Cancer stem cells target of new grant to UCSD scientists – The San Diego Union-Tribune

Californias stem cell agency has awarded $5.8 million to UC San Diego researchers to develop a new variation of cancer immunotherapy.

The California Institute for Regenerative Medicine, or CIRM, approved the grant last week to adapt CAR T-cell technology to fight cancer stem cells. These deadliest of cancer cells have stem cell-like properties that enable them to survive treatments against them and grow profusely. One surviving cell can re-create an entire tumor.

CAR T-cell therapy, pioneered by Dr. Carl June at the University of Pennsylvania, has been used against blood cancers. While not all of those gravely ill patients have survived, a number have experienced dramatic and long-lasting remissions.

UC San Diego Moores Cancer Center physicians led by Ezra Cohen will experiment with the therapy to deal with a variety of hard-to-treat solid tumors. These include head and neck squamous cell carcinoma, triple-negative breast cancer, pancreatic cancer and ovarian cancers. The preliminary research that yielded this potential treatment was funded by the San Diego-based Immunotherapy Foundation.

Heres how CAR T-cell therapy works: Doctors genetically engineer a patients T cells, part of the immune system, to recognize a protein, called an antigen, on cancer cells so they can destroy them.

The T cells are given what is called a chimeric antigen receptor, or CAR. This is an artificial construct that can recognize the antigen on cancer cells, signaling the immune system to attack. The antigen targeted varies with different versions of the technology.

The T cells are removed from the patient, given the cancer-fighting receptor construct, grown to sufficient numbers, then re-infused into the patient. The cells act as living drugs. They tend to stick around in the patient, ready to grow and attack again if the cancer recurs.

While this has been demonstrated in blood cancers, solid tumors pose a more difficult problem, because immune cells have more limited access to the interior of these tumors.

Cohen, associate director for translational science at UC San Diego Moores Cancer Center, is a specialist in head and neck cancer. Among his patients: Ricki Rockett, the drummer from the band Poison.

Rockett, facing amputation of his tongue when he met Cohen, was given another kind of cancer immunotherapy, two drugs called checkpoint inhibitors that remove a molecular cloak that cancer cells use to hide from the immune system.

The treatment worked. The cancer disappeared, and Rocketts tongue was saved.

Its one year after his complete response, and hes still cancer-free, Cohen said. Rockett also went on tour with the band.

Cohen said the newly funded work with CAR T cells builds on earlier UC San Diego research that identified a receptor on some cancer cells as a promising new target. Its made in both solid tumors and blood cancers, but not in normal cells.

The receptor, tyrosine kinase-like orphan receptor or ROR1, is the target of a drug now being tested by Cohens colleague Dr. Thomas Kipps in patients with relapsed or refractory chronic lymphocytic leukemia. The drug, a monoclonal antibody called cirmtuzumab, is named after CIRM, which funded the research that produced the drug.

ROR1 is produced almost exclusively in the embryonic and early fetal stage, and helps the nascent tissues migrate to the right parts of the body, Cohen said. It appears to have virtually no use after that stage. So it appears to be a safe target. Thats been a challenge to find with cancer stem cells, because their genetic activity somewhat resembles that of normal stem cells.

For obvious reasons you don't want to eliminate all the stem cells in a person's body, Cohen said.

Theres some hints ROR1 might be produced in certain precursors to B cells, which are immune cells that make antibodies, he said. Its possible to live without B cells, as in the case where drugs destroy B cells to stop B-cell lymphoma.

The new project was sparked by Kipps research indicated that ROR1 was produced in high amounts in the hard-to-treat cancers. Cohen began thinking of how this knowledge could be applied with CAR T-cell technology

Cohen said preclinical research has already been performed for the new project. In cell culture tests, CAR T cells with the ROR1 receptor kill cancer stem cells with the receptor in those difficult cancers.

Funding for that research came from the Immunotherapy Foundation, created by San Diego philanthropists Ralph and Fernanda Whitworth in 2015 after Ralph Whitworth was diagnosed with cancer. He died of the disease in September 2016.

