Zika Virus’ Key into Brain Cells ID’d, Leveraged to Block Infection and Kill Cancer Cells – UC San Diego Health

Zika virus infection can stunt neonatal brain development, a condition known as microcephaly, in which babies are born with abnormally small heads. To determine how best to prevent and treat the viral infection, scientists first need to understand how the pathogen gets inside brain cells.

Employing different approaches to answer different questions, two research teams at University of California San Diego School of Medicine independently identified the same molecule v5 integrin as Zika virus key to entering brain stem cells.

In a pair of papers published January 16, 2020 by Cell Press, the researchers also found ways to take advantage of the integrin to both block Zika virus from infecting cells and turn it into something good: a way to shrink brain cancer stem cells.

Integrins are molecules embedded in cell surfaces. They play important roles in cell adherence and communication, and are known to be involved in cancer progression and metastasis. Several other integrins are known entry points for other viruses, including adenovirus, foot-and-mouth disease virus and rotavirus, but v5 was not previously known for its role in viral infections.

One team, led by Tariq Rana, PhD, professor and chief of the Division of Genetics in the Department of Pediatrics at UC San Diego School of Medicine and Moores Cancer Center, used CRISPR gene editing to systematically delete every gene in a 3D culture of human glioblastoma (brain cancer) stem cells growing in a laboratory dish. Then they exposed each variation to Zika virus to determine which genes, and the proteins they encode, are required for the virus to enter the cells. The virus was for the first time labeled with green fluorescent protein (GFP) to allow the researchers to visualize viral entry into the cells.

3D human brain organoids. Left: normal, uninfected. Center: infected with Zika virus. Right: infected with Zika virus and treated with cilengitide, which protects the cells from destruction by the virus.

Their study, published in Cell Reports, uncovered 92 specific human brain cancer stem cell genes that Zika virus requires to infect and replicate in the cells. But one gene stood out, the one that encodes v5 integrin.

Integrins are well known as molecules that many different viruses use as doorknobs to gain entry into human cells, Rana said. I was expecting to find Zika using multiple integrins, or other cell surface molecules also used by other viruses. But instead we found Zika uses v5, which is unique. When we further examined v5 expression in brain, it made perfect sense because v5 is the only integrin member enriched in neural stem cells, which Zika preferentially infects. Therefore, we believe that v5 is the key contributor to Zikas ability to infect brain cells.

The second study, published in Cell Stem Cell, was led by Jeremy Rich, MD, professor in the Department of Medicine at UC San Diego School of Medicine and director of neuro-oncology and of the Brain Tumor Institute at UC San Diego Health. Knowing that many viruses use integrins for entry into human cells, Richs team inhibited each integrin with a different antibody to see which would have the greatest effect.

When we blocked other integrins, there was no difference. You might as well be putting water on a cell, said Rich, who is also a faculty member in the Sanford Consortium for Regenerative Medicine and Sanford Stem Cell Clinical Center at UC San Diego Health. But with v5, blocking it with an antibody almost completely blocked the ability of the virus to infect brain cancer stem cells and normal brain stem cells.

Richs team followed up by inhibiting v5 in a glioblastoma mouse model with either an antibody or by deactivating the gene that encodes it. Both approaches blocked Zika virus infection and allowed the treated mice to live longer than untreated mice. They also found that blocking the v5 integrin in glioblastoma tumor samples removed from patients during surgery blocked Zika virus infection.

Ranas team also blocked v5 in mice, treating them daily with cilengitide or SB273005, two experimental cancer drugs that target the integrin. Six days after Zika virus infection, the brains of their drug-treated mice contained half as much virus as mock-treated mice.

The neat thing is that these findings not only help advance the Zika virus research field, but also opens the possibility that we could similarly block the entry of multiple viruses that use other integrins with antibodies or small molecule inhibitors, Rana said.

Rana and team are now engineering a mouse model that lacks v5 integrin in the brain a tool that would allow them to definitively prove the molecule is necessary for Zika viral entry and replication.

Rich is a neuro-oncologist who specializes in diagnosing and treating patients with glioblastoma, a particularly aggressive and deadly type of brain tumor. When he first saw how the Zika virus shrinks brain tissue, it reminded him of what he hopes to achieve when hes treating a patient with glioblastoma. In 2017, he and collaborators published a study in which they determined that Zika virus selectively targets and kills glioblastoma stem cells, which tend to be resistant to standard treatments and are a big reason why glioblastomas recur after surgery and result in shorter patient survival rates.

Richs latest study helps account for the virus preference for glioblastoma stem cells over healthy brain cells. The v5 integrin is made up of two separate subunits v and 5. The team found that glioblastoma stem cells produce a lot of both the v subunit (associated with stem cells) and 5 subunit (associated with cancer cells). Together, these units form the v5 integrin, which, the team discovered, plays an important role in glioblastoma stem cell survival. Those high levels of v5 integrin also help explain why, in the study, glioblastoma stem cells were killed by Zika virus at much higher rates than normal stem cells or other brain cell types.

It turns out that the very thing that helps cancer cells become aggressive cancer stem cells is the same thing Zika virus uses to infect our cells, Rich said.

To see how this might play out in a more realistic model of human disease, Richs team partnered with an expert in human brain disease modeling Alysson Muotri, PhD, professor at UC San Diego School of Medicine, director of the UC San Diego Stem Cell Program and a member of the Sanford Consortium for Regenerative Medicine, and team. Pinar Mesci, PhD, a postdoctoral researcher in Muotris lab, generated a new brain tumor model, where human glioblastoma tumors were transplanted into human brain organoids, laboratory mini-brains that can be used for drug discovery. The researchers discovered that Zika virus selectively eliminates glioblastoma stem cells from the brain organoids. Inhibiting v5 integrin reversed that anti-cancer activity, further underscoring the molecules crucial role in Zika virus ability to destroy cells.

