Making CAR T-Cell Therapy Safer The Scientist JCAR015 is not the first CAR T-cell therapy to have been associated with patient deaths. In fact, even those trials considered a success sometimes have troubling safety profiles. For example, Novartis's lead candidate, the CD19-targeting CLT019, ... |
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Making CAR T-Cell Therapy Safer - The Scientist
Patients with advanced non-Hodgkin lymphoma have limited options after treatment failure with chemotherapy or transplant.
In this video, Frederick Locke, MD, of the Moffitt Cancer Center in Tampa, Florida, discusses results of the ZUMA-1 trial, which tested chimeric antigen receptor (CAR) T-cell therapy with axicabtagene ciloleucel (axi-cel; KTE-C19) in this patient population. The treatment is given as a single infusion after conditioning chemotherapy with fludarabine and cyclophosphamide.
The multicenter clinical trial enrolled 111 patients with diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, and transformed follicular lymphoma. Nearly all (99%) were able to have axi-cel manufactured from their cells. A total of 101 patients (91%) received the CAR T-cell therapy (10 patients were unable to receive therapy after cell collection, most due to disease progression).
Locke highlights the overall and complete response rates in the trial, compares the results to previous data involving other treatments in a similar patient population, and reviews toxicities associated with CAR T-cell therapy.
The results of ZUMA-1, which showed a 6-month overall survival of 80% (compared to 55% for historical controls), were presented at the 2017 American Association for Cancer Research Annual Meeting, held April 15 in Washington, DC.
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CAR T-Cell Therapy Yields High Response Rate in Aggressive ... - Cancer Network
Patient Care Treatment
Dr. Krishna Komanduri talks with a patient in the inpatient stem cell transplant unit.
The Adult Stem Cell Transplant Program treats patients with various types of cancer and hematological diseases, including:
The program operates a pre- and post-transplant outpatient clinic as well as an inpatient unit at Sylvester Comprehensive Cancer Center/UMHCUniversity of Miami Hospital & Clinics. The 13,964-square-foot inpatient unit opened at Sylvester/UMHC in 2011 with six apheresis chairs, twelve specialized transplant beds, and seven ICU beds.
The Adult Stem Cell Transplant Program (SCTP), which treats patients from 17 to 75 years old, is led by Krishna Komanduri, M.D., who also co-leads the Tumor Immunobiology Program at Sylvester. The Adult Stem Cell Transplant Program was established in 1992 and is accredited by the Foundation for the Accreditation of Cellular Therapy (FACT). In May 2010, Sylvester opened an Outpatient Clinic designed for the unique needs of stem cell transplant patients. This outpatient treatment center has a dedicated waiting room and phlebotomy area, as well as 10 exam rooms with capability for handling infusions and transfusions required for the care of recently transplanted patients.
Before starting any type of treatment, you will meet with one of our transplant physicians and other members of our multidisciplinary transplant team to determine if a stem cell transplant is recommended for you.
To support stem cell research for cancer, Sylvester dedicated the Kalish Family Endowed Chair in Stem Cell Transplantation in 2010. The generous gift of the Kalish family will support Dr. Komanduris clinical and academic activities. Dr. Komanduris laboratory research is currently supported by grants from the National Institute of Health and the Bankhead-Coley Research Program.
The Sylvester Adult Stem Cell Transplant Program also offers opportunities to participate in clinical trials, including those developed by the Bone Marrow Transplant Clinical Trials Network, a consortium of academic stem cell transplant programs.
The National Marrow Donor Program has established recommendations regarding the appropriate timing for a stem cell transplant consultation. Visitwww.bethematch.org for more information.
Before starting any type of treatment, you will meet with one of Sylvester/UMHCs transplant physicians and other members of our multidisciplinary transplant team to determine if a transplant is recommended for you.
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Stem Cell Transplant - Treatment - Patient Care ...
National Institutes of Health (press release) | NHLBI stem cell consortium provides new insights into genetics of ... National Institutes of Health (press release) Largest, most diverse collection of stem cells of its kind could lead to improved diagnoses, treatments. |
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NHLBI stem cell consortium provides new insights into genetics of ... - National Institutes of Health (press release)
CBS New York | Stem Cell Treatment Might Reverse Symptoms Of Multiple Sclerosis ... CBS New York There's potentially exciting news for the two and a half million people around the world struggling with multiple sclerosis. |
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Stem Cell Treatment Might Reverse Symptoms Of Multiple Sclerosis ... - CBS New York
April 6, 2017 Human EPS cells (green) can be detected in both the embryonic part (left) and extra-embryonic parts (placenta and yolk sac, right) of a mouse embryo. Credit: Salk Institute
When scientists talk about laboratory stem cells being totipotent or pluripotent, they mean that the cells have the potential, like an embryo, to develop into any type of tissue in the body. What totipotent stem cells can do that pluripotent ones can't do, however, is develop into tissues that support the embryo, like the placenta. These are called extra-embryonic tissues, and are vital in development and healthy growth.