Christina Martinez, the Immunotherapy Foundations executive director, said Whitworth met with Cohen after his diagnosis, and became personally interested in advancing the research.

It was a serendipitous encounter, but he really saw the potential for a lasting partnership in his ability to be able to make a long-term contribution to the area of immunotherapy, Martinez said. This project was just one that fell under kind of an umbrella of projects that he was interested in and funding at UCSD. So he and Fernanda seeded that initial investment.

To further improve cancer immunotherapy, the Whitworths established the Immunotherapy Foundation. Fernanda Whitworth, president and co-founder, said shes pleased with the progress.

Ralph and I liked that these projects were designed to be tightly interconnected to leverage information and allow efficient movement into the clinic, she said. Today, I am proud to see this rational, focused approach is working.

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Cancer stem cells target of new grant to UCSD scientists - The San Diego Union-Tribune

UCI researchers use stem cells as cancer-seeking missiles – 89.3 KPCC

A close-up of cell mutations that cause cancer. Steve Gschmeissner/Science Source

Chemotherapy is brutal a medicinal atomic bomb that destroys large swaths of cells, both cancerous and normal. And as a result, patients are often left physically devastated.

In a new study published in Science Translational Medicine, scientists at UC Irvine say they've come up with a way to use stem cells to help ameliorate those side effects. Think of it as a surgical strike with cancer-seeking missiles.

Professor Weian Zhao and his colleagues from UC Irvine modified stem cells so that they'd be attracted to enzymes released by breast cancer tumors. So, when injected into the body, the stem cells seek out the cells and bond with them.

The enzymes the scientists identified cause tissue to clump up into bundles of collagen and protein to create stiff tumors. The tumors become lumps that a patient can sometimes feel, and they act as a protective home for the cancerous cells.

The stem cells release an enzyme of their own, in turn, activating a type of chemotherapy that's been injected into the patient, which is inert until in comes in contact with the enzyme. The idea being that the chemotherapy only causes toxicity to a localized area, instead of destroying everything in its path.

"We can use a stem cells to specifically localize and produce the drugs only at the tumor site, so that we can spare the healthy tissue," said Zhao. "So, we can make the treatment more effective and less toxic to the patient."

"I think this is pretty unique in a way that it can target specific metastatic tissues with reduced toxicity overall," said Min Yu, assistant professor at the department of Stem Cell Biology and Regenerative Medicine at USC. "So, in that sense, I think it's very novel and very unique approach."

Yu, who was not involved in the research, complimented the UCI team's methods and results, especially how effective the treatment was on the particular cancer cell that they focused on. However, she said, from patient to patient and cancer to cancer, there are a myriad of different cells responsible, making treatment notoriously difficult to generalize. The therapy isn't a sure thing.

Zhao acknowledged that his team has a while to go before it can prove that the treatment is effective in people. So far, it's only been tested in mice. As a result, FDA approval and human trials could be years away.

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UCI researchers use stem cells as cancer-seeking missiles - 89.3 KPCC

New approach may kill tumor cells in the brain – Harvard Gazette

Investigators from Brigham and Womens Hospital (BWH) and the Harvard Stem Cell Institute (HSCI) may have discovered a way to kill tumor cells that have metastasized to the brain.

The team has developed cancer-killing viruses that can deliver stem cells via the carotid artery, and applied them to metastatic tumors in the brains of clinically relevant mouse models. The elimination of metastatic skin cancer cells from the brains of these preclinical models resulted in prolonged survival, the investigators report. The study, published online this week in the journal PNAS, also describes a strategy of combining this therapy with immune checkpoint inhibitors.

Metastatic brain tumors often from lung, breast, or skin cancers are the most commonly observed tumors within the brain and account for about 40 percent of advanced melanoma metastases. Current therapeutic options for such patients are limited, particularly when there are many metastases, said Khalid Shah, director of the Center for Stem Cell Therapeutics and Imaging (CSTI) in the BWH Department of Neurosurgery, who led the study. Our results are the first to provide insight into ways of targeting multiple brain metastatic deposits with stem-cell-loaded oncolytic viruses that specifically kill dividing tumor cells.