Now Richs team is partnering with other research groups to perform targeted drug studies. In addition to searching for drugs to block Zika virus, as Ranas group is doing, Rich is interested in genetic modifications to the virus that could help better target its destruction to brain cancer cells, while leaving healthy cells alone.

While we would likely need to modify the normal Zika virus to make it safer to treat brain tumors, we may also be able to take advantage of the mechanisms the virus uses to destroy cells to improve the way we treat glioblastoma, Rich said. We should pay attention to viruses. They have evolved over many years to be very good at targeting and entering specific cells in the body.

Zika virus was perhaps best known in 2015-16, when a large outbreak affected primarily Latin America, but also several other regions of the world. While that particular epidemic has passed, Zika virus has not gone away. Smaller, local outbreaks continue and this past summer, the first few cases of native Zika virus infection were recorded in Europe. Scientists warn Zika could continue to spread as climate change affects the habitat range of the mosquito that carries it. The virus can also be transmitted from pregnant mother to fetus, and via sexual contact. More than half of all people on Earth are at risk for Zika virus infection, and there is no safe and effective treatment or vaccine.

Co-authors of Ranas study, published January 16, 2020 in Cell Reports, include: Shaobo Wang, Qiong Zhang, Shashi Kant Tiwari, Gianluigi Lichinchi, Edwin H. Yau, Hui Hui, Wanyu Li, UC San Diego; and Frank Furnari, UC San Diego and Ludwig Institute for Cancer Research.

This research was funded, in part, by the National Institutes of Health (grants AI125103, CA177322, DA039562, DA046171 and DA049524).

Co-authors of Richs study, published January 16, 2020 in Cell Stem Cell, also include: Zhe Zhu, Jean A. Bernatchez, Xiuxing Wang, Hiromi I. Wettersten, Sungjun Beck, Alex E. Clark, Qiulian Wu, Sara M. Weis, Priscilla D. Negraes, Cleber A. Trujillo, Jair L. Siqueira-Neto, David A. Cheresh, UC San Diego; Ryan C. Gimple, Leo J.Y. Kim, UC San Diego and Case Western Reserve University; Simon T. Schafer, Fred H. Gage, Salk Institute for Biological Studies; Briana C. Prager, UC San Diego, Case Western Reserve University and Cleveland Clinic; Rekha Dhanwani, Sonia Sharma, La Jolla Institute for Allergy and Immunology; Alexandra Garancher, Robert J. Wechsler-Reya, Sanford Burnham Prebys Medical Discovery Institute; Stephen C. Mack, Baylor College of Medicine, Texas Childrens Hospital; Luiz O. Penalva, Childrens Cancer Research Institute; Jing Feng, Zhou Lan, Rong Zhang, Alex W. Wessel, Michael S. Diamond, Hongzhen Hu, Washington University School of Medicine; Sanjay Dhawan, and Clark C. Chen, University of Minnesota.

The research was funded, in part, by the National Institutes of Health (grants CA217065, CA217066, CA203101, CA159859, CA199376, NS097649-01, CA240953-01, NS096368, R01DK103901,R01AA027065, MH107367, N5105969, CA045726, CA050286, CA197718, CA154130, CA169117, CA171652, NS087913, NS089272), California Institute for Regenerative Medicine (CIRM, grants FA1-00607, DISC209649) and International Rett Syndrome Foundation.

Disclosures: Tariq Rana is a co-founder of, member of the scientific advisory board for, and has equity interest in ViRx Pharmaceuticals. Alysson Muotri is a co-founder and has equity interest in TISMOO, a company dedicated to genetic analysis focusing on therapeutic applications customized for autism spectrum disorder and other neurological disorders. David Cheresh is a co-founder of TargeGen and AlphaBeta Therapeutics, a new but currently unfunded company developing an antibody to integrin v5 involved in cancer treatment. The terms of these arrangements have been reviewed and approved by UC San Diego in accordance with its conflict of interest policies. In addition, Michael Diamond, of Washington University School of Medicine, is a consultant for Inbios and Atreca and serves on the Scientific Advisory Board of Moderna.

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Zika Virus' Key into Brain Cells ID'd, Leveraged to Block Infection and Kill Cancer Cells - UC San Diego Health

Koepka Tied for 3rd in Abu Dhabi in Return From Knee Injury – The New York Times

ABU DHABI, United Arab Emirates Brooks Koepka shot a 6-under 66 Thursday in his return to competition after a knee injury and was tied for third place after the opening round of the Abu Dhabi Championship.

Koepka, ranked No. 1 in the world, missed three months after re-injuring his knee when he slipped while walking off the tee on Oct. 18 at the CJ Cup in South Korea. He previously had stem cell treatment for a partially torn tendon in his patella.

The four-time major winner had physical therapy in San Diego for most of December and began to hit balls before Christmas. He has said he's pain free, but acknowledged earlier this week his left knee doesn't feel the same as my right.

Koepka is two shots behind co-leaders Shaun Norris, of South Africa, and Renato Paratore, of Italy.

He looked sharp Thursday, making birdies on two of the first three holes on the way to a bogey-free round.

The first day I picked up the club, same thing, felt like I hadn't left," Koepka said. I've done it for years and years. You don't forget how to swing the golf club.

