Stem Cell Clinic

Comprehensive cancer study assesses potential targets for personalized medicine and finds new ones – Medical Xpress

May 18, 2017 Dr. Chad Creighton. Credit: Baylor College of Medicine

Looking to improve cancer treatment, a multi-institutional research team has taken a comprehensive approach to evaluating which molecular changes in cancer cells are most likely involved in the development of the disease. This approach resulted in the confirmation of previously known cancer molecular changes and in the discovery of others that had not been typically linked to cancer before. Targeting particular patient alterations with specific drugs might help one day improve response to treatment. The report appears in Cancer Cell.

"We studied the PI3K pathway, one of the most important pathways of the cell," said senior author Dr. Chad Creighton, associate professor of medicine and member of the Dan L Duncan Comprehensive Cancer Center Division of Biostatistics at Baylor College of Medicine. "A cellular pathway is a chain of events involving several proteins. The PI3K pathway has a number of diverse functions, including altering the cell's metabolism and driving cell growth and proliferation."

"PI3K is the most commonly mutated pathway in cancer that can be targeted by drugs. Thus, understanding how the pathway and mutations in cancer affect the many different cancer lineages is important," said co-author Dr. Gordon Mills, professor of medicine and immunology at MD Anderson Cancer Center.

Previous studies had identified a number of the genes, proteins and processes involved in the PI3K pathway in cells grown in the lab.

"In this study, we have taken what we have learned in the lab regarding how the pathway works and analyzed it together with information about the genes and the proteins present in cancer cells taken from human patients," Creighton said. "We looked at nearly 11,000 human cancers representing 32 major types. This is the largest study of its kind, and it was possible in part thanks to the Cancer Genome Atlas, a publicly available dataset of genomic changes in 32 types of cancer."

To carry out the complex analysis of this vast amount of data, the research team pulled the resources of experts in cancer protein data, in molecular biology of the pathway, and in the use of powerful analytical tools that provided genomic analysis and integration of the protein data.

The challenge is to know which mutations in cancer are important

To assess which cancer mutations are important, the researchers carried out a comprehensive analysis that allowed them to distinguish which of the altered genes and proteins were more likely to affect the normal function of the PI3K pathway.

"What makes this analysis complex is that there is a large number of gene and protein alterations that can be present in a given patient's tumor, and it is possible that different alterations are present in different patients," Creighton said. "In addition, not all mutations necessarily cause disease. The challenge is to find out which mutations are altering the pathway in a way that can lead to cancer. We hope that one day we will be able to apply this knowledge to personalized medicine."

There were a few surprises in the study.

"For some genes there was previous work indicating they were implicated in this pathway, but we discovered other genes, such as IDH1 and VHL, which had not been typically associated with the pathway in cancer before," Creighton said. "These genes, as well as others that may be discovered in the future, may now be incorporated into the group of genes linked to the PI3K pathway and considered as potential candidates for targeted therapy."

"Finding several cancers and mutations that we didn't know before could activate this pathway supports moving up the priority of testing drugs toward the new mutations found in specific cancer types," said co-author Dr. David Kwiatkowski, professor of medicine at Harvard Medical School and senior physician at Brigham and Women's Hospital and the Dana Farber Cancer Institute.

The future of personalized medicine

"The comprehensive nature of this project that integrates information from multiple levels has the potential to impact patient management and to eventually improve outcomes for the large population of patients with abnormalities in this very important pathway," Mills said.

"This comprehensive approach expands our knowledge regarding which types of cancer this pathway is activated and why, and that's important in terms of thinking about therapies that go after this pathway," Kwiatkowski said.

Imagine the following possible future scenario in a personalized medicine setting: a patient provides a sample of tumor and the physician sends it to a lab that runs a sequencing assay that shows where the genetic changes are located and the type of changes. Then, from the protein data, the team of physicians and scientists can determine which genetic changes are associated with greater activation of the PI3K pathway and which may not. These data would help the team in terms of selecting patients for whom specific drugs may be effective.

Explore further: New subtypes of lung cancer can lead to personalized therapies with better outcome

More information: Cancer Cell (2017). DOI: 10.1016/j.ccell.2017.04.013

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Comprehensive cancer study assesses potential targets for personalized medicine and finds new ones - Medical Xpress

NantKwest Appoints Dr. John Lee as Senior Vice President of Adult Medical Affairs – Business Wire (press release)

CULVER CITY, Calif.--(BUSINESS WIRE)--NantKwest Inc.(NASDAQ:NK), a pioneering, next generation, clinical-stage immunotherapy company focused on harnessing the unique power of our immune system using natural killer (NK) cells to treat cancer, infectious diseases and inflammatory diseases, announced todaythe appointment ofJohn Lee, MD, FACS, as Senior Vice President of Adult Medical Affairs.In his new role, Dr. Lee will oversee regulatory strategy for clinical trials, medical writing and translation of pre-clinical science into the development of new trials.