Now, scientists at the Salk Institute, in collaboration with researchers from Peking University, in China, are reporting their discovery of a chemical cocktail that enables cultured mouse and human stem cells to do just that: generate both embryonic and extra-embryonic tissues. Their technique, described in the journal Cell on April 6, 2017, could yield new insights into mammalian development that lead to better disease modeling, drug discovery and even tissue regeneration. This new technique is expected to be particularly useful for modeling early developmental processes and diseases affecting embryo implantation and placental function, possibly paving the way for improved in vitro fertilization techniques.
"During embryonic development, both the fertilized egg and its initial cells are considered totipotent, as they can give rise to all embryonic and extra-embryonic lineages. However, the capture of stem cells with such developmental potential in vitro has been a major challenge in stem cell biology," says Salk Professor Juan Carlos Izpisua Bemonte, co-senior author of the paper and holder of Salk's Roger Guillemin Chair. "This is the first study reporting the derivation of a stable stem cell type that shows totipotent-like bi-developmental potential towards both embryonic and extra-embryonic lineages."
Once a mammalian egg is fertilized and begins dividing, the new cells segregate into two groups: those that will develop into the embryo and those that will develop into supportive tissues like the placenta and amniotic sac. Because this division of labor happens relatively early, researchers often can't maintain cultured cell lines stably until cells have already passed the point where they could still become either type. The newly discovered cocktail gives stem cells the ability to stably become either type, leading the Salk team to dub them extended pluripotent stem (EPS) cells.
"The discovery of EPS cells provides a potential opportunity for developing a universal method to establish stem cells that have extended developmental potency in mammals," says Jun Wu, a senior scientist at Salk and one of the paper's first authors. "Importantly, the superior interspecies chimeric competency of EPS cells makes them especially valuable for studying development, evolution and human organ generation using a host animal species."
To develop their cocktail, the Salk team, together with the team from Peking University, first screened for chemical compounds that support pluripotency. They discovered that a simple combination of four chemicals and a growth factor could stabilize the human pluripotent stem cells at a developmentally less mature state, thereby allowing them to more efficiently contribute to chimera (a mix of cells from two different species) formation in a developing mouse embryo. They also applied the same factors to mouse cells and found, surprisingly, that the newly derived mouse stem cells could not only give rise to embryonic tissue types but also differentiate into cells from the extra-embryonic lineages. Moreover, the team found that the new mouse stem cells have a superior ability to form chimeras and a single cell could give rise to an entire adult mouse, which is unprecedented in the field, according to the team.
"The superior chimeric competency of both human and mouse EPS cells is advantageous in applications such as the generation of transgenic animal models and the production of replacement organs," adds Wu. "We are now testing to see whether human EPS cells are more efficient in chimeric contribution to pigs, whose organ size and physiology are closer to humans." Human EPS cells, combined with the interspecies blastocyst complementation platform as reported by the same Salk team in Cell in January 2017, hold great potential for the generation of human organs in pigs to meet the rising demand for donor organs.
"We believe that the derivation of a stable stem cell line with totipotent-like features will have a broad and resounding impact on the stem cell field," says Izpisua Belmonte.
Explore further: New tools to study the origin of embryonic stem cells
More information: Derivation of Pluripotent Stem Cells with InVivo Embryonic and Extraembryonic Potency, Cell (2017). DOI: dx.doi.org/10.1016/j.cell.2017.02.005 , http://www.cell.com/cell/fulltext/S0092-8674(17)30183-6
Journal reference: Cell
Provided by: Salk Institute
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Scientists expand ability of stem cells to regrow any tissue type - Phys.Org
In this photo, mouse ovarian cancer cells light up with different proteins targeted by the engineered T cells. Image by Kristin Anderson and Ingunn Stromnes / Greenberg Lab
For some patients, certain forms of immunotherapy are showing promise in treating previously difficult-to-treat cancers. In the case of T-cell therapies, though, most of the early experimental successes have been seen in blood cancers. Solid tumors, like breast, lung, ovarian and pancreatic cancers, pose a tougher nut to crack for this new wave of cancer therapies.