It was a little sore last night, the American said, "just did some treatment on it, that's expected.

The 23-year-old Paratore is seeking his second European Tour title. He was beaten by Rasmus Hojgaard in a playoff at the Mauritius Open in December.

Koepka, who is tied with Australian Jason Scrivener, said his knee felt fine.

Sergio Garcia is among six players tied fourth after an opening 67.

Defending champion Shane Lowry opened with a 2-under 70.

___

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Koepka Tied for 3rd in Abu Dhabi in Return From Knee Injury - The New York Times

Novel form of cell-free therapy revealed by researchers – Drug Target Review

Researchers have developed cytochalasin B-induced membrane vesicles which they suggest could be a new form of cell-free therapy in regenerative medicine.

Work on extracellular microvesicles (ECMVs) derived from human mesenchymal stem cells (MSCs) has revealed a potential new form of cell-free therapy.

ECMVs are microstructures surrounded by a cytoplasm membrane; they have proven to be a prospective therapeutic tool in regenerative medicine due to their biocompatibility, miniature size, safety and regenerative properties. These can be used to circumvent the limitations of existing cell therapies without losing any effectiveness.

Cell therapies are grafts or implants of living tissue, such as bone marrow transplants, used to replace and regenerate damaged organ tissue. They currently have limited applications, as they work differently dependent on conditions and the environment they are placed into. They can also be rejected by the immune system.

A study at Kazan Federal University, Russia, has investigated cytochalasin B-induced membrane vesicles (CIMVs) which are also derived from MSCs and are very similar to natural ECMVs.

Proteome analysis of human MSCs and CIMVs-MSCs. Venn diagram of identified proteins MSCs and CIMVs-MSCs (A). Distribution of the identified proteins in organelles, percent of unique identified proteins (B) (credit: Kazan Federal University).

The scientists studied and characterised the biological activity of MSC-derived CIMVs. A number of biologically active molecules were found in CIMVs, such as growth factors, cytokines and chemokines; their immunophenotype was also classified.They also found that CIMVs could stimulate angiogenesis in the same way as stem cells.

The team came to the conclusion that human CIMVs-MSCs can be used for cell-free therapy of degenerative diseases. Induction of therapeutic angiogenesis is necessary for the treatment of ischemic tissue damage (eg, ischemic heart disease, hind limb ischemia, diabetic angiopathies and trophic ulcers) and neurodegenerative diseases (eg, multiple sclerosis and Alzheimers disease), as well as therapies for damage of peripheral nerves and spinal cord injury.

The group say they are continuing to research the therapeutic potential for artificial microvesicles for autoimmune diseases.

The study was published in Cells.

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Novel form of cell-free therapy revealed by researchers - Drug Target Review

Giraffe Will Go Through Risky Procedure At Cheyenne Mountain Zoo To Treat Ongoing Health Issues – CBS Denver

COLORADO SPRINGS, Colo. (CBS4) A 16-year-old giraffe named Mahali will go through a risky procedure as animal care specialists work to treat some ongoing health issues. Animal care specialists say Mahali has arthritis and fractures in his feet, which hes recently indicated have become painful.

Zoo officials say theyve treated similar conditions before with special shoes and stem cell injections but Mahali has recently regressed in his training and isnt allowing them to attempt those treatments.

Weve exhausted all of our usual treatment options. This means we are now gearing up for an anesthetization to immobilize and treat Mahali, officials stated Wednesday.

The VP of Mission and Programs, Dr. Liza, and Giraffe Animal Care Manager, Jason, explained that giraffe anesthesia is risky but say it is in Mahalis best interest in this case.

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Giraffe Will Go Through Risky Procedure At Cheyenne Mountain Zoo To Treat Ongoing Health Issues - CBS Denver

Choosing the Best Therapy for Patients with Chronic Lymphocytic Leukemia – Curetoday.com

With many targeted treatment options for patients with CLL to use upfront, the question arises as to which one is best for the individual.

Targeted therapies, such as Imbruvica (ibrutinib), Calquence (acalabrutinib) and Venclexta (venetoclax) plus Gazyva (obinutuzumab), have been approved by the Food and Drug Administration (FDA) and have shown to keep patients in remission or reduce the risk of disease progression or death.

The most recent study is the ELEVATE-TN study, which led to the approval of acalabrutinib, Woyach, an associate professor at The Ohio State University Comprehensive Cancer CenterJames, said in an interview with OncLive, a sister publication of CURE. That study was (Leukeran [chlorambucil])/obinutuzumab versus acalabrutinib alone versus acalabrutinib plus obinutuzumab. Acalabrutinib and acalabrutinib/obinutuzumab had significantly improved (progression free survival [PFS]) with about a 90% two-year PFS rate.

In addition to using these medications alone, researchers are studying their use in combination with other drugs, such as Venclexta with Imbruvica, a type of Brutons tyrosine kinase (BTK) inhibitor. BTK inhibitors work by keeping the cancer cells from growing and have shown great results in CLL.

One study looked at combining venetoclax with the BTK inhibitor (Imbruvica) to see if you can both capitalize on the efficacy of the two agents, and then potentially get patients into such deep remissions that they can come off therapy, she said. At the 2019 ASH Annual Meeting, we had the follow-up of The University of Texas MD Anderson Cancer Center study in both the frontline and relapsed/refractory settings, in which the majority of patients are getting minimal residual disease-negative responses. There are a lot of complete responses with fairly limited follow-up off treatment. Most patients are still in remission.