Adding Dr. Lee to our adult medical affairs team will help accelerate our efforts towards bringing impactful clinical trials to life,said Patrick Soon-Shiong, MD, Chairman and CEO of NantKwest. As an esteemed medical professor and surgeon with extensive experience in oncology research, Dr. Lees leadership will be crucial to advancing the development of effective immunotherapy treatments.

In addition to joining NantKwest, Dr. Lee currently serves as Co-Director of the Chan Soon-Shiong Institute of Medicine, and has been asurgical oncologist with Sanford Health since 2008.

Our ultimate goal is to reduce the overall cancer mortality rate by leveraging the bodys immune system to combat all types of cancer, said Dr. Lee. From our recent authorization from the U.S. Food & Drug Administration (FDA) for an Investigational New Drug (IND) application for the NANT Cancer Vaccine, to our partnership with Viracta Therapeutics, Inc. to combine our platform of natural killer (NK) cell therapies with the companys Phase 2 drug candidate, Im thrilled to be a part of a company that is on its way to revolutionizing the way we treat this complex disease.

Dr. Lees prior experience at Sanford Health was largely focused on developing a comprehensive head and neck cancer program aimed at bringing immuno-oncology drugs to patients. In addition, as medical director of cancer research, he helped develop several other cancer multi-disciplinary teams that focused on clinical and research excellence. By initiating and overseeing the health systems protocol review committee for all incoming oncology trials, Dr. Lee has developed several clinical trials within Sanford. Throughout his time there, he was promoted to full professor and Dr. Lees lab produced more than 40 peer-reviewed papers, multiple patents and helped increase institutional funded research from the National Institutes of Health (NIH). His surgical training in head and neck surgery was completed at the University of Iowa, where he was eventually promoted to associate professor. Dr. Lee received his MD from the University of Minnesota and completed his undergraduate education at Stanford University.

About NantKwest

NantKwest (NASDAQ:NK) is a pioneering, next generation, clinical-stage immunotherapy company focused on harnessing the unique power of our immune system using natural killer (NK) cells to treat cancer, infectious diseases and inflammatory diseases. NK cells are the bodys first line of defense due to the innate ability of NK cells to rapidly identify and destroy cells under stress, such as cancer or virally-infected cells.

NantKwests unique NK cell-based platform, with the capacity to grow active killer cells as a biological cancer therapy, has been designed to induce cell death against cancer or infected cells by three different modes of action: (1) Direct killing using activated NK cells (aNK) that release toxic granules directly into the cell through cell to cell contact; (2) Antibody-mediated killing using haNKs, which are NK cells engineered to incorporate a high affinity receptor that binds to an administered antibody, enhancing the cancer cell killing effect of that antibody; and (3) Chimeric Antigen Receptor (CAR) activated killing using taNKs, which are NK cells engineered to incorporate CARs to target tumor-specific antigens found on the surface of cancer cells.

Our aNK, haNK and taNK platform addresses certain limitations of T cell therapies, including the reduction of risk of serious cytokine storms reported after T cell therapy. As an off-the-shelf therapy, NantKwests NK cells do not rely on a patients own often compromised immune system. In Phase 1 clinical trials in patients with late stage cancer, NantKwests NK cells have been successfully administered as an outpatient infusion therapy without any reported severe side effects, even at doses of 10 billion cells.

By leveraging an integrated and extensive genomics and transcriptomics discovery and development engine, together with a pipeline of multiple, clinical-stage, immuno-oncology programs that include a Phase 2 trial for a rare form of melanoma and the planned initiation of a clinical trial of NK cells targeted to breast cancer, we believe NantKwest is uniquely positioned to be the premier immunotherapy company and transform medicine by delivering living drugs in a bag and bringing novel NK cell-based therapies to routine clinical care. For more information please visit http://www.nantkwest.com and follow Dr. Soon-Shiong on Twitter @DrPatSoonShiong.

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NantKwest Appoints Dr. John Lee as Senior Vice President of Adult Medical Affairs - Business Wire (press release)

Weill Cornell Medicine Team Creates Self-Renewing Hematopoietic Stem Cells for Transplantation – Cornell Chronicle

Researchers at Weill Cornell Medicine have discovered an innovative method to make an unlimited supply of healthy blood cells from the readily available cells that line blood vessels. This achievement marks the first time that any research group has generated such blood-forming stem cells.

