CAR T-Cell Immunotherapy for ALL – National Cancer Institute

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For years, the cornerstones of cancer treatment have been surgery, chemotherapy, and radiation therapy. Over the last decade, targeted therapies like imatinib (Gleevec) and trastuzumab (Herceptin)drugs that target cancer cells by homing in on specific molecular changes seen primarily in those cellshave also emerged as standard treatments for a number of cancers.

Illustration of the components of second- and third-generation chimeric antigen receptor T cells. (Adapted by permission from the American Association for Cancer Research: Lee, DW et al. The Future Is Now: Chimeric Antigen Receptors as New Targeted Therapies for Childhood Cancer. Clin Cancer Res; 2012;18(10); 278090. doi:10.1158/1078-0432.CCR-11-1920)

And now, despite years of starts and stutter steps, excitement is growing for immunotherapytherapies that harness the power of a patients immune system to combat their disease, or what some in the research community are calling the fifth pillar of cancer treatment.

One approach to immunotherapy involves engineering patients own immune cells to recognize and attack their tumors. And although this approach, called adoptive cell transfer (ACT), has been restricted to small clinical trials so far, treatments using these engineered immune cells have generated some remarkable responses in patients with advanced cancer.

For example, in several early-stage trials testing ACT in patients with advanced acute lymphoblastic leukemia (ALL) who had few if any remaining treatment options, many patients cancers have disappeared entirely. Several of these patients have remained cancer free for extended periods.

Equally promising results have been reported in several small trials involving patients with lymphoma.

These are small clinical trials, their lead investigators cautioned, and much more research is needed.

But the results from the trials performed thus far are proof of principle that we can successfully alter patients T cells so that they attack their cancer cells, said one of the trial's leaders, Renier J. Brentjens, M.D., Ph.D., of Memorial Sloan Kettering Cancer Center (MSKCC) in New York.

Adoptive cell transfer is like giving patients a living drug, continued Dr. Brentjens.

Thats because ACTs building blocks are T cells, a type of immune cell collected from the patients own blood. After collection, the T cells are genetically engineered to produce special receptors on their surface called chimeric antigen receptors (CARs). CARs are proteins that allow the T cells to recognize a specific protein (antigen) on tumor cells. These engineered CAR T cells are then grown in the laboratory until they number in the billions.

The expanded population of CAR T cells is then infused into the patient. After the infusion, if all goes as planned, the T cells multiply in the patients body and, with guidance from their engineered receptor, recognize and kill cancer cells that harbor the antigen on their surfaces.

Although adoptive cell transfer has been restricted to small clinical trials so far, treatments using these engineered immune cells have generated some remarkable responses in patients with advanced cancer.

This process builds on a similar form of ACT pioneered by Steven Rosenberg, M.D., Ph.D., and his colleagues from NCIs Surgery Branch for patients with advanced melanoma.

The CAR T cells are much more potent than anything we can achieve with other immune-based treatments being studied, said Crystal Mackall, M.D., of NCIs Pediatric Oncology Branch (POB).

Even so, investigators working in this field caution that there is still much to learn about CAR T-cell therapy. But the early results from trials like these have generated considerable optimism.

CAR T-cell therapy eventually may become a standard therapy for some B-cell malignancies like ALL and chronic lymphocytic leukemia, Dr. Rosenberg wrote in a Nature Reviews Clinical Oncology article.

More than 80 percent of children who are diagnosed with ALL that arises in B cellsthe predominant type of pediatric ALLwill be cured by intensive chemotherapy.

For patients whose cancers return after intensive chemotherapy or a stem cell transplant, the remaining treatment options are close to none, said Stephan Grupp, M.D., Ph.D., of the Childrens Hospital of Philadelphia (CHOP) and the lead investigator of a trial testing CAR T cells primarily in children with ALL. This treatment may represent a much-needed new option for such patients, he said.