Side effect profile and patient preference can be used to help guide oncologists on which treatment is best to start with, Woyach explained. We have the discussion for patients who are very high-risk, meaning those with TP53 mutations or 17p deletions, she said. The data with the BTK inhibitors looks a little bit stronger compared with that fixed duration of venetoclax/obinutuzumab. For those patients, I'm still trying to steer them towards the BTK inhibitor; however, it's not wrong to (give) venetoclax/obinutuzumab to those patients either.

Imbruvica has the stronger safety and efficacy data, Woyach added. However, with longer follow-up, Imbruvica has more side effects, such as hypertension; bleeding risk; and atrial fibrillation (AFib), or an irregular heartbeat, which has been seen in 10% to 15% of patients, generally those who are older. In addition, arthralgia, myalgia, diarrhea, bruising and gastrointestinal issues can also been experience by patients treated with Imbruvica.

Although patients have to take Calquence twice a day, the medication has fewer side effects, including less cases of AFib and hypertension. The same bleeding risk as Imbruvica is present, Woyach said. She added that the downside to the Venclexta and Gazyva combination is that they are time consuming.

Overall, these therapies continue to show great promise, but if a patient relapses or becomes resistant to therapy, Woyach explained that reversible BTK inhibitors are in development. A few of those reversible molecules (were presented) at the 2019 ASH Annual Meeting and showed very interesting efficacy; these included ARQ 531 and LOXO-305, she said.

This article was adapted from an article that originally appeared on OncLive, titled Woyach Highlights Progress and Next Steps in CLL Paradigm.

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Astellas, Adaptimmune to develop CAR-T & TCR T-cell therapies – BSA bureau

Astellas will pay Adaptimmune an upfront payment, research funding, development and commercial milestones, and royalties on net sales on co-commercialized products

Japan based Astellas Pharma Inc., through its wholly-owned subsidiary Universal Cells, Inc. and Adaptimmune Therapeutics plc, a leader in cell therapy to treat cancer, have announced that they have entered into a co-development and co-commercialization agreement to bring new stem-cell derived allogeneic T-cell therapies to people with cancer.

Astellas and Adaptimmune will agree on up to three targets and co-develop T-cell therapy candidates directed to those targets. These targets will exclude target specific T-cell products in pre-clinical or clinical trials or those developed for other partners at Adaptimmune. The collaboration will leverage Adaptimmune's target identification and validation capabilities for generating target-specific T-cell Receptors (TCRs), chimeric antigen receptors (CARs), and HLA-independent TCRs that recognize surface epitopes independently of the HLA profile of the tumor cell. The collaboration will also utilize Astellas Universal Donor Cell and Gene Editing Platform it obtained through the acquisition of Seattle-based Universal Cells.

Adaptimmune has been collaborating with Universal Cells since 2015 on development of gene-edited iPSC cell lines, for which Adaptimmune has rights to develop and commercialize resulting T-cell therapy products using its proprietary process for generating T cells from stem cells without the use of feeder cell lines.

Astellas will fund research up until completion of a Phase 1 trial for each candidate. Upon completion of the Phase 1 trial for each candidate, Astellas and Adaptimmune will elect whether to progress with co-development and co-commercialization of the candidate, or to allow the other Party to pursue the candidate independently through a milestone and royalty bearing licence, with the agreement allowing for either company to opt out. The companies will each have a co-exclusive licence covering the co-development and co-commercialization of the product candidates within the field of T-cell therapy. If a candidate is developed by one company only, the appropriate licences will become exclusive to the continuing party.

Astellas will also have the right to select two targets and develop allogeneic cell therapy candidates independently. Astellas will have sole rights to develop and commercialize these products, subject to necessary licenses and the payment of milestones and royalties.

Under the terms of the agreement, Adaptimmune may receive up to $897.5 million in payments, including:

In addition, Adaptimmune will receive research funding of up to $7.5 million per year.

Finally, Adaptimmune would receive tiered royalties on net sales in the mid-single to mid-teen digits.

Under the terms of the agreement, Astellas may receive up to $552.5 million, including:

In addition, Astellas would receive tiered royalties on net sales in the mid-single to mid-teen digits.

To the extent that Astellas and Adaptimmune co-develop and co-commercialize any T-cell therapy, they will equally share the costs of such co-development and co-commercialization, with the resulting profits from co-commercialization also shared equally. Further details governing co-development and co-commercialization will be articulated in a product-specific commercialization agreement.

The impact of this transaction on Astellas financial results in the fiscal year ending March 31, 2020 will be limited.

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Astellas, Adaptimmune to develop CAR-T & TCR T-cell therapies - BSA bureau

Melton parents of seriously ill little girl appeal for help to treat her – Melton Times

The parents of a two-year-old Melton girl, who suffers regular seizures and has brain damage, are desperately trying to raise tens of thousands of pounds to pay for treatment here and abroad to help her live a healthier life.

Anika Wojciechowski has been diagnosed with Wolf-Hirschhorn syndrome and has spent a large part of her short life being treated in hospital.

She has severe epilepsy, endures up to 90 seizures a day and often requires oxygen or CPR to revive her.

Dad, Mariusz, and mum, Katarzyna, are hopeful that treatment elsewhere in Europe can ease their daughters condition depite being told by doctors in the UK that there is little more they can do for her other than prescribing the medication she is on.

They are hopeful that a course of growth hormone therapy and, possibly, stem cell transplantation can help her.

Mariusz told the Melton Times: Anika needs to be watched 24/7 as nobody knows what the next seizure is going to be like.