This is a game-changing breakthrough that brings us closer not only to treat blood disorders, but also deciphering the complex biology of stem-cell self-renewal machinery, said senior author Dr. Shahin Rafii, director of the Ansary Stem Cell Institute, chief of the Division of Regenerative Medicine and the Arthur B. Belfer Professor at Weill Cornell Medicine.

This is exciting because it provides us with a path towards generating clinically useful quantities of normal stem cells for transplantation that may help us cure patients with genetic and acquired blood diseases, added co-senior author Dr. Joseph Scandura, an associate professor of medicine and scientific director of the Silver Myeloproliferative Neoplasms Center at Weill Cornell Medicine.

Hematopoietic stem cells (HSCs) are long-lasting cells that mature into all types of blood cells: white blood cells, red blood cells and platelets. Billions of circulating blood cells do not survive long in the body and must be continuously replenished. When this does not happen, severe blood diseases, such as anemia, bleeding or life-threatening infections, can occur. A special property of HSCs is that they can also self-renew to form more HSCs. This property allows just a few thousand HSCs to produce all of the blood cells a person has throughout ones life.

This image shows reprogrammed hematopoietic stem cells (green) that are arising from mouse cells. These stem cells are developing close to a group of cells, called the vascular niche cells (gray), which provides them with the nurturing factors necessary for the reprogramming.

Researchers have long hoped to find a way to make the body produce healthy HSCs in order to cure these diseases. But this has never been accomplished, in part because scientists have been unable to engineer a nurturing environment within which stem cells can convert into new, long-lasting cellsuntil now.

In a paper published May 17 in Nature, Dr. Rafii and his colleagues demonstrate a way to efficiently convert cells that line all blood vessels, called vascular endothelial cells, into abundant, fully functioning HSCs that can be transplanted to yield a lifetime supply of new, healthy blood cells. The research team also discovered that specialized types of endothelial cells serve as that nurturing environment, known as vascular niche cells, and they choreograph the new converted HSCs self-renewal. This finding may solve one of the most longstanding questions in regenerative and reproductive medicine: How do stem cells constantly replenish their supply?

The research team showed in a 2014 Nature study that converting adult human vascular endothelial cells into hematopoietic cells was feasible. However, the team was unable to prove that they had generated true HSCs because human HSCs function and regenerative potential can only be approximated by transplanting the cells into mice, which dont truly mimic human biology.

To address this issue, the team applied their conversion approach to mouse blood marrow transplant models that are endowed with normal immune function and where definitive evidence for HSC potential could rigorously tested. The researchers took vascular endothelial cells isolated from readily accessible adult mice organs and instructed them to overproduce certain proteins associated with blood stem-cell function. These reprogrammed cells were grown and multiplied in co-culture with the engineered vascular niche. The reprogrammed HSCs were then transplanted as single cells with their progenies into mice that had been irradiated to destroy all of their blood forming and immune systems, and then monitored to see whether or not they would self-renew and produce healthy blood cells.

Study co-authors, from left: Dr. Joseph Scandura, Dr. Raphael Lis, Dr. Jason Butler, Michael Poulos, Balvir Kunar Jr., Chaitanya R. Badwe, Koji Shido, Dr. Zev Rozenwaks, Jose-Gabriel Barcia-Duran, Dr. Shahin Rafii and Dr. Jenny Xiang. Not pictured: Charles Karrasch, David Redmond, Dr. Will Schachterle, Michael Ginsberg, Dr. Arash Rafii. Photo credit: Michael Gutkin.

In collaboration withDr. Olivier Elemento, associate director of the HRH Prince Alwaleed Bin Talal Bin Abdulaziz Al-Saud Institute for Computational Biomedicine, andDr. Jenny Xiang, the director of Genomics Services, Dr. Rafii and his team also showed that the reprogrammed HSCs and their differentiated progenies including white and redbloodscells, as well as the immune cells were endowed with the same genetic attributes to that of normal adult stem cells. These findings suggest that the reprogramming process results in the generation of true HSCs that havegeneticsignature thatarevery similar to normal adult HSCs.Remarkably, the conversion procedure yielded a plethora of transplantable HSCs that regenerated the entire blood system in mice for the duration of their lifespans, a phenomenon known as engraftment. We developed a fully-functioning and long-lasting blood system, said lead authorDr. Raphael Lis, an instructor in medicine and reproductive medicine at Weill Cornell Medicine. In addition, the HSC-engrafted mice developed all of the working components of the immune systems. This is clinically important because the reprogrammed cells could be transplanted to allow patients to fight infections after marrow transplants, Dr. Lis said. The mice in the study went on to live normal-length lives and die natural deaths, with no sign of leukemia or any other blood disorders.

