Per the FDA, we were monitoring HHV6 and HHV7 levels, as we do for most of our CAR T-cell therapy trials. We were monitoring this [and when his levels were high enough that we decided to treat], the patient got admitted for antivirals, improved, went home, and then came back with an encephalitis picture. Initially, we treated him dexamethasone and gave the rituximab kill switch thinking that if it was immune effector cell-associated neurotoxicity, we could kill off some of the cells. But in the end, it was HHV6 encephalitis.

Although the patient did improve, and he had double antiviral coverage, he eventually passed away on day 109 from organizing pneumonia in the context of prolonged lymphopenia in the absence of multiple myeloma progression.

At the time, he did not have any myeloma and he had [experienced] this response that he had never had before, a near complete response Patel explained. We looked at his bone marrow, which was minimal residual diseasenegative at the 10-5 level. However, because of the prolonged lymphopenia, he ended up with this infection.

Multiple factors may have contributed to the prolonged lymphopenia, including viral reactivation, concomitant antivirals, and recent prior stem cell transplant, Patel explained.

The other patient with expansion, patient 102-113, was observed to have 25% CD45+ CAR-positive lymphocytes in the peripheral blood at day 9, 77% of which were CD8+ effector cells, according to Patel. Notably, investigators were unable to collect a bone marrow sample from the patient. In the peripheral blood, investigators observed expansion at day 7 and then a peak, and then the vector copy number persisted over the time the blood samples were obtained.

This patient had previously received 14 lines of therapy, including 2 previous BCMA-directed CAR T-cell therapies and associated lymphodepleting regimens, autologous transplant, and venetoclax (Venclexta), as his last line of therapy. The patient did not have any options left and we saw this fantastic response, where the lambda light chains had gone done by almost 90%; his M protein had at least a PR by just day 14.

However, this patient had CRS and HLH, as well. We treated him with etoposide, anakinra, dexamethasone, and the rituximab kill switch and he had improvement in his platelet and his liver function tests, Patel added. The HLH clinically improved for him. However, at day 25, he passed away.

An autopsy revealed G5 hemorrhagic pancreatitis, although he had not exhibited any clinical signs of this condition during his hospital stay. Investigators also found disseminated mucormycosis and pseudomonal pneumonia.

Select serum cytokine changes over time were found to correlate with expansion of the CAR T-cell product. Cytokines were increased much more in the patients who expanded vs those who did not expand at all, Patel noted.

MELANI-01 is currently enrolling patients with protocol modifications, including restarting at dose level -1 (3 x 105). Moreover, lower doses of lymphodepleting chemotherapy are being administered now in an attempt to address lymphopenia and lead to added expansion. The trial will also have additional requirements for monitoring and managing patients with regard to opportunistic infections, as well as CRS and HLH.

Patel KK, Bharathan M, Siegel D, et al. UCARTCS1A, an allogeneic CAR T-cell therapy targeting CS1 in patients with relapsed/refractory multiple myeloma (RRMM): preliminary translational results from a first-in-human phase I trial (MELANI-01). 2021 American Society of Gene and Cell Therapy Annual Meeting; May 11-14, 2021; Virtual. Accessed May 13, 2021. Abstract 118.

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CAR T-Cell Therapy UCARTCS1A Shows Early Activity in Relapsed/Refractory Myeloma - OncLive

Rinri Therapeutics Secures Innovate UK Funding Grant for 3.2m Project to Advance its Novel Cell-Based Therapy to Restore Hearing Loss – PRNewswire

SHEFFIELD, England, May 13, 2021 /PRNewswire/ -- Rinri Therapeutics ('Rinri'), a biotechnology company developing a novel cell-based therapy to restore hearing loss, is delighted to announce that it has secured, a grant from Innovate UK, the UK's innovation agency. This grant will fund a 3.2 million project to further develop Rinri's novel stem cell therapy to reverse sensorineural hearing loss (SNHL) an area / a condition where there remains a significant global unmet need.

The project will be led by Rinri in collaboration with the Cell and Gene Therapy Catapult (CGTC), and the Universities of Sheffield and Nottingham.