Her seizures are unpredictable and so one time she will need a bit of oxygen to get over it but the next time she will have a cardiac or respiratory arrest and need CPR done before an ambulance arrives.

He added: Every day, Anika proves how brave she is and she doesnt give up despite everything that has happened to her.

Last year she spent three months in intensive care, being incubated many times and having continuous doses of morphine, ketamine and many other medical agents which kept her in a pharmacological coma to stop her continuous epilepsy attacks.

Many doctors have already given up and see no hope for her but we do continue to fight for her to get the treatment abroad which can help her.

Anika spent the first month of her life in hospital after being born at just 34 weeks and weighing only just over three pounds.

But she developed severe epilepsy and was then diagnosed with the rare Wolf-Hirschhorn syndrome, where the symptoms are a characteristic facial appearance, delayed growth and development, intellectual disability and seizures.

Last year, she was also found to have brain damage and lost her eyesight, all speech abilities and the power in her legs and hands.

In addition, she is very delicate and easily catches a cold and infections, which also result in hospital stays.

Medical professionals did not give her any chance of survival but the couple have sought advice and they say recent initial treatment in europe has perked her up.

Anika already feels and looks better, said Mariusz

She has begun to smile and, even wonderfully, laugh.

Her fragile body is getting stronger and Anika is able to partially control the movement of her head and hands.

What has brought such a great positive effect is only the beginning of the whole treatment, which unfortunately is expensive and requires travelling abroad.

Mariusz and Katarzyna have used their savings and a large proportion of their earnings to fund treatment for their daughter.

They are also grateful for the 4,000 people have pledged on online fundraising pages and collection boxes in local shops.

The couple plan to visit clinics in Poland, Italy and Germany to seek treatment and their main aim is to fund growth hormone therapy for Anika, which is not available on the NHS and which costs around 10,000 just to get started on.

Mariusz added: We are asking people to please help Anika because we know that she can have a normal life and enjoy it like other children but time is running out.

Go to http://www.facebook.com/marian.wojciech.9 to pledge money for Anikas treatment.

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Landmark Results for CaverStem Procedure Published in Journal of Translational Medicine to Create Paradigm Shift in Treatment of Erectile Dysfunction…

PHOENIX, Jan. 15, 2020 /PRNewswire/ -- Creative Medical Technology Holdings, Inc. (OTC: CELZ), a leading commercial stage biotechnology company focused on Urology, Neurology and Orthopedics using stem cell treatments, today announced publication of clinical trial data on CaverStem procedure for drug resistant erectile dysfunction (ED) patients in the Journal of Translational Medicine.

The peer reviewed publication describes a total of 140 patients treated with the CaverStem procedure (40 patients in primary trial and 100 in the clinical registry) that suffered from erectile dysfunction for whom standard drug interventions such as Cialis, Levitra, and Viagra (PDE-5) were ineffective.

The CaverStem trial, one of the largest clinical studies of a non-drug treatment for erectile dysfunction, supports the safety and efficacy of autologous, non-expanded bone marrow concentrate for treatment of ED patients.

We would like to thank all the patients and the Clinical teams which have made the CaverStem program possible. The independently monitored data demonstrated the safety of the program along with the real world clinical registry which demonstrated early efficacy signals, said Amit Patel, MD, MS, Board Member of the Company.

Its exciting to see the evolution of our patented cell based intervention first described in 2013 in the Journal of Translational Medicine (now being offered in the clinic through qualified physicians) having such a positive impact on the lives of treated patients, said Thomas Ichim PhD, co-inventor of CaverStem and Chief Scientific Officer at Creative Medical Technology Holdings, Inc.

The positive results reflected in the publication validates the many years of devotion and investment in the CaverStem Program, said Timothy Warbington, President and CEO of Creative Medical Technology Holdings, Inc. 2020 is setting up to be a breakthrough year for the company as we plan to partner this landmark publication with heavy investment in physician recruitment and consumer awareness to accelerate commercialization of CaverStem.

Link to the complete peer reviewed publication: https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-019-02195-w

About Erectile Dysfunction Erectile dysfunction (ED) is characterized by the lack of ability to achieve and maintain penile erection for intercourse. Methods used to quantify ED include the Erectile Function Visual Analog Scale (EF-VAS) and the International Index of Erectile Function (IIEF-5), however clinically it is primarily diagnosed based on symptomology. In our aging society, ED is becoming an increasing problem. According to one study 39% of men at age 40 experience symptoms of ED, whereas by age 70 the incidence rises to 67%. In this latter age group, it is believed that 50-85% of ED cases are associated with hypertension, diabetes, cardiovascular disease and dyslipidemia. Overall, it is estimated that over 30 million American men suffer from this condition.

About Creative Medical Technology Holdings, Inc. Creative Medical Technology Holdings, Inc. is a commercial stage biotechnology company currently trading on the OTC under the ticker symbol CELZ. For further information about the company go to http://www.creativemedicaltechnology.com. For more information on our CaverStem procedure please go to http://www.caverstem.com.

Forward-Looking Statements OTC Markets has not reviewed and does not accept responsibility for the adequacy or accuracy of this release. This news release may contain forward-looking statements including but not limited to comments regarding the timing and content of upcoming clinical trials and laboratory results, marketing efforts, funding, etc. Forward-looking statements address future events and conditions and, therefore, involve inherent risks and uncertainties. Actual results may differ materially from those currently anticipated in such statements. See the periodic and other reports filed by Creative Medical Technology Holdings, Inc. with the Securities and Exchange Commission and available on the Commissions website at http://www.sec.gov.