Fred Hutchinson Cancer Research Center immunotherapy researchers Drs. Kristin Anderson and Phil Greenberg and their colleagues are working on ways to tweak their teams early successes with T-cell therapy for leukemia to apply to solid tumors. In a presentation Tuesday at the annual meeting of the American Association of Cancer Research in Washington, D.C., Anderson described her preclinical results working toward T-cell therapy for ovarian tumors and the hurdles any clinical version of this therapy will need to overcome. To date, the therapies Anderson and her colleagues are developing have only been tested in mice and in mouse and human cells in the lab.
Developing T-cell therapy for solid tumors is more challenging than for leukemias and lymphomas, Anderson said, but many patients with these cancers are in desperate need of new treatment options. The top five cancer killers in the U.S. are all solid tumors, according to the American Cancer Society. Although ovarian cancer is less common in the U.S. than other solid cancers, its highly deadly it tends to be diagnosed at late stages, in part because it often doesnt cause obvious symptoms, and it has a high relapse rate, Anderson said.
All of these are huge problems, she said. An estimated 22,000 women in the U.S. are diagnosed per year with the disease, according to the ACS, and approximately 14,000 die of the cancer.
The challenges of T-cell therapy for cancers like ovarian cancer include the simple issue of access patients with leukemia or lymphoma can receive an infusion of engineered T cells directly into their bloodstream, but it can be more difficult to tweak the cells to traffic to a tumor tucked away in the body. Another major roadblock to adopting T-cell therapy to solid tumors is whats known as the tumor microenvironment, the local milieu of non-cancerous cells and molecules in and around the tumor.
Tumor microenvironment issues come hand-in-hand with working on solid tumors, said Anderson, who is one of 10 recipients of this years AACR Women in Cancer Research Scholar Awards, a travel award given to female early-career cancer researchers presenting at the meeting.
She and her colleagues have identified proteins overproduced by ovarian cancer cells, known as WT1 and mesothelin, and have found that T cells engineered to specifically recognize these proteins can kill both human and mouse ovarian cancer cells in the lab. Theyve also found that the T cells significantly extend survival in a mouse model of the cancer, but theres a ways to go before this therapy is ready for clinical trials in humans, Anderson said.
In her presentation, Anderson outlined three types of tumor microenvironment roadblocks to an effective ovarian cancer T-cell therapy and how the research team is working to overcome each. They are:
Immunosuppressive cells and proteins in the microenvironment that can signal the engineered T cells to shut down or ignore tumors. Existing checkpoint inhibitor drugs could circumvent this problem, Anderson said, and the Fred Hutch team is also exploring engineering the therapeutic T cells to block those immunosuppressive signals.
A death signal produced by both ovarian tumor cells and nearby blood vessels on their surfaces. This molecular signal causes T cells heading to the tumor from the bloodstream to commit suicide before they can fight the cancer. Dr. Shannon Oda in the Greenberg lab is working on a new type of fusion protein the engineered T cells will carry that will rewire their internal circuitry to instead boost their anti-tumor activity in response to the death signal.
The tumors low-sugar environment. Fast-growing ovarian cancer cells churn through the glucose in their environment the same energy source engineered T cells need to do their work. Researchers in the Greenberg lab are working to re-engineer the therapeutic T cells to process other sources of energy.
Although her current work focuses on ovarian cancer, a particularly difficult-to-treat solid tumor, Anderson hopes the work will shed light on new therapeutic avenues for other solid tumors as well.
If we can solve some of the issues that really plague us with these hard ones, then we can more readily apply [the solutions] to cancers that have fewer of these hurdles, she said.
The researchers are hoping to launch a clinical trial of the engineered T cells for patients with ovarian cancer in the next few years, Anderson said.
Paying it forward
For Anderson, the work is not just academic. Five years ago, while she was completing her doctorate research, Anderson was diagnosed with triple negative breast cancer when she was just 28. After her diagnosis, she learned she carried a mutation in the breast cancerlinked gene BRCA1, a mutation which also increases her risk for ovarian cancer.
An immunologist by training, Andersons own experience with cancer spurred her to look for research opportunities where she could one day have a direct impact on other cancer patients. She wasnt particularly looking to study breast or ovarian cancer, she said, but she was very interested in the burgeoning field of immunotherapy. It seemed a prime research area where she could use her background to make a difference.
When Anderson met with Greenberg, whos long been a leader in the field of T-cell therapy, to discuss research options for her postdoctoral fellowship, he proposed the ovarian cancer project to her. Anderson jumped at the chance.