Trials of CAR T cells in adults and children with leukemia and lymphoma have used T cells engineered to target the CD19 antigen, which is present on the surface of nearly all B cells, both normal and cancerous.

In the CHOP trial, which is being conducted in collaboration with researchers from the University of Pennsylvania, all signs of cancer disappeared (a complete response) in 27 of the 30 patients treated in the study, according to findings published October 16 in the New England Journal of Medicine.

Nineteen of the 27 patients with complete responses have remained in remission, the study authors reported, with 15 of these patients receiving no further therapy and 4 patients withdrawing from the trial to receive other therapy.

According to the most recent data from a POB trial that included children with ALL, 14 of 20 patients had a complete response. And of the 12 patients who had no evidence of leukemic cells, called blasts, in their bone marrow after CAR T-cell treatment, 10 have gone on to receive a stem cell transplant and remain cancer free, reported the studys lead investigator, Daniel W. Lee, M.D., also of the POB.

Dr. Crystal Mackall

Our findings strongly suggest that CAR T-cell therapy is a useful bridge to bone marrow transplant for patients who are no longer responding to chemotherapy, Dr. Lee said.

Similar results have been seen in phase I trials of adult patients conducted at MSKCC and NCI.

In findings published in February 2014, 14 of the 16 participants in the MSKCC trial treated to that point had experienced complete responses, which in some cases occurred 2 weeks or sooner after treatment began. Of those patients who were eligible, 7 underwent a stem cell transplant and are still cancer free.

The NCI-led trial of CAR T cells included 15 adult patients, the majority of whom had advanced diffuse large B-cell lymphoma. Most patients in the trial had either complete or partial responses, reported James Kochenderfer, M.D., and his NCI colleagues.

Our data provide the first true glimpse of the potential of this approach in patients with aggressive lymphomas that, until this point, were virtually untreatable, Dr. Kochenderfer said. [NCI Surgery Branch researchers have also reported promising results from one of the first trials testing CAR T cells derived from donors, rather than the patients themselves, to treat leukemia and lymphoma.]

Other findings from the trials have been encouraging, as well. For example, the number of CAR T cells increased dramatically after infusion into patients, as much as 1,000-fold in some individuals. In addition, after infusion, CAR T cells were detected in the central nervous system, a so-called sanctuary site where solitary cancer cells that have evaded chemotherapy or radiation may hide. In two patients in the NCI pediatric trial, the CAR T-cell treatment eradicated cancer that had spread to the central nervous system.

If CAR T cells can persist at these sites, it could help fend off relapses, Dr. Mackall noted.

CAR T-cell therapy can cause several worrisome side effects, perhaps the most troublesome being cytokine-release syndrome.

The infused T cells release cytokines, which are chemical messengers that help the T cells carry out their duties. With cytokine-release syndrome, there is a rapid and massive release of cytokines into the bloodstream, which can lead to dangerously high fevers and precipitous drops in blood pressure.

Cytokine-release syndrome is a common problem in patients treated with CAR T cells. In the POB and CHOP trials, patients with the most extensive disease prior to receiving the CAR T cells were more likely to experience severe cases of cytokine-release syndrome.

For most patients, trial investigators have reported, the side effects are mild enough that they can be managed with standard supportive therapies, including steroids.

The research team at CHOP noticed that patients experiencing severe reactions all had particularly high levels of IL-6, a cytokine that is secreted by T cells and macrophages in response to inflammation. So they turned to two drugs that are approved to treat inflammatory conditions like juvenile arthritis: etanercept (Enbrel) and tocilizumab (Actemra), the latter of which blocks IL-6 activity.

The patients had excellent responses to the treatment, Dr. Grupp said. We believe that [these drugs] will be a major part of toxicity management for these patients.

The other two teams subsequently used tocilizumab in several patients. Dr. Brentjens agreed that both drugs could become a useful way to help manage cytokine-release syndrome because, unlike steroids, they dont appear to affect the infused CAR T cells activity or proliferation.