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Study: Mutations in stem cells of young donors can be passed to recipients – STAT

Doctors use stem cell transplants to treat patients with certain cancers or blood disorders. And donors, whose blood or bone marrow is used for the procedures, are typically young, for a variety of reasons.

But a pilot study released Wednesday raised the possibility that such donors are also passing along mutations in stem cells that could lead to health problems for some recipients.

The study found that nearly 45% of younger donors had mutations in the transplanted stem cells that could raise the risk of conditions that are sometimes seen in recipients, a higher rate than presumed. Researchers also reported that some of these mutations persisted and proliferated in the recipients bone marrow for at least a year.

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What remains unknown is whether those mutations are actually contributing to health problems for recipients.

The study was small, with just 25 donors included and was not large enough and did not last long enough to determine whether people who received cells with these mutations had worse outcomes after a transplant than recipients who got cells without those mutations. Dr. Todd Druley, the senior author of the paper, which was published in the journal Science Translational Medicine, emphasized that patients should continue to receive these stem cells to treat their leukemias or anemias when recommended.

What were trying to say is that now we can provide surveillance before, during, and after a bone marrow transplant so that if theres an increased risk for a particular outcome, treatment for that and surveillance for that can be instituted sooner, said Druley, a pediatric oncologist at Washington University in St. Louis.

Researchers not involved with the study praised its technical prowess, and said it was worth investigating further to see if the transplanted mutations did lead to worse outcomes for recipients projects that Druley and his colleagues have underway. But they agreed it should not yet change clinical practice.

Donors are already screened to make sure they have a clean bill of health and make for a good match for recipients, based on their immune systems. Experts said it would be unrealistic to screen every potential donor for the kinds of mutations Druley and his team found. Those mutations were infrequent, and it wasnt clear they posed health risks to recipients.

We know that younger donors are better than older donors. We know that the better the donor the better the outcomes. We dont know how these ultra-low level mutations affect outcomes at all, said Dr. Corey Cutler, the medical director of the adult stem cell transplantation program at Dana-Farber Cancer Institute.

Hematopoietic stem cells generate blood and immune cells. They are sometimes transplanted into patients with certain blood or immune disorders or cancers whose own cells have been wiped out by chemotherapy, essentially restocking the recipients with healthy cells.

But recipients of these transplants sometimes experience graft versus host disease (when the transplant attacks the recipients tissues), heart or immune conditions, or even secondary cancers. Some experts have suspected these conditions might be caused by mutations in donor stem cells, among other factors. Its in part why they favor younger donors, who are expected to have fewer mutations than older donors. (Donors from 18 to 44 account for 86% of transplants for unrelated patients. Relatives often make for better donors because they are more likely to be matched to recipients based on immune system molecules.)

Most of these mutations are probably benign. But its possible that other mutations not only pose a health risk, but also give their host cells a boost over other cells, helping them proliferate over time. That might mean someone who is 40 could have a bad mutation in one in 5,000 cells, but by the age of 50, it could be in one in 50 cells, Druley explained.

The challenge is detecting those mutations. Standard sequencing technology may pick up mutations if they appear in just a small percentage of cells, but for young donors, it would be like finding the few pebbles in a beach full of sand.

Next-generation sequencing is good if you want to find a mutation thats in 20% of cells youre looking at, or even 5%, Druley said. Were looking at mutations that are one in a thousand, or down to one in ten thousand.

For the new study, Druley and colleagues trained a more powerful tool they call error-corrected sequencing on the cells of the 25 donors, who ranged from 20 to 58 years old. (Fifty-eight would be considered older donors, but the median age of the donors in the study was 26.) They looked for mutations in 80 genes in particular, including genes that, when mutated, are associated with leukemia.

What they found: 11 donors had a collective 19 mutations that were not picked up by standard sequencing technology 16 of which were pathogenic, meaning disease causing.

The researchers also studied the recipients, finding that 14 of the 19 mutations had engrafted, or been taken up by the recipient and started to generate other cells, and were still there a year after the transplant. Thirteen of these mutations were pathogenic.

Researchers said it made sense that younger adults had these types of mutations, even if scientists hadnt previously been able to spot them.

Its known that mutations accumulate over time, said Dr. Ross Levine, a leukemia specialist at Memorial Sloan Kettering Cancer Center, who was not involved in the new study. The question has always been in other scenarios if you can detect these clones at earlier or in different contexts, and if they mean anything.

The new study was not set up to answer that last question.

Thats the next phase of this research, Druley said. Some of these mutations, if theyre going to have an effect, may not have an effect for many, many years. And we had a small population. So we didnt have enough numbers or enough time.

Outside researchers said that if these stem cell mutations do contribute to diseases once transferred to recipients, it might take so long or happen so infrequently that it would be difficult to study. Dana-Farbers Cutler said that, for example, cases of donor-derived leukemia when the recipient develops blood cancer after a transplant occur in less than 1% of transplants from unrelated donors.

If the mutations do increase the likelihood of complications in recipients, then why arent they posing a problem for the donors themselves? That might also be tied to the prevalence of these mutations, the researchers said.

In donors, these mutations might appear in, say, 1% of cells, and there is competition among cells of all different types of genetic variants to multiply. Plus, donors have healthy immune systems that can help suppress bad actors.

But if cells with these mutations make their way into recipients who have had their own cells blasted away with chemotherapy, its a new race. The mutations might give them some advantage to multiply faster than other cells that were transplanted. And as the percentage of cells with these mutations rises, they might be more likely to cause disease.