Study co-author Dr. Olivier Elemento. Photo credit: Roger Tully.

The Weill Cornell Medicine team is the first to achieve cellular reprogramming to create engraftable and authentic HSCs, which have been considered the holy grail of stem cell research. We think the difference is the vascular niche, said contributing authorDr. Jason Butler, an assistant professor of regenerative medicine at Weill Cornell Medicine. Growing stem cells in the vascular niche puts them back into context, where they come from and multiply. We think this is why we were able to get stem cells capable of self-renewing.

If this method can be scaled up and applied to humans, it could have wide-ranging clinical implications. It might allow us to provide healthy stem cells to patients who need bone marrow donors but have no genetic match, Dr. Scandura said. It could lead to new ways to cure leukemia, and may help us correct genetic defects that cause blood diseases like sickle-cell anemia.

More importantly, our vascular niche-stem-cell expansion model may be employed to clone the key unknown growth factors produced by this niche that are essential for self-perpetuation of stem cells, Dr. Rafii said. Identification of those factors could be important for unraveling the secrets of stem cells longevity and translating the potential of stem cell therapy to the clinical setting.

Additional study co-authors include Charles Karrasch, Dr. Michael Poulos, Balvir Kunar, David Redmond, Jose-Gabriel Barcia-Duran, Chaitanya Badwe, Koji Shido and Dr. Zev Rosenwaks of Weill Cornell Medicine; Dr. Will Schachterle, formerly of Weill Cornell Medicine, Dr. Arash Rafii of Weill Cornell Medicine-Qatar; Dr. Michael Ginsberg of Angiocrine Bioscience; and Dr. Nancy Speck of the Abramson Family Cancer Research Institute in the Perelman School of Medicine at the University of Pennsylvania.

Various study authors have relationships with Angiocrine Bioscience that are independent of Weill Cornell Medicine.

This study was funded in part by the National Institutes of Health, grants NIH-R01 DK095039, HL119872, HL128158, HL115128, HL099997, CA204308, HL133021, HL119872, HL128158 and HL091724; U54 CA163167; and NIH-T32 HD060600.

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Weill Cornell Medicine Team Creates Self-Renewing Hematopoietic Stem Cells for Transplantation - Cornell Chronicle

Injured bones reconstructed by gene and stem cell therapies – Medical Xpress

May 17, 2017 This illustration shows the bone-tissue engineering technique developed by Cedars-Sinai investigators. 'Endogenous MSCs' refers to stem cells from a patient's bone. The 'BMP gene' is a gene that promotes bone repair. Credit: Gazit Group/Cedars-Sinai

A Cedars-Sinai-led team of investigators has successfully repaired severe limb fractures in laboratory animals with an innovative technique that cues bone to regrow its own tissue. If found to be safe and effective in humans, the pioneering method of combining ultrasound, stem cell and gene therapies could eventually replace grafting as a way to mend severely broken bones.

"We are just at the beginning of a revolution in orthopedics," said Dan Gazit, PhD, DMD, co-director of the Skeletal Regeneration and Stem Cell Therapy Program in the Department of Surgery and the Cedars-Sinai Board of Governors Regenerative Medicine Institute. "We're combining an engineering approach with a biological approach to advance regenerative engineering, which we believe is the future of medicine."

Gazit was the principal investigator and co-senior author of the research study, published in the journal Science Translational Medicine.

More than 2 million bone grafts, frequently necessitated by severe injuries involving traffic accidents, war or tumor removal, are performed worldwide each year. Such injuries can create gaps between the edges of a fracture that are too large for the bone to bridge on its own. The grafts require implanting pieces from either the patient's or a donor's bone into the gap.

"Unfortunately, bone grafts carry disadvantages," said Gazit, a professor of surgery at Cedars-Sinai. "There are huge unmet needs in skeleton repair."

One problem is that enough healthy bone is not always available for repairs. Surgeries to remove a bone piece, typically from the pelvis, and implant it can lead to prolonged pain and expensive, lengthy hospitalizations. Further, grafts from donors may not integrate or grow properly, causing the repair to fail.

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The new technique developed by the Cedars-Sinai-led team could provide a much-needed alternative to bone grafts.

