Cells Weekly – August 21, 2016

by Alexey Bersenev on August 22, 2016 · 1 comment

in notes

Cells Weekly is a digest of the most interesting news and events in stem cell research, cell therapy and regenerative medicine. Cells Weekly is posted every Sunday night!

1. “Money back guarantee” for cell-gene therapy drug
High prices for marketed cell/ gene therapy products is a hot and controversial topic. For example, approved gene therapy drug Glybera was priced in 2015 as high as 1 million euros in Europe. The second approved in Europe gene therapy drug Strimvelis was recently priced for 594,000 euros. Still very expensive, but the twist is that manufacturer GSK offers “money back guarantee” policy:

“The drug has to deliver what you say or we don’t pay,” says Luca Pani, director general of the Italian Medicines Agency, known as AIFA, which set the price and terms during negotiations with the British drug giant. “If it does not work, they will return the money.”

This is historic moment for the field of cell/ gene therapy. GSK was considering different options in pricing/ reimbursement and decided to blaze a trail in such new model as “money back guarantee”. We will continue to watch post-marketing commercialization sales and adoption of Strimvelis.

2. CRISPR whistleblower
This week, email from whistleblower revealed some information, related to ongoing CRISPR patents fight:

In the e-mail, sent on February 28, 2015, Lin called the Broad’s claims “a joke” and “unfair to me and [to] science history.”

Lin’s account is striking not only because he worked in Zhang’s lab at the time but because he is listed as an inventor on Broad’s earliest patent filing, from December 2012.
The e-mail was sent as part of a job request to Doudna. In it, Lin, who is from China, seemed ready to barter inside information and assistance with the patent case in exchange for a job. “I am willing to give more details and records if you are interested or whoever is interested to clear the truth,” he said.

The Broad Institute posted very long and detailed response:

Although the rotation student’s email makes several claims, the Opposition Document does not include any evidence to support them.
Abundant evidence already shows that the student’s claims are false…

In a meantime Editas Medicine spent $10.9M this year only to pay Broad “legal bills in patent dispute over CRISPR”.

3. Results of RENEW cardiac cell therapy trial
Phase 3 clinical trial to assess autologous CD34+ cells in refractory angina was initiated by Baxter Corp. in 2012 (later managed by Bazalta – Baxter’s spin off). Couple of years ago, company suspended enrollment and later decided to terminate the trial. The results of terminated trial were recently published. The study analyses enrolled 112 patients (planned enrollment 444). Primary end points were not met. Some secondary end points were barely met. So, strategic business decision to stop the trial was probably based on interim analysis of the data.

4. Antibody-based conditioning in hematopoietic stem cell transplantation
Researchers from Stanford University described a new method for antibody-based conditioning of bone marrow in experimental hematopoietic stem cell transplantation. They added anti-CD47 antibody to previously used anti-c-Kit:

We show that host HSC clearance is dependent on Fc-mediated antibody effector functions, and enhancing effector activity through blockade of CD47, a myeloid-specific immune checkpoint, extends anti–c-Kit conditioning to fully immunocompetent mice. The combined treatment leads to elimination of >99% of host HSCs and robust multilineage blood reconstitution after HSC transplantation.

Antibody-based conditioning is not new approach and such antibody as anti-CD45 underwent clinical trials before. Antibody combinations could be more efficient and less toxic.

5. Advances in hematopoietic cells expansion
Sara Nolte of the Signals blog wrote a nice post on recent advances in hematopoietic stem cell expansion. She covered recent study about role of miR-125a and approach of startup company ExCellThera.

6. Testing self-renewal of human CD271+ MSC
Researchers from University of Lund (Sweden) described isolation and testing of self-renewal potential of CD271+ human mesenchymal stromal cells:

Furthermore, CD271pos/CD140alow/neg BMSCs gave rise to non-adherent sphere colonies (mesenspheres) with typical surface marker profile and tri-lineage in vitro differentiation potential. Importantly, serial transplantations of CD271pos/CD140alow/neg BMSC-derived mesenspheres (single cell and bulk) into immunodeficient NOD scid gamma (NSG) mice showed increased mesensphere numbers and full differentiation potential after both primary and secondary transplantations. On the other hand, BMSC self-renewal potential decreased under standard adherent culture conditions.

6. Plans of Fujifilm in regenerative medicine
Japanese company Fujifilm made a big buzz with aquisition of US-based iPS cell developer Cellular Dynamics International in 2015. CIRM’s blogger Karen Ring recently interviewed Fujifilm’s manager of Regeneratvie Medicine devision Toshikazu Ban:

FCDI plans to start iPS cell therapy clinical studies in the U.S. for age related macular degeneration in the year 2017, and clinical studies for retinitis pigmentosa, Parkinson’s and heart failure around 2019.

7. Gene therapy patient stories
Ricki Lewis of DNA Science Blog posted an overview of few patient (and companies!) stories, who underwent pioneering gene therapy interventions. Highly recommended to read!

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Cells Weekly – August 7, 2016

by Alexey Bersenev on August 8, 2016 · 0 comments

in notes

Cells Weekly is a digest of the most interesting news and events in stem cell research, cell therapy and regenerative medicine. Cells Weekly is posted every Sunday night!