In their search for novel, tumor-specific therapies that could target multiple metastases in the brain without damaging adjacent tissues, the research team first developed different BRAF wild-type and mutant mouse models that more closely mimicked what is seen in patients.

They found that injecting patient-derived, brain-seeking melanoma cells into the carotid arteries of the preclinical models resulted in metastatic tumors forming throughout the brain, mimicking what is seen in advanced melanoma cancer patients. The injected cells express markers that allow them to enter the brain and are labeled with bioluminescent and fluorescent markers to enable tracking by imaging technologies.

To devise a potential new therapy, the investigators engineered a population of bone marrow-derived mesenchymal stem cells loaded with oncolytic herpes simplex virus (oHSV), which specifically kills dividing cancer cells while sparing normal cells.

Previous research by Shah and his colleagues had shown that different stem cell types were naturally attracted to tumors in the brain. After first verifying that stem cells injected to the brain would travel to multiple metastatic sites and not to tumor-free areas in their model, the team injected the oHSV-laden stem cells into the carotid arteries of metastasis-bearing mice. This led to significantly slower tumor growth and increased survival, compared with the models that received unaltered stem cells or control injections.

Shah and his colleagues also developed an immunocompetent melanoma mouse model and explored treatments with both stem cell-loaded oHSV and immune checkpoint blockers such as those that target the PD-1/PD-L1 pathway. They found that PD-L1 immune checkpoint blockade significantly improved the therapeutic efficacy of stem cell-based oncolytic virotherapy in melanoma brain metastasis.

We are currently developing similar animal models of brain metastasis from other cancer types, as well as new oncolytic viruses that have the ability to specifically kill a wide variety of resistant tumor cells, said Shah, who is also a professor at Harvard Medical School and a principal faculty member at the Harvard Stem Cell Institute. We are hopeful that our findings will overcome problems associated with current clinical procedures. This work will have direct implications for designing clinical trials using oncolytic viruses for metastatic tumors in the brain.

The study was supported by a Department of Defense Idea Award and a grant from the National Institutes of Health.

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New approach may kill tumor cells in the brain - Harvard Gazette

CReM Stem Cell Researcher Is Innovator of the Year – BU Today

Those who know ancient historythe first decade of the 21st centuryrecall that embryonic stem cell research was a combustible issue, with supporters cheering the potential to create new tissues from stem cells and opponents decrying the destruction of human embryos that it required. A breakthrough arrived in 2006, when a Japanese researcher developed induced pluripotent stem cells (iPS), adult cells that behaved like embryonic stem cells and had an amazing ability to develop into muscles, skin, nerves, and almost any other cell type. Two years later, a second breakthrough, this one by Gustavo Mostoslavsky, a School of Medicine associate professor of gastroenterology, produced a tool that made it simpler and more efficient to generate iPS. BU patented his tool, called STEMCCA, and he says that its been adopted by more than 700 laboratories worldwide for making iPS.

That contribution to the field has earned Mostoslavsky this years University Innovator of the Year award. The Technology Developmentoffice presents the award to a faculty member whose research yields inventions or innovations benefiting society. Mostoslavsky will receive the award today at BUs annual Tech, Drugs, and Rock n Roll networking event connecting BU researchers and Boston entrepreneurs.

I was humbly surprised and happy, he says, when Gloria Waters, vice president and associate provost for research, emailed him the news. Sometimes it is easy to lose perspective when we get busy on the many tasks of running a labgrant writing, mentoring, budget, and so forthso I guess it is nice, once in a while, to just stop and enjoy the moment, enjoy what we have done so far, and even better, if on the way we have helped many others succeed.

One way Mostoslavsky has helped others succeedthe way that makes him most proud, he saysis to have cofounded, in 2010, BUs Center for Regenerative Medicine, which he codirects. The center, which pursues stem cell research with an emphasis on lung, blood, and gastrointestinal tract diseases, practices open source biology: sharing its discoveries with scientists around the world for free rather than patenting them. In 2013, CReM moved into its own physical quarters on Albany Street on the Medical Campus.