In their experiment, the investigators constructed a matrix of collagen, a protein the body uses to build bones, and implanted it in the gap between the two sides of a fractured leg bone in laboratory animals. This matrix recruited the fractured leg's own stem cells into the gap over a period of two weeks. To initiate the bone repair process, the team delivered a bone-inducing gene directly into the stem cells, using an ultrasound pulse and microbubbles that facilitated the entry of the gene into the cells.

Eight weeks after the surgery, the bone gap was closed and the leg fracture was healed in all the laboratory animals that received the treatment. Tests showed that the bone grown in the gap was as strong as that produced by surgical bone grafts, said Gadi Pelled, PhD, DMD, assistant professor of surgery at Cedars-Sinai and the study's co-senior author.

"This study is the first to demonstrate that ultrasound-mediated gene delivery to an animal's own stem cells can effectively be used to treat nonhealing bone fractures," Pelled said. "It addresses a major orthopedic unmet need and offers new possibilities for clinical translation."

The study involved six departments at Cedars-Sinai, plus investigators from Hebrew University in Jerusalem; the University of Rochester in Rochester, New York; and the University of California, Davis.

"Our project demonstrates how scientists from diverse disciplines can combine forces to find solutions to today's medical challenges and help develop treatments for the patients of tomorrow," said Bruce Gewertz, MD, surgeon-in-chief and chair of the Department of Surgery at Cedars-Sinai.

Explore further: Combining adult stem cells with hormone may speed bone fracture healing

More information: DOI: 10.1126/scitranslmed.aal3128 "In situ bone tissue engineering via ultrasound-mediated gene delivery to endogenous progenitor cells in mini-pigs," Science Translational Medicine (2017). http://stm.sciencemag.org/lookup/doi/10.1126/scitranslmed.aal3128

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Injured bones reconstructed by gene and stem cell therapies - Medical Xpress

Cancer therapy may work in unexpected way – Stanford Medical Center Report

Using antibodies to PD-1 or PD-L1 is one of the major advances in cancer immunotherapy, said Weissman, who is also the Virginia and D.K. Ludwig Professor for Clinical Investigation in Cancer Research, director of the Stanford Institute for Stem Cell Biology and Regenerative Medicine and director of the Ludwig Center for Cancer Stem Cell Research and Medicine at Stanford. While most investigators accept the idea that anti-PD-1 and PD-L1 antibodies work by taking the brakes off of the T-cell attack on cancer cells, we have shown that there is a second mechanism that is also involved.

What Weissman and his colleagues discovered is that PD-1 activation also inhibits the anti-cancer activity of other immune cells called macrophages. Macrophages that infiltrate tumors are induced to create the PD-1 receptor on their surface, and when PD-1 or PD-L1 is blocked with antibodies, it prompts those macrophage cells to attack the cancer, Gordon said.

This mechanism is similar to that of another antibody studied in the Weissman lab: the antibody that blocks the protein CD47. Weissman and his colleagues showed that using anti-CD47 antibodies prompted macrophages to destroy cancer cells. The approach is now the subject of a small clinical trial in human patients.

As it stands, its unclear to what degree macrophages are responsible for the therapeutic success of the anti-PD-1 and anti-PD-L1 antibodies.

The practical implications of the discovery could be important, the researchers said. This could lead to novel therapies that are aimed at promoting either the T-cell component of the attack on cancer or promoting the macrophage component, Gordon said.

Another implication is that antibodies to PD-1 or PD-L1 may be more potent and broadly effective than previously thought. In order for T cells to attack cancer when you take the brakes off with antibodies, you need to start with a population of T cells that have learned to recognize specific cancer cells in the first place, Weissman said. Macrophage cells are part of the innate immune system, which means they should be able to recognize every kind of cancer in every patient.

Other Stanford co-authors of the study are associate professor of pathology Andrew Connolly, MD, PhD; visiting scholar Gregor Hutter, MD, PhD;instructor Rahul Sinha, PhD; postdoctoral scholars Roy Maute, PhD, Daniel Corey, MD, and Melissa McCracken, PhD; graduate students Benjamin Dulken, Benson George and Jonathan Tsai; and former graduate student Aaron Ring, MD, PhD.

The research was supported by the D.K. Ludwig Fund for Cancer Research, the A.P. Giannini Foundation, the Stanford Deans Fellowship, the National Institutes of Health (grant GM07365), the Swiss National Science Foundation and the National Center for Research Resources.

Weissman is a founder of the company Forty Seven Inc., which is sponsoring the clinical trial of the anti-CD47 antibody.

Stanfords departments of Pathology and of Developmental Biology also supported the work.

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Cancer therapy may work in unexpected way - Stanford Medical Center Report