Even with these encouraging preliminary findings, more research is needed before CAR T-cell therapy becomes a routine option for patients with ALL.

We need to treat more patients and have longer follow-up to really say what the impact of this therapy is [and] to understand its true performance characteristics, Dr. Grupp said.

We need to treat more patients and have longer follow-up to really say what the impact of this therapy is [and] to understand its true performance characteristics.

Dr. Stephan Grupp

Several other trials testing CAR T cells in children and adults are ongoing and, with greater interest and involvement from the pharmaceutical and biotechnology sector, more trials testing CAR T cells are being planned.

Researchers are also studying ways to improve on the positive results obtained to date, including refining the process by which the CAR T cells are produced.

Research groups like Dr. Brentjens are also working to make a superior CAR T cell, including developing a better receptor and identifying better targets.

For example, Dr. Lee and his colleagues at NCI have developed CAR T cells that target the CD22 antigen, which is also present on most B cells, although in smaller quantities than CD19. The CD22-targeted T cells, he believes, could be used in concert with CD19-targeted T cells as a one-two punch in ALL and other B-cell cancers. NCI researchers hope to begin the first clinical trial testing the CD22-targeted CAR T cells in November 2014.

Based on the success thus far, several research groups across the country are turning their attention to developing engineered T cells for other cancers, including solid tumorslike pancreatic and brain cancers.

The stage has now been set for greater progress, Dr. Lee believes.

NCI investigators, for example, now have a platform to plug and play better CARs into that system, without a lot of additional R&D time, he continued. Everything else should now come more rapidly.

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CAR T-Cell Immunotherapy for ALL - National Cancer Institute

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Stem-cell therapy – Wikipedia, the free encyclopedia

This article is about the medical therapy. For the cell type, see Stem cell.

Stem-cell therapy is the use of stem cells to treat or prevent a disease or condition.

Bone marrow transplant is the most widely used stem-cell therapy, but some therapies derived from umbilical cord blood are also in use. Research is underway to develop various sources for stem cells, and to apply stem-cell treatments for neurodegenerative diseases and conditions, diabetes, heart disease, and other conditions.

With the ability of scientists to isolate and culture embryonic stem cells, and with scientists' growing ability to create stem cells using somatic cell nuclear transfer and techniques to create induced pluripotent stem cells, controversy has crept in, both related to abortion politics and to human cloning. Additionally, efforts to market treatments based on transplant of stored umbilical cord blood have been controversial.

For over 30 years, bone marrow has been used to treat cancer patients with conditions such as leukaemia and lymphoma; this is the only form of stem-cell therapy that is widely practiced.[1][2][3] During chemotherapy, most growing cells are killed by the cytotoxic agents. These agents, however, cannot discriminate between the leukaemia or neoplastic cells, and the hematopoietic stem cells within the bone marrow. It is this side effect of conventional chemotherapy strategies that the stem-cell transplant attempts to reverse; a donor's healthy bone marrow reintroduces functional stem cells to replace the cells lost in the host's body during treatment. The transplanted cells also generate an immune response that helps to kill off the cancer cells; this process can go too far, however, leading to graft vs host disease, the most serious side effect of this treatment.[4]

Another stem-cell therapy called Prochymal, was conditionally approved in Canada in 2012 for the management of acute graft-vs-host disease in children who are unresponsive to steroids.[5] It is an allogenic stem therapy based on mesenchymal stem cells (MSCs) derived from the bone marrow of adult donors. MSCs are purified from the marrow, cultured and packaged, with up to 10,000 doses derived from a single donor. The doses are stored frozen until needed.[6]

The FDA has approved five hematopoietic stem-cell products derived from umbilical cord blood, for the treatment of blood and immunological diseases.[7]

In 2014, the European Medicines Agency recommended approval of Holoclar, a treatment involving stem cells, for use in the European Union. Holoclar is used for people with severe limbal stem cell deficiency due to burns in the eye.[8]