Over the course of the project, the CGTC will help establish a process and analytical tools for clinical trial manufacture of Rinri's stem cell therapy for hearing loss, Sheffield University will further the nonclinical data package and Nottingham University will develop the necessary techniques for the first in human trial of Rinri's cell-based therapy to restore hearing loss.

Rinri's underlying technology, based on innovative stem cell research originating from the University of Sheffield, seeks to reverse SNHL by repairing the damaged cytoarchitecture in the inner ear. SNHL happens when there is damage to the hair cells in the cochlear and/or the auditory nerve. There are currently no pharmacological treatments available for SNHL despite the rapid increase in the number of patients that suffer from this condition globally.

Dr Simon Chandler, CEO of Rinri Therapeutics, commented: "We are delighted to receive this substantial grant from Innovate UK to conduct further important research into our stem cell therapy for hearing loss. We have made superb progress in refining and optimising our technology following our ground-breaking proof of concept data. This grant will be instrumental in supporting the development and initiating clinical studiesof our pioneering approach to reverse hearing loss."

Matthew Durdy, CEO of the Cell and Gene Therapy Catapult added: "Rinri's cutting-edge stem cell therapy is a very exciting development in the field, and we look forward to working with them to prepare for clinical manufacture. Combining forces under this Innovate UK funded grant will help accelerate the development of this promising technology."

Andrew Hogben, Head of Impact and Intellectual Property at the University of Sheffieldsaid: "Given Rinri was founded on pioneering research led by Professor Marcelo Rivolta at the University of Sheffield, we are really excited to participate in Rinri's Innovate UK funded project alongside Cell and Gene Therapy Catapult and Nottingham University to advance this novel treatment into the clinic."

Professor Douglas Hartley, from the School of Medicine at the University of Nottingham, said: "This significant award from Innovate UK is a substantial boost to our pioneering UK partnership that could lead to a revolution in the treatment of disabling hearing loss."

About Rinri Therapeutics

Rinri Therapeutics is a private biotechnology company developing advanced stem cell-based therapeutics to restore hearing. The company's pioneering technology seeks to reverse sensorineural hearing loss (SNHL) through the repair of the damaged cytoarchitecture in the inner ear. SNHL is estimated to affect 64 million patients in the US and 34 million in Europe. There are currently no pharmacological treatment options for SNHL patients.

Rinri, is backed by Boehringer Ingelheim Venture Fund (BIVF), UCB Ventures, BioCity, the University of Sheffield and the UK Future Fund. Rinri was founded in late-2018 and is headquartered in Sheffield, UK.

For more information, please visit: http://www.rinri-therapeutics.com

Contacts:

Rinri Therapeutics Dr Simon Chandler, CEO [emailprotected]

Citigate Dewe Rogerson Sylvie Berrebi, Frazer Hall E: [emailprotected] T: +44 (0)20 7638 9571

About Cell and Gene Therapy CatapultThe Cell and Gene Therapy Catapult was established as an independent centre of excellence to advance the growth of the UK cell and gene therapy industry, by bridging the gap between scientific research and full-scale commercialisation. With more than 330 employees focusing on cell and gene therapy technologies, it works with partners in academia and industry to ensure these life-changing therapies can be developed for use in health services throughout the world. It offers leading-edge capability, technology and innovation to enable companies to take products into clinical trials and provide clinical, process development, manufacturing, regulatory, health economics and market access expertise. Its aim is to make the UK the most compelling and logical choice for UK and international partners to develop and commercialise these advanced therapies. The Cell and Gene Therapy Catapult works with Innovate UK. For more information please visit ct.catapult.org.uk or visit http://www.gov.uk/innovate-uk.

For further information please contact

FTI Consulting for the CGT Catapult:

Michael Trace +44 (0) 203 319 5674 / [emailprotected]

George Kendrick +44 (0) 203 727 1411/ [emailprotected]

About The University of Sheffield With almost 29,000 of the brightest students from over 140 countries, learning along-side over 1,200 of the best academics from across the globe, the University of Shef-field is one of the world's leading universities. A member of the UK's prestigious Russell Group of leading research-led institutions, Sheffield offers world-class teach-ing and research excellence across a wide range of disciplines. Unified by the power of discovery and understanding, staff and students at the university are committed to finding new ways to transform the world we live in. Sheffield has six Nobel Prize win-ners among former staff and students and its alumni go on to hold positions of great responsibility and influence all over the world, making significant contributions in their chosen fields.