Someone did a lot of research to come up with the drug that got rid of my cancer. Part of the reason that I wanted to go into cancer therapy was so I could pay it forward and do that for someone else, she said. It just so happened coincidentally to be [a cancer] that is close to my heart.
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T-cell Therapy for Ovarian Cancer Shows Promise | Technology ... - Technology Networks
Evotec and Sanofi have achieved preclinical proof-of-concept for a new beta cell therapy for diabetes, triggering a 3M milestone payment from Sanofi.
In 2015, Sanofi and the German CRO Evotecpartnered to jointly develop a beta cell replacement therapy for the treatment of diabetes in a deal that could reach more then 300Min potential milestone payments. Today, the first one arrived as Evotec received 3M for itsfirst preclinical success.
The new cell therapy will be based onfunctional beta cells, which are derived from human stem cells. These beta cells could not only serve as abeta cell replacement, but also ahigh-throughput drug screening platformto identify small molecules or biologicsbeneficial for beta cell activity.
Beta cells play a key role in pathogenesis of diabetes, an epidemic disease, which currently affects about 422M people worldwide.They reside within the pancreas and respond to elevated blood levels by secreting the glucose lowering hormone insulin.While in type 1 diabetes, beta cellsare destroyed by the patients own immune system, in type 2 diabetes these cells often become functionally impaired.
Given thepersistent need for new treatment opportunities and the incredible market opportunity, cell therapy for diabetes has become a popular field of research.Just recently, scientists from the Diabetes Research Institute (DRI) at the University of Miami have cured the first patient from diabetes after implantation of a bioengineered mini organ that mimics the native pancreas. The DRI Biohub is currently in Phase I/II studies.
Other companies such as British Islexa are working on reprogramming thepancreatic cells into functional islets for transplantation. Belgian Orgenesis uses the patients own liver cells and aims to convert these into functional insulin producing cells. The company has completed preclinical safety and efficacy studies and is currently planning to move into the clinic.
Eventually cell therapy approaches could obviatethe need to follow a life-long regimen of insulin injections, which often cannot fully prevent the long-term complications of high blood sugar.
However, Evotec and Sanofi are not only facing a crowded market, but the technology is also still in its infancy. In light of the high costs and safety risks of cell therapies, the new approaches will still have to prove that they can hold up to what they are promising.
You can read more about whats going on in the diabetes field in our recent review.
Images viaSyda ProductionsandDesignua / shutterstock.com
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Evotec and Sanofi Hit the First Milestone for a Diabetes Cell Therapy - Labiotech.eu (blog)
Nicola Lavin, nee Glynn, who is originally from Menlo, was diagnosed with Lyme Disease last year following a 16-year battle with an invisible bacteria which has attacked her organs and her immune system.
A table quiz will take place at Monroes Tavern, Dominick Street, next Thursday night (April 13) to support the young Galway mother who is suffering from the debilitating disease.
Nicola (38) can trace her troubles back to a bite from a tick during a summer in New York in 2000.
This resulted in heart failure while she was pregnant with her son, but she was only correctly diagnosed by a laboratory in Germany last year.
Over the years, her health has deteriorated so much that she is unable to work in the career she loves and has no quality of life. At times, she can barely comb her hair or brush her teeth.
Stem cell treatment in Germany can change Nicolas life and give her a second chance. Her friends and family have rallied around Nicola to organise this table quiz in a bid to transform her life. The treatment will cost 23,000.
A table quiz will take place in Monroes on Thursday April 13th at 8pm to help raise the much needed funds that will make such a difference. Donations can also be made through Go Fund Me.
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Fundraiser for Galway girl's life-changing stem cell treatment - Connacht Tribune Group
A stem cell treatment for heart failure patients is safe and shows early signs of effectiveness, according to a study published Wednesday.
The study was conducted by Japanese researchers in 27 patients, who received transplants of stem cells taken from their own thigh muscles. There were no major complications, and most patients showed considerable improvement in their symptoms.
The study was published in the open-access Journal of the American Heart Association. Dr Yoshiki Sawa of Osaka University Graduate School of Medicine was the senior author. It can be found at j.mp/stemheart.
However, two San Diego cardiologists who do stem cell research on heart disease cautioned that similar clinical trials have shown promise over the years, only to fail at the end for various reasons. There is no approved stem cell therapy for heart failure.
So while the trial itself appears to be well-conducted, the researchers are very far from actually proving their treatment is effective, said Dr. Richard Schatz of Scripps Health and Dr. Eric Adler of UC San Diego School of Medicine.
For one thing, the trial was small, they said, and larger trials are where the most rigorous scientific evaluations are made.