Research has been conducted to learn whether stem cells may be used to treat brain degeneration, such as in Parkinson's, Amyotrophic lateral sclerosis, and Alzheimer's disease.[9][10][11]

Healthy adult brains contain neural stem cells which divide to maintain general stem-cell numbers, or become progenitor cells. In healthy adult animals, progenitor cells migrate within the brain and function primarily to maintain neuron populations for olfaction (the sense of smell). Pharmacological activation of endogenous neural stem cells has been reported to induce neuroprotection and behavioral recovery in adult rat models of neurological disorder.[12][13][14]

Stroke and traumatic brain injury lead to cell death, characterized by a loss of neurons and oligodendrocytes within the brain. A small clinical trial was underway in Scotland in 2013, in which stem cells were injected into the brains of stroke patients.[15]

Clinical and animal studies have been conducted into the use of stem cells in cases of spinal cord injury.[16][17][18]

The pioneering work[19] by Bodo-Eckehard Strauer has now been discredited by the identification of hundreds of factual contradictions.[20] Among several clinical trials that have reported that adult stem-cell therapy is safe and effective, powerful effects have been reported from only a few laboratories, but this has covered old[21] and recent[22] infarcts as well as heart failure not arising from myocardial infarction.[23] While initial animal studies demonstrated remarkable therapeutic effects,[24][25] later clinical trials achieved only modest, though statistically significant, improvements.[26][27] Possible reasons for this discrepancy are patient age,[28] timing of treatment[29] and the recent occurrence of a myocardial infarction.[30] It appears that these obstacles may be overcome by additional treatments which increase the effectiveness of the treatment[31] or by optimizing the methodology although these too can be controversial. Current studies vary greatly in cell-procuring techniques, cell types, cell-administration timing and procedures, and studied parameters, making it very difficult to make comparisons. Comparative studies are therefore currently needed.

Stem-cell therapy for treatment of myocardial infarction usually makes use of autologous bone-marrow stem cells (a specific type or all), however other types of adult stem cells may be used, such as adipose-derived stem cells.[32] Adult stem cell therapy for treating heart disease was commercially available in at least five continents as of 2007.[citation needed]

Possible mechanisms of recovery include:[9]

It may be possible to have adult bone-marrow cells differentiate into heart muscle cells.[9]

The first successful integration of human embryonic stem cell derived cardiomyocytes in guinea pigs (mouse hearts beat too fast) was reported in August 2012. The contraction strength was measured four weeks after the guinea pigs underwent simulated heart attacks and cell treatment. The cells contracted synchronously with the existing cells, but it is unknown if the positive results were produced mainly from paracrine as opposed to direct electromechanical effects from the human cells. Future work will focus on how to get the cells to engraft more strongly around the scar tissue. Whether treatments from embryonic or adult bone marrow stem cells will prove more effective remains to be seen.[33]

In 2013 the pioneering reports of powerful beneficial effects of autologous bone marrow stem cells on ventricular function were found to contain "hundreds" of discrepancies.[34] Critics report that of 48 reports there seemed to be just five underlying trials, and that in many cases whether they were randomized or merely observational accepter-versus-rejecter, was contradictory between reports of the same trial. One pair of reports of identical baseline characteristics and final results, was presented in two publications as, respectively, a 578 patient randomized trial and as a 391 patient observational study. Other reports required (impossible) negative standard deviations in subsets of patients, or contained fractional patients, negative NYHA classes. Overall there were many more patients published as having receiving stem cells in trials, than the number of stem cells processed in the hospital's laboratory during that time. A university investigation, closed in 2012 without reporting, was reopened in July 2013.[35]

One of the most promising benefits of stem cell therapy is the potential for cardiac tissue regeneration to reverse the tissue loss underlying the development of heart failure after cardiac injury.[36]

Initially, the observed improvements were attributed to a transdifferentiation of BM-MSCs into cardiomyocyte-like cells.[24] Given the apparent inadequacy of unmodified stem cells for heart tissue regeneration, a more promising modern technique involves treating these cells to create cardiac progenitor cells before implantation to the injured area.[37]