When you have these mutations in a host, it may take decades for them to expand to the point of causing issues, Levine said. In a recipient, however, its almost like youve reset the playing field.

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Study: Mutations in stem cells of young donors can be passed to recipients - STAT

Actinium Pharmaceuticals Announces Iomab-ACT Program Gene Therapy Collaboration with UC Davis in Ongoing Clinical Trial for Patients with HIV-Related…

- Trial will replace currently used chemotherapy conditioning with apamistamab-I-131, Actinium's targeted conditioning ARC, to selectively eliminate lymphoma cancer cells and stem cells to enable engraftment of stem cell gene therapy

- Anti-HIV stem cell gene therapy intended to simultaneously treat patients' HIV-related lymphoma and develop immune cells resistant to HIV

NEW YORK, Jan. 13, 2020 /PRNewswire/ --Actinium Pharmaceuticals, Inc. (NYSE AMERICAN: ATNM) ("Actinium"), announced today that it has entered into an agreement with the University of California, Davis (UC Davis) to utilize Actinium's Antibody Radiation-Conjugate or ARC apamistamab-I-131 for targeted conditioning and replace the chemotherapy conditioning being used in an ongoing Phase 1/2 stem cell gene therapy clinical trial. In the trial, patients with relapsed or refractory HIV-related lymphoma are being treated with autologous stem cell gene therapy. This is the first gene therapy clinical trial that will utilize ARC based conditioning. The clinical trial will be conducted at UC Davis and may be expanded to additional sites in the future.

(PRNewsfoto/Actinium Pharmaceuticals, Inc.)

Dr. Mehrdad Abedi, Professor, Hematology and Oncology at UC Davis and study lead, said, "This collaboration represents an exciting combination of revolutionary technologies that could further our ability to treat patients with HIV and other life-threatening diseases with gene therapy. Despite the advances made in the field of gene therapy, the reliance on non-targeted chemotherapy and external radiation as conditioning regimens is less than optimal and poses a problem that we hope to reduce or eliminate as part of this collaboration by replacing our conditioning regimen in this study with Actinium's ARC based targeted conditioning. Advances in HIV therapies have dramatically improved patient survival, but current therapies require life-long daily use to keep the HIV virus at bay, can have severe side effects, may be overcome by HIV resistance and do not address the needs of all patients like those in this study with HIV-related lymphomas. We envision a future where a single treatment of our stem cell gene therapy can cure patients of their lymphoma and HIV leaving the patient with a new immune system that can fight, be resistant to and prevent the mutation of HIV. Apamistamab-I-131's demonstrated antitumor effect against lymphoma and ability to condition patients in a targeted manner with a demonstrated tolerable safety profile in the bone marrow transplant setting makes it an ideal conditioning agent for this patient population. Based on these factors and extensive supporting clinical data in the Iomab-B program, we selected this ARC as the conditioning agent for the next phase of our trial as we believe antibody radiation-conjugates are more advanced and hold distinct advantages over novel but unproven conditioning technologies such as Antibody Drug Conjugates and naked antibodies that are beginning to be developed albeit at the preclinical stage."

In the current clinical trial, the anti-HIV stem cell gene therapy is produced by taking a patient's own or autologous, blood forming stem cells and genetically modifying them via gene therapy with a combination of three anti-HIV genes. The intended result is for the gene modified bone marrow stem cells to produce a new immune system and newly arising immune cells that are resistant to HIV via a single treatment. Conditioning is necessary prior to adoptive cell therapies such as gene therapy to eliminate certain cell types such as immune cells and stem cells in the bone marrow so the transplanted cells can engraft. Until now, conditioning in this trial, as is typical, used a multi-drug chemotherapy regimen administered over several days. This approach is non-targeted, associated with toxicities that impairs patients and restricts the use and efficacy of cellular therapy. Apamistamab-I-131, which requires just one therapeutic administration, will displace the non-targeted chemotherapy to condition patients in a targeted manner with the goal of reducing conditioning related toxicities and improving patient outcomes. Actinium and UC David will cross-reference their respective Investigational New Drug applications and will work collaboratively to obtain necessary regulatory and institutional approvals. In this clinical collaboration, Actinium will provide drug product, support for its administration and certain trial costs. UC Davis will be responsible for the production of the anti-HIV stem cell gene therapy and overall conduct of the study and its cost.

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Dr. Dale Ludwig, Actinium's Chief Scientific Officer, said, "We are excited to be working with Dr. Abedi on this clinical study and we appreciate his recognition of the value of our Iomab-ACT targeted conditioning program may provide in support of gene stem cell therapy. This targeted approach using our CD45 ARC, enables both anti-tumor activity and effective conditioning with the potential for reduced toxicity compared to non-targeted chemotherapy and external radiation in the bone marrow transplant setting. Supported by extensive clinical investigation in 12 trials and over 300 patients, a single therapeutic dose of apamistamab-I-131 is sufficient for conditioning and, due to its dual activity, even a patient with active disease could expect to receive therapy within two weeks, which is anticipated to lead to better outcomes compared to chemotherapy, external beam radiation, or exploratory approaches such as naked antibodies or Antibody Drug Conjugates. In addition, CD45, the target of apamistamab-I-131, is ideal for targeted conditioning, as it is not expressed outside of the haemopoietic system and, because it is a poorly internalizing receptor. An ARC approach which does not require internalization of its radionuclide warhead for target cell killing, is anticipated to be more viable and more effective than Antibody Drug Conjugate approaches which need to internalize their payloads. Given the potential of this ARC targeted conditioning technology for bone marrow transplant, we are grateful to Dr. Abedi for the opportunity to advance the Iomab-ACT program into the promising field of gene stem cell therapy."