About The University of Nottingham The University of Nottingham is a research-intensive university with a proud heritage, consistently ranked among the world's top 100. We have a pioneering spirit, expressed in the vision of our founder Sir Jesse Boot, which has seen us lead the way in establishing campuses in China and Malaysia - part of a globally connected network of education, research and industrial engagement. We are ranked eighth for research power in the UK according to REF 2014. We have six beacons of research excellence helping to transform lives and change the world; we are also a major employer and industry partner - locally and globally. Alongside Nottingham Trent University, we lead the Universities for Nottingham initiative, a pioneering collaboration which brings together the combined strength and civic missions of Nottingham's two world-class universities and is working with local communities and partners to aid recovery and renewal following the COVID-19 pandemic.

SOURCE Rinri Therapeutics

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Rinri Therapeutics Secures Innovate UK Funding Grant for 3.2m Project to Advance its Novel Cell-Based Therapy to Restore Hearing Loss - PRNewswire

With $52 Million Series A, Appia Bio Anticipates a Bright Future in Cell Therapy – BioSpace

Appia co-founder and chief executive officer, JJ Kang/Photo Courtesy of Appia Bio

Backed by $52 million in Series A financing led by 8VC and named after a feat of engineering in ancient Rome, Appia Bio jumped into the cell therapy fray this morning with a promising scalable technology platform.

The company is named after the Aqua Appia, which is the first Roman aqueduct. It was kind of a feat of engineering and it brought water to a lot more people, and that thematically connects well. We want to engineer these cells and provide a broader reach for cell therapy through allogeneic off-the-shelf, said Appia co-founder and chief executive officer, JJ Kang, Ph.D.

Appia is developing engineered allogeneic cell therapies from hematopoietic stem cells (HSCs) for cancer patients. Its ACUA platform utilizes the biology of lymphocyte development with CAR and TCR gene engineering to produce CAR-engineered invariant natural killer T (CAR-iNKT) cells from HSCs.

The Los Angeles-based biotech is spun out of the pioneering work ofLili Yang, Ph.D., an associate professor at the University of California, Los Angeles (UCLA).

In addition to the $52 million votes of confidence provided by 8VC, Two Sigma Ventures, and seed investors, Sherpa Healthcare Partners and Freeflow Ventures, Appias newly announced scientific board is packed to the brim with wisdom.

Appia is co-founded by Nobel laureate winner and former president of theCalifornia Institute of Technology, Dr. David Baltimore. Edmund Kim, Ph.D., former VP of corporate development atKite Pharma(Gilead Sciences), comes on board as chief operating officer, while Jeff Wiezorek, MD, former head of cell therapy development at Kite and a previous student of Baltimores, joins as chief medical officer.

One of those guys, Jeff, has been a post-doc with me, so hes well-trained, quipped Baltimore.

In an exploding and crowded field, how does Appia differentiate itself?

I think in being an off-the-shelf allogeneic cell, charged and ready to go, said Baltimore. The secret here is Lili Yang, who figured out how to grow very large numbers of iNKT cells from a single harvest of hematopoietic stem cells. So we can make large numbers of cells to treat many multiples of patients from a single donor source. And we can prepare that ahead of time. So that means that no matter what their own HLA [human leukocyte antigen] is, these cells can be used therapeutically.

AQUA is also able to leverage these iNKT cells in a scaleable manner.

The big step forward with this technology is that starting from these hematopoietic stem cells, we can drive to the these invariant NKT cells that are actually naturally quite rare. Through this platform, we can produce a lot of these cells and do so in a scaleable, fullyex vivomanner that gives us a path forward for industry use for commercialization, said Kang.

Appia is now ready to power its extensive research forward into the clinic.

We have space now and we have money, we have people, said Baltimore. Were in the process of the technology transfer. The second step is to show that it will work in animal systems. Lili has done that, but we want to be able to show that we can do that. Then is the big step: Preparing ourselves for initial clinical trials. That will be a little ways down the road, but with the investments that we have now, we should be in a position to carry that step through.

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With $52 Million Series A, Appia Bio Anticipates a Bright Future in Cell Therapy - BioSpace