The specificity of the human immune-cell repertoire is what allows the human body to defend itself from rapidly adapting antigens. However, the immune system is vulnerable to degradation upon the pathogenesis of disease, and because of the critical role that it plays in overall defense, its degradation is often fatal to the organism as a whole. Diseases of hematopoietic cells are diagnosed and classified via a subspecialty of pathology known as hematopathology. The specificity of the immune cells is what allows recognition of foreign antigens, causing further challenges in the treatment of immune disease. Identical matches between donor and recipient must be made for successful transplantation treatments, but matches are uncommon, even between first-degree relatives. Research using both hematopoietic adult stem cells and embryonic stem cells has provided insight into the possible mechanisms and methods of treatment for many of these ailments.[citation needed]

Fully mature human red blood cells may be generated ex vivo by hematopoietic stem cells (HSCs), which are precursors of red blood cells. In this process, HSCs are grown together with stromal cells, creating an environment that mimics the conditions of bone marrow, the natural site of red-blood-cell growth. Erythropoietin, a growth factor, is added, coaxing the stem cells to complete terminal differentiation into red blood cells.[38] Further research into this technique should have potential benefits to gene therapy, blood transfusion, and topical medicine.

Hair follicles also contain stem cells, and some researchers predict these follicle stem cells may lead to successes in treating baldness through activation of progenitor stem cells. This treatment is expected to work by activating already existing stem cells on the scalp. Later treatments may be able to simply signal follicle stem cells to give off chemical signals to nearby follicle cells which have shrunk during the aging process, which in turn respond to these signals by regenerating and once again making healthy hair.

In 2004, scientists at King's College London discovered a way to cultivate a complete tooth in mice[39] and were able to grow bioengineered teeth stand-alone in the laboratory. Researchers are confident that the tooth regeneration technology can be used to grow live teeth in human patients.

In theory, stem cells taken from the patient could be coaxed in the lab turning into a tooth bud which, when implanted in the gums, will give rise to a new tooth, and would be expected to be grown in a time over three weeks.[40] It will fuse with the jawbone and release chemicals that encourage nerves and blood vessels to connect with it. The process is similar to what happens when humans grow their original adult teeth. Many challenges remain, however, before stem cells could be a choice for the replacement of missing teeth in the future.[41][42]

Research is ongoing in different fields, alligators which are polyphyodonts grow up to 50 times a successional tooth (a small replacement tooth) under each mature functional tooth for replacement once a year.[43]

Heller has reported success in re-growing cochlea hair cells with the use of embryonic stem cells.[44]

Since 2003, researchers have successfully transplanted corneal stem cells into damaged eyes to restore vision. "Sheets of retinal cells used by the team are harvested from aborted fetuses, which some people find objectionable." When these sheets are transplanted over the damaged cornea, the stem cells stimulate renewed repair, eventually restore vision.[45] The latest such development was in June 2005, when researchers at the Queen Victoria Hospital of Sussex, England were able to restore the sight of forty patients using the same technique. The group, led by Sheraz Daya, was able to successfully use adult stem cells obtained from the patient, a relative, or even a cadaver. Further rounds of trials are ongoing.[46]

In April 2005, doctors in the UK transplanted corneal stem cells from an organ donor to the cornea of Deborah Catlyn, a woman who was blinded in one eye when acid was thrown in her eye at a nightclub. The cornea, which is the transparent window of the eye, is a particularly suitable site for transplants. In fact, the first successful human transplant was a cornea transplant. The absence of blood vessels within the cornea makes this area a relatively easy target for transplantation. The majority of corneal transplants carried out today are due to a degenerative disease called keratoconus.