Sandesh Seth, Actinium's Chairman and Chief Executive Officer, said, "Actinium is thrilled to be working with UC Davis and honored to now be part of this important trial. It has become evident that better conditioning regimens are needed for cell and gene therapies to reach their full potential. Our team is proud to be the first company to establish a clinical stage targeted conditioning portfolio for both cell and gene therapy. We are pleased to extend our ARC technology for targeted conditioning into these rapidly advancing fields and we are committed to establishing a strong leadership position in enabling these adoptive cell therapies fully realize their great potential for improving patients' lives."

Apamistamab-I-131's demonstrated conditioning and antitumor effect in lymphoma1

Actinium's apamistamab-I-131 ARC has been studied as a targeted conditioning agent in over 300 patients in the bone marrow transplant setting in the Iomab-B Program and is currently being studied in a pivotal Phase 3 clinical (SIERRA) trial in patients with relapsed or refractory acute myeloid leukemia. Clinical proof of concept has been established with Iomab-B for targeted conditioning in high-risk, relapsed or refractory lymphoma patients prior to an autologous stem cell transplant where a favorable safety profile with no dose limiting toxicities and minimal non-hematologic toxicities observed and promising efficacy with median overall survival not reached (range: 29 months to infinity) and 31% of patients in prolonged remission at a median of 36 months follow up (range: 25 41 months)1.

1) Cassaday et al. Phase I Study of a CD45-Targeted AntibodyRadionuclide Conjugate for High-Risk Lymphoma. AACR Clin Cancer Res Published OnlineFirst September 3, 2019

About Actinium Pharmaceuticals, Inc.

Actinium Pharmaceuticals, Inc. is a clinical-stage biopharmaceutical company developing ARCs or Antibody Radiation-Conjugates, which combine the targeting ability of antibodies with the cell killing ability of radiation. Actinium's lead application for our ARCs is targeted conditioning, which is intended to selectively deplete a patient's disease or cancer cells and certain immune cells prior to a BMT or Bone Marrow Transplant, Gene Therapy or Adoptive Cell Therapy (ACT) such as CAR-T to enable engraftment of these transplanted cells with minimal toxicities. With our ARC approach, we seek to improve patient outcomes and access to these potentially curative treatments by eliminating or reducing the non-targeted chemotherapy that is used for conditioning in standard practice currently. Our lead product candidate, apamistamab-I-131 (Iomab-B) is being studied in the ongoing pivotal Phase 3 Study of Iomab-B in Elderly Relapsed or Refractory Acute Myeloid Leukemia (SIERRA) trial for BMT conditioning. The SIERRA trial is over fifty percent enrolled and promising single-agent, feasibility and safety data has been highlighted at ASH, TCT, ASCO and SOHO annual meetings. Apatmistamamb-I-131 will also be studied as a targeted conditioning agent in a Phase 1/2 anti-HIV stem cell gene therapy with UC Davis and is expected to be studied with a CAR-T therapy in 2020. In addition, we are developing a multi-disease, multi-target pipeline of clinical-stage ARCs targeting the antigens CD45 and CD33 for targeted conditioning and as a therapeutic either in combination with other therapeutic modalities or as a single agent for patients with a broad range of hematologic malignancies including acute myeloid leukemia, myelodysplastic syndrome and multiple myeloma. Ongoing combination trials include our CD33 alpha ARC, Actimab-A, in combination with the salvage chemotherapy CLAG-M and the Bcl-2 targeted therapy venetoclax. Underpinning our clinical programs is our proprietary AWE (Antibody Warhead Enabling) technology platform. This is where our intellectual property portfolio of over 100 patents, know-how, collective research and expertise in the field are being leveraged to construct and study novel ARCs and ARC combinations to bolster our pipeline for strategic purposes. Our AWE technology platform is currently being utilized in a collaborative research partnership with Astellas Pharma, Inc.

Forward-Looking Statements for Actinium Pharmaceuticals, Inc.

This press release may contain projections or other "forward-looking statements" within the meaning of the "safe-harbor" provisions of the private securities litigation reform act of 1995 regarding future events or the future financial performance of the Company which the Company undertakes no obligation to update. These statements are based on management's current expectations and are subject to risks and uncertainties that may cause actual results to differ materially from the anticipated or estimated future results, including the risks and uncertainties associated with preliminary study results varying from final results, estimates of potential markets for drugs under development, clinical trials, actions by the FDA and other governmental agencies, regulatory clearances, responses to regulatory matters, the market demand for and acceptance of Actinium's products and services, performance of clinical research organizations and other risks detailed from time to time in Actinium's filings with the Securities and Exchange Commission (the "SEC"), including without limitation its most recent annual report on form 10-K, subsequent quarterly reports on Forms 10-Q and Forms 8-K, each as amended and supplemented from time to time.

Contacts:

Investors:Hans VitzthumLifeSci Advisors, LLCHans@LifeSciAdvisors.com(617) 535-7743

Media:Alisa Steinberg, Director, IR & Corp Commsasteinberg@actiniumpharma.com(646) 237-4087

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SOURCE Actinium Pharmaceuticals, Inc.

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Actinium Pharmaceuticals Announces Iomab-ACT Program Gene Therapy Collaboration with UC Davis in Ongoing Clinical Trial for Patients with HIV-Related...