I am delighted to see Dr. Mostoslavskys colleagues choose him for this award, says Waters. STEMCCA has dramatically improved the efficiency with which new stem cells can be generated to treat disease. His success in patenting a tool that has become industry-standard, at the same time as he and the codirectors of the CReM have become renowned for their open source biology, serves as a model to students and other researchers of how to advance science through sharing, at the same time protecting important intellectual property.

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CReM Stem Cell Researcher Is Innovator of the Year - BU Today

Cesca Therapeutics subsidiary acquires assets of Sacramento’s SynGen Inc. – Sacramento Bee

Sacramento Business Journal

Cesca Therapeutics subsidiary acquires assets of Sacramento's SynGen Inc. Sacramento Bee Rancho Cordova's Cesca Therapeutics Inc., a stem cell medicine and medical technology company, announced Monday that its subsidiary has acquired the assets of SynGen Inc., the privately held Sacramento medical device company specializing in cell ... Cesca Therapeutics Acquires the Cell Processing Systems of SynGen Under Asset Acquisition AgreementNasdaq Cesca Therapeutics Inc (KOOL)'s Stock Is Buy After Today's Huge IncreaseFinance News Daily all 16 news articles »

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Cesca Therapeutics subsidiary acquires assets of Sacramento's SynGen Inc. - Sacramento Bee

‘Stem-cell tourism’ needs tighter controls, say medical experts – The … – Washington Post

By Reuters By Reuters July 8

Stem cell tourism in which patients travel to developing countries for unproven and potentially risky therapies should be more tightly regulated, according to a group of international health experts.

With hundreds of medical centers around the world claiming to be able to repair tissue damaged by conditions such as multiple sclerosis and Parkinsons disease, tackling unscrupulous advertising of such procedures is crucial.

These therapies are advertised directly to patients with the promise of a cure, but there is often little or no evidence to show they will help or that they will not cause harm, the 15 experts wrote in the journal Science Translational Medicine.

Some types of stem cell transplant mainly using blood and skin stem cells have been approved by regulators after full clinical trials found they could treat certain types of cancer and grow skin grafts for burn patients.

But many other potential therapies are only in the earliest stages of development and have not been approved by regulators.

Stem cell therapies hold a lot of promise, but we need rigorous clinical trials and regulatory processes to determine whether a proposed treatment is safe, effective and better than existing treatments, said one of the 15, Sarah Chan of Britains University of Edinburgh.

The experts called for global action, led by the World Health Organization, to introduce controls on advertising and to agree on international standards for the manufacture and testing of cell- and tissue-based therapies.

The globalization of health markets and the specific tensions surrounding stem cell research and its applications have made this a difficult challenge, they wrote. However, the stakes are too high not to take a united stance.

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'Stem-cell tourism' needs tighter controls, say medical experts - The ... - Washington Post

Consider risks of unapproved stem cell treatment – Kamloops This … – Kamloops This Week

Editor:

Re: (Stem cells to stem the wait? June 27):

There is a reason Health Canada has not approved certain stem-cell treatments: they have not been shown to work yet and even ones own minimally manipulated cells can be considered risky.

There is a great deal of research happening in Canada and globally and clinical trials are underway to test and improve the quality, safety and effectiveness of stem-cell therapies because scientists and industry believe they hold great promise.

As the KTW article noted, the federal government committed $20 million to the Centre for Commercialization of Regenerative Medicine in 2016, but it wasnt to establish a stem-cell therapy development facility in Toronto. Rather, the funding is to find better ways of manufacturing therapeutic cells, including stem cells, in the billions that are required for clinical use.

Not all stem cells are the same and it is crucial to ensure the purity of stem cells before they are injected into people.

There is a lot of support for stem-cell research and manufacturing in Canada and, if the public is patient, treatments will come.

For now, people seeking unapproved treatments should consider the risks (because they exist in the short-term and long-term) and be prepared to throw away their money if the treatment doesnt work.