The University Hospital of New Jersey reports that the success rate for growth of new cells from transplanted stem cells varies from 25 percent to 70 percent.[47]

In 2014, researchers demonstrated that stem cells collected as biopsies from donor human corneas can prevent scar formation without provoking a rejection response in mice with corneal damage.[48]

In January 2012, The Lancet published a paper by Steven Schwartz, at UCLA's Jules Stein Eye Institute, reporting two women who had gone legally blind from macular degeneration had dramatic improvements in their vision after retinal injections of human embryonic stem cells.[49]

In June 2015, the Stem Cell Ophthalmology Treatment Study (SCOTS), the largest adult stem cell study in ophthalmology ( http://www.clinicaltrials.gov NCT # 01920867) published initial results on a patient with optic nerve disease who improved from 20/2000 to 20/40 following treatment with bone marrow derived stem cells.[50]

Diabetes patients lose the function of insulin-producing beta cells within the pancreas.[51] In recent experiments, scientists have been able to coax embryonic stem cell to turn into beta cells in the lab. In theory if the beta cell is transplanted successfully, they will be able to replace malfunctioning ones in a diabetic patient.[52]

Human embryonic stem cells may be grown in cell culture and stimulated to form insulin-producing cells that can be transplanted into the patient.

However, clinical success is highly dependent on the development of the following procedures:[9]

Clinical case reports in the treatment orthopaedic conditions have been reported. To date, the focus in the literature for musculoskeletal care appears to be on mesenchymal stem cells. Centeno et al. have published MRI evidence of increased cartilage and meniscus volume in individual human subjects.[53][54] The results of trials that include a large number of subjects, are yet to be published. However, a published safety study conducted in a group of 227 patients over a 3-4-year period shows adequate safety and minimal complications associated with mesenchymal cell transplantation.[55]

Wakitani has also published a small case series of nine defects in five knees involving surgical transplantation of mesenchymal stem cells with coverage of the treated chondral defects.[56]

Stem cells can also be used to stimulate the growth of human tissues. In an adult, wounded tissue is most often replaced by scar tissue, which is characterized in the skin by disorganized collagen structure, loss of hair follicles and irregular vascular structure. In the case of wounded fetal tissue, however, wounded tissue is replaced with normal tissue through the activity of stem cells.[57] A possible method for tissue regeneration in adults is to place adult stem cell "seeds" inside a tissue bed "soil" in a wound bed and allow the stem cells to stimulate differentiation in the tissue bed cells. This method elicits a regenerative response more similar to fetal wound-healing than adult scar tissue formation.[57] Researchers are still investigating different aspects of the "soil" tissue that are conducive to regeneration.[57]

Culture of human embryonic stem cells in mitotically inactivated porcine ovarian fibroblasts (POF) causes differentiation into germ cells (precursor cells of oocytes and spermatozoa), as evidenced by gene expression analysis.[58]

Human embryonic stem cells have been stimulated to form Spermatozoon-like cells, yet still slightly damaged or malformed.[59] It could potentially treat azoospermia.

In 2012, oogonial stem cells were isolated from adult mouse and human ovaries and demonstrated to be capable of forming mature oocytes.[60] These cells have the potential to treat infertility.

Destruction of the immune system by the HIV is driven by the loss of CD4+ T cells in the peripheral blood and lymphoid tissues. Viral entry into CD4+ cells is mediated by the interaction with a cellular chemokine receptor, the most common of which are CCR5 and CXCR4.1 Because subsequent viral replication requires cellular gene expression processes, activated CD4+ cells are the primary targets of productive HIV infection.[61] Recently scientists have been investigating an alternative approach to treating HIV-1/AIDS, based on the creation of a disease-resistant immune system through transplantation of autologous, gene-modified (HIV-1-resistant) hematopoietic stem and progenitor cells (GM-HSPC).[62]