These early trials have looked beneficial in the past, Adler said. When we do the larger trials, the results are more equivocal.
Adler said the signs of efficacy in this trial are modest. For example, the change in ejection fraction, a measurement of efficiency in pumping blood, rose from 27 percent to 30 percent in 15 of the 27 patients. Their heart failure was associated with a lack of blood flow, or ischemia. The remaining non-ischemic patients actually had a slight decline.
The entire field of stem cell and regenerative therapy for heart disease has been a disappointment to date, Schatz said.
Weve been at it for 20 years now, and we dont have a product or a positive (late-stage) trial, so that tells you pretty much everything you need to know, he said. Its not for lack of trying or billions of dollars invested. Its just very, very difficult.
The cardiac field has had more success with other technologies, such as cardiac stents. Schatz is the co-inventor of the first stent.
In the study, the researchers acknowledge that previous attempts had only been modestly effective. They devised a method of producing sheets of muscle stem cells and attaching them to the inner layer of the sac that encloses the heart, a layer that rests directly on the heart surface.
The stem cell sheets stimulate healing by producing chemicals that stimulate cardiac regeneration, the study said. The cells themselves dont survive in the long term, but by the time they die they have served their purpose.
Loss of function
Heart failure is a progressive disease in which the heart gradually loses its ability to pump blood. This can be triggered by a heart attack or any other cause that damages the heart muscle.
When damaged heart muscle is replaced with scar tissue, as often happens, the heart loses pumping capacity. It becomes overstressed, and its output of blood declines. This limits the patients ability to engage in intensive physical activity. In advanced cases, patients may become bedridden.
Existing treatments include drugs and LVAD units, which take over some of the hearts function to relieve stress. Some drugs may help the heart work more efficiently, but none have been shown to improve heart failure by actually regenerating lost heart muscle.
Stem cell therapy is tested in patients who havent responded well to other treatments. Trials have been and are being conducted in San Diego area hospitals.
Scripps Health has been testing a cardiac stem cell therapy from Los Angeles-based Capricor. The cells, taken from donor hearts, are injected into the coronary artery, where they are expected to settle in the heart and encourage regrowth.
UC San Diego is testing a heart failure therapy from Teva Pharmaceutical Industries. It consists of bone marrow derived mesenchymal precursor cells. These can give rise to several different cell types, including muscle cells.
And many other trials are going on throughout the country and internationally.
Adler and Schatz said theres reason for optimism in the long run, as technologies improve.
Just because the other trials have been negative doesnt mean this technique wont be beneficial, Adler said. Its just too early to tell.
That said, Schatz emphasized that the nature of the three-phase clinical trial process means that the show-stoppers for a treatment typically appear late.
Tighter standards needed
Clean trials trials where we all agree that this is the patient population we want to look at, are needed, he said.
For example, heart failure comes in two types, he said. Ischemic heart failure is caused by heart attacks and blocked arteries, which impede blood flow. Non-ischemic heart failure can be caused by damage from diseases, such as a virus.
Non-ischemics can be younger people, in their 20s and 30s, while the ischemic patients are older. Mixing those patient groups in a single trial is a mistake, he said.
Theyre different animals, Schatz said.
Another pitfall is failing to screen carefully enough to enroll only patients likely to benefit, Schatz said.
You can have a patient who has chest pain, and coronary disease just incidentally, he said.
His shoulder or chest pain is from a virus. So he goes into the trial and gets a placebo injection in his arm of cortisone, and his arm pain goes away. And because hes in that placebo group, hes counted as a success the pain went away. It has nothing to do with his heart. Thats an extreme example, but we actually saw that happen.
In a failed gene therapy trial for heart disease, some patients apparently had received the injection in the wrong location, missing the heart muscle, Schatz said.
You assume they got the gene, but they didnt, Schatz said. The study was negative, and thats why I think it was negative.
Such errors dont show up in Phase 1 trials, Adler and Schatz said, because theyre focused on evaluating safety. And these early trials dont have many patients, there arent enough to comfortably determine the therapy is really effective.
By the last stage of the trial, these sources of error have often been identified and trial standards have tightened up. And thats when the faulty assumptions made early appear as the trial ends in failure.
Despite those forbidding hurdles, Adler said research should continue.
This disease is killing a lot of people. Theres not going to be enough hearts to go around for transplant. Theres six million Americans with heart failure, and theres 2,000 heart transplants a year. So coming up with novel regenerative cell-based therapy is something were still excited about.
bradley.fikes@sduniontribune.com
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