Stacey Johnsondirector of communications and marketingCentre for Commercialization of Regenerative MedicineToronto

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Consider risks of unapproved stem cell treatment - Kamloops This ... - Kamloops This Week

Colon Cancer-Driven Stem Cells Linked to High-Fat Diet – Genetic Engineering & Biotechnology News

Scientists in the U.S. have identified a molecular pathway that appears to play a key role in the link between a high-fat diet (HFD) and the development of colorectal cancer. The research, led by the Cleveland Clinics Sheerlarani Karunanithi, and Matthew Kalady, suggests that it may one day be possible to develop drugs that reduce tumor growth associated with obesity and a diet that is high in fat.

Their research is published today, in Stem Cell Reports, in a paper titled, RBP4-STRA6 Pathway Drives Cancer Stem Cell Maintenance and MediatesHigh-Fat Diet-Induced Colon Carcinogenesis.

The Cleveland Clinic teams review of published research indicated that high expression levels of two vitamin A signalling proteinsserum retinol binding protein (RPB4), stimulated by retinoic acid 6 (STRA6)in colorectal cancer tumors is associated with poor prognosis, increased tumor metastasis and recurrence, and resistance to cancer therapy. The RBP4-STRA6 pathway triggers the JAK2-STAT3 signaling cascade.

The researchers engineered STRA6- or RBP4-knockdown cancer cells to demonstrate that the RBP4-STRA6 pathway is important for promoting cancer cell proliferation and survival and for maintaining the expression of core stem cell transcription factors. They also found that the RBP4-STRA6 pathway plays a key role in maintaining colon cancer stem cells (CSCs), both in cell lines and in patient-derived xenografts.

The teams previous work had shown that knocking down STRA6 in a xenograft cancer model decreased tumor growth. In a new round of studies, they injected RBP4-knockdown cancer cells into experimental mice, and found that RBP4 deficiency resulted in the development of fewer tumors, and slower tumor growth and progression.

With evidence building for the role of RBPA4-STRA6 pathway in colorectal cancer development and progression, the team turned to look at diet-related cancer. A prior study had already suggested that HFDinduced obesity leads to increased intestinal stem cells and may impact colorectal cancer risk. This finding, combined with independent research establishing a role for the RBPA4-STRA6 pathway in diet-induced metabolic syndrome, prompted the Cleveland Clinic team to look at the relationship between HFD, cancer development, and the RBPA4-STRA6 pathway.

They injected either STRA6-deficient colorectal cancer cells or unmodified cancer cells into obesity-resistant mice fed either a normal diet or an HFD. HFD mice injected with unmodified cancer cells exhibited significantly increased tumor growth compared with mice fed a normal diet. In contrast, there was no relative increase in tumor growth among HFD animals receiving the STRA6-deficient tumor cells.

Our data clearly indicate that RBP4-STRA6 pathway is necessary for the optimal expression of stem cell markers such as NANOG, SOX2, and LGR5, and thereby for maintaining the colon CSC pool, the authors conclude in their published paper. "We have known the influence of diet on colorectal cancer, commented Matthew Kalady, M.D., colorectal surgeon, and co-director of the Cleveland Clinic Comprehensive Colorectal Cancer Program. However, these new findings are the first to show the connection between high-fat intake and colon cancer via a specific molecular pathway. We can now build upon this knowledge to develop new treatments aimed at blocking this pathway and reducing the negative impact of a high-fat diet on colon cancer risk."

The interesting finding here is that the high fat diet-induced effects appear to also involve the stem cell program, which is interesting for tumor growth and has implications on therapies, as tumor stem cells are also therapeutically resistant, the authors told GEN. In terms of treatments, what we might envision is targeting a new component of the signaling axis we identified to reduce cancer growth. The pathways we have identified are known to control many aspects of cell behavior, but the input to these signaling programs is new and may represent a possible target. In terms of next steps, one would be to see whether this can be applied to other obesity-driven tumors. Can lessons from colon cancer be leveraged to other tumor types? We also are interested in inhibiting this new signaling axis as well as trying to understand more about this signaling program, as we may be able to identify signaling nodes that can be efficiently targeted.