On 23 January 2009, the US Food and Drug Administration gave clearance to Geron Corporation for the initiation of the first clinical trial of an embryonic stem-cell-based therapy on humans. The trial aimed evaluate the drug GRNOPC1, embryonic stem cell-derived oligodendrocyte progenitor cells, on patients with acute spinal cord injury. The trial was discontinued in November 2011 so that the company could focus on therapies in the "current environment of capital scarcity and uncertain economic conditions".[63] In 2013 biotechnology and regenerative medicine company BioTime (NYSEMKT:BTX) acquired Geron's stem cell assets in a stock transaction, with the aim of restarting the clinical trial.[64]

Scientists have reported that MSCs when transfused immediately within few hours post thawing may show reduced function or show decreased efficacy in treating diseases as compared to those MSCs which are in log phase of cell growth(fresh), so cryopreserved MSCs should be brought back into log phase of cell growth in invitro culture before these are administered for clinical trials or experimental therapies, re-culturing of MSCs will help in recovering from the shock the cells get during freezing and thawing. Various clinical trials on MSCs have failed which used cryopreserved product immediately post thaw as compared to those clinical trials which used fresh MSCs.[65]

There is widespread controversy over the use of human embryonic stem cells. This controversy primarily targets the techniques used to derive new embryonic stem cell lines, which often requires the destruction of the blastocyst. Opposition to the use of human embryonic stem cells in research is often based on philosophical, moral or religious objections.[104] There is other stem cell research that does not involve the destruction of a human embryo, and such research involves adult stem cells, amniotic stem cells and induced pluripotent stem cells.

Stem-cell research and treatment was practiced in the People's Republic of China. The Ministry of Health of the People's Republic of China has permitted the use of stem-cell therapy for conditions beyond those approved of in Western countries. The Western World has scrutinized China for its failed attempts to meet international documentation standards of these trials and procedures.[105]

State-funded companies based in the Shenzhen Hi-Tech Industrial Zone treat the symptoms of numerous disorders with adult stem-cell therapy. Development companies are currently focused on the treatment of neurodegenerative and cardiovascular disorders. The most radical successes of Chinese adult stem cell therapy have been in treating the brain. These therapies administer stem cells directly to the brain of patients with cerebral palsy, Alzheimer's, and brain injuries.[citation needed]

Since 2008 many centres and doctors tried a diversity of methods; in Lebanon proliferative and non-proliferative, in-vivo and in-vitro techniques were used. The regenerative medicine also took place in Jordan and Egypt.[citation needed]

Stem-cell treatment is currently being practiced at a clinical level in Mexico. An International Health Department Permit (COFEPRIS) is required. Authorized centers are found in Tijuana, Guadalajara and Cancun. Currently undergoing the approval process is Los Cabos. This permit allows the use of stem cell.[citation needed]

In 2005, South Korean scientists claimed to have generated stem cells that were tailored to match the recipient. Each of the 11 new stem cell lines was developed using somatic cell nuclear transfer (SCNT) technology. The resultant cells were thought to match the genetic material of the recipient, thus suggesting minimal to no cell rejection.[106]

As of 2013, Thailand still considers Hematopoietic stem cell transplants as experimental. Kampon Sriwatanakul began with a clinical trial in October 2013 with 20 patients. 10 are going to receive stem-cell therapy for Type-2 diabetes and the other 10 will receive stem-cell therapy for emphysema. Chotinantakul's research is on Hematopoietic cells and their role for the hematopoietic system function in homeostasis and immune response.[107]

Today, Ukraine is permitted to perform clinical trials of stem-cell treatments (Order of the MH of Ukraine 630 "About carrying out clinical trials of stem cells", 2008) for the treatment of these pathologies: pancreatic necrosis, cirrhosis, hepatitis, burn disease, diabetes, multiple sclerosis, critical lower limb ischemia. The first medical institution granted the right to conduct clinical trials became the "Institute of Cell Therapy"(Kiev).

Other countries where doctors did stem cells research, trials, manipulation, storage, therapy: Brazil, Cyprus, Germany, Italy, Israel, Japan, Pakistan, Philippines, Russia, Switzerland, Turkey, United Kingdom, India and many others.

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