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Colon Cancer-Driven Stem Cells Linked to High-Fat Diet - Genetic Engineering & Biotechnology News

Photo-responsive protein hydrogels as agent for controlled stem cell/protein release – Phys.Org

July 6, 2017 Material design empowered by protein sequence space. Credit: Department of Chemical and Biological Engineering, HKUST

Hydrogels, noted for their biomimetic properties, are the leading materials for biomedical applications, such as drug delivery and stem cell therapy. Traditional hydrogels made up of either synthetic polymers or natural biomolecules often serve as passive scaffolds for molecular or cellular species, which render these materials unable to fully recapitulate the dynamic signaling involved in biological processes, such as cell/tissue development.

Photo-responsive hydrogels are of particular interest to material scientists, because light is regarded as an ideal tool to control molecules or cell behavior with high spatiotemporal precision and little invasiveness. The major challenge for scientist is how to assemble these complex globular proteins into supramolecular architectures efficiently while preserving their function.

In a recent research, a group of scientists from The Hong Kong University of Science and Technology created a B12-dependent light-sensing hydrogel by covalently stitching together the photoreceptor C-terminal adenosylcobalamin binding domain (CarHC) proteins under mild conditions. This direct assembly of stimuli-responsive proteins into hydrogels represents a versatile solution for designing "smart" materials and opens up enormous opportunities for future material biology.

The findings were published in the journal PNAS on June 6, 2017.

"In our research, we were able to create an entirely recombinant protein-based light-sensitive hydrogels by covalently assembling the CarHC photoreceptor proteins using genetically encoded SpyTag-SpyCatcher chemistry," said Fei Sun, author of the paper and assistant professor at HKUST's department of chemical and biomolecular engineering. "The AdoB12-dependent CarHC tetramerization has been shown to be essential for the formation of an elastic hydrogel in the dark, which can undergo a rapid gel-sol transition caused by light-induced CarHC disassembly."

"The resulting hydrogel composed of physically self-assembled CarHC polymers exhibited a rapid gel-sol transition on light exposure, which enabled the facile release/recovery of 3T3 fibroblasts and human mesenchymal stem cells (hMSCs) from 3D cultures while maintaining their viability." Sun added. "Given the growing demand for creating stimuli-responsive "smart" hydrogels, the direct assembly of stimuli-responsive proteins into hydrogels represents a versatile strategy for designing dynamically tunable materials."

Explore further: Investigating folding stability and dynamics of proteins

More information: Ri Wang et al, B12-dependent photoresponsive protein hydrogels for controlled stem cell/protein release, Proceedings of the National Academy of Sciences (2017). DOI: 10.1073/pnas.1621350114

Journal reference: Proceedings of the National Academy of Sciences

Provided by: Hong Kong University of Science and Technology

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Medical Experts Call for Tighter Controls on Stem Cell Tourism – Voice of America

LONDON

Stem cell tourism involving patients who travel to developing countries for treatment with unproven and potentially risky therapies should be more tightly regulated, international health experts said Wednesday.

With hundreds of medical centers around the world claiming to be able to repair damaged tissue in conditions such as multiple sclerosis and Parkinson's disease, tackling unscrupulous advertising of such procedures is crucial, the experts said.

These therapies are advertised directly to patients with the promise of a cure, but there is often little or no evidence to show they will help, or that they will not cause harm, the 15 experts wrote in the journal Science Translational Medicine.

Some types of stem cell transplant mainly using blood and skin stem cells have been approved by regulators after full clinical trials found they could treat certain types of cancer and grow skin grafts for burns patients.

But many other potential therapies are only in the earliest stages of development and have not been approved by international regulators.

"Stem cell therapies hold a lot of promise, but we need rigorous clinical trials and regulatory processes to determine whether a proposed treatment is safe, effective and better than existing treatments," said one of the 15, Sarah Chan of Britain's University of Edinburgh.

The experts called for global action, led by the World Health Organization, to introduce controls on advertising and agree on international standards for the manufacture and testing of cell- and tissue-based therapies.

"The globalization of health markets and the specific tensions surrounding stem cell research and its applications have made this a difficult challenge," they wrote. "However, the stakes are too high not to take a united stance."

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Medical Experts Call for Tighter Controls on Stem Cell Tourism - Voice of America