1. Anti-aging trial uses young blood
New clinical trial (sanctioned by FDA!), launched by company Ambrosia has captured a lot of attention this week. It uses “young plasma” for evaluation of potential anti-aging effects in healthy volunteers. But volunteers have to pay:

… a startup company has now launched the first clinical trial in the United States to test the antiaging benefits of young blood in relatively healthy people. But there’s a big caveat: It’s a pay-to-participate trial, a type that has raised ethical concerns before, most recently in the stem cell field.
The firm’s co-founder and trial principal investigator is a 31-year-old physician named Jesse Karmazin. His company, Ambrosia in Monterey, California, plans to charge participants $8000 for lab tests and a one-time treatment with young plasma. The volunteers don’t have to be sick or even particularly aged—the trial is open to anyone 35 and older. Karmazin notes that the study passed ethical review and argues that it’s not that unusual to charge people to participate in clinical trials.

The trial was highly discussed and criticized on twitter due to ethical issues. I’d also recommend you to read a post on Science-based Medicine – Parabiosis – The Next Snakeoil:

As of right now, young blood transfusions as the next elixir of youth is enjoying its 15 minutes of fame. The science is genuinely interesting, and seems deserving of further research. What is clearly needed is high quality clinical research, before any clinical claims are made.

2. NIH to lift a ban of human-animal chimeras research funding
Last year, US funding agency NIH put a moratorium on human-animal chimera research, due to ethical considerations. This week, NIH announced that it could be reconsidered, based on public comments. From the STAT:

In the blog post, Wolinetz said the NIH was creating a steering committee that would advise NIH officials on funding decisions regarding early embryonic human-animal chimeras. Research conducted with nonhuman primate embryos would only be supported after a certain stage of embryonic development, she wrote. For now, the NIH is asking for feedback on the proposed rule changes through Sept. 4.
The blog post also said that the NIH is not going to fund research that involves the breeding of chimeras that include human egg or sperm cells. In theory, that could lead to a mostly human embryo being carried in a mouse womb, which would presumably be miscarried.

Very good news!

3. Global distribution of direct-to-consumer stem cell clinics
Very interesting study was published this week in Cell Stem Cell. The authors mapped 417 unique businesses, which marketing unproven stem cell-based interventions worldwide. Surprisingly, the highest concentration of clinics (websites) were in US and Australia. See maps here.

Our findings of increased overall activity at the global level lend new quantitative support to the large body of media and scholarly reports that direct-to-consumer stem cell marketing remains widespread. We show that the global industry engaged in direct-to-consumer marketing of stem cell interventions in English shows geographic concentrations in highly developed countries, including the US.

4. Big deals in cell-gene therapy industry
This week, two “big deals” in industry have captured my attention. First, Pharma giant Pfizer has acquired gene therapy startup company Bamboo Therapeutics. Potential size of the deal is more than $0.5 billions! With this acquisition, Pfizer “aims to become industry leader in gene therapy”! Great example of how small molecules drug companies may switch to gene therapy.
Second deal is related to CART-/TCR field. Biotech giant Regeneron jumped into CAR T-cell game through partnership with Aditcet Bio. Interestingly, Regeneron decided to jump in now, because developments in allo- CAR T-cells. Regeneron thinks that auto- CAR T-cell model is not commercially viable!

5. Profiling cellular immunotherapy
New York Times has posted a good long piece about history and key people behind of progress in cellular immunotherapy of cancer. My favorite part:

Somewhat predictably, success provoked jostling and envy. Rather than being allies against a disbelieving world, the pioneers now had something worth fighting over — credit, and the gleam of a possible Nobel Prize.
While the Sloan Kettering researchers had done some of the early genetic engineering, they did not publish strong results in five patients until 2013. By then, they had been scooped by Dr. Rosenberg with one patient and Dr. June with three.

Highly recommended!

6. Pay-to-participate “trials” in NCT database
The Washington Post has very interested story about a patient, who came across “pay-to-participate” trial, listed on ClinicalTrials.gov database:

She scoured the government-run website ClinicalTrials.gov, and focused on stem-cell therapy — a promising but unproven approach for her condition.
She thought she had scored with StemGenex Medical Group, a company in La Jolla, Calif., and called for more details about a study it was doing. The screener asked a long list of questions, then dropped a bomb: If Smith wanted in, she’d have to pay “associated” costs. Total charge: $14,000.
“I was outraged,” said Smith, a retired hospital administrator who knew enough about clinical studies to realize that the price tag was unusual. Most trials are free, and some even pay people to take part because of the possible risks and inconvenience involved.

ClinicalTrials.gov database is highly criticized for lack of information about potential charges and legitimacy of listings.

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Will Prodigy change everything?

by Alexey Bersenev on August 6, 2016 · 5 comments

in cell product, cell separation

In the last decade advanced cell therapies are becoming highly commercialized. Industry developers, in general, favor so-called centralized model of cell product manufacturing/ delivery. In centralized model, one big manufacturing plant produces and delivers many many (thousands) products within a country or internationally. In the last few years, Biotech and cell therapy companies (Novartis, Kite Pharma, UniQure…) heavily invested in development of centralized facilities. In the other camp, academics, physicians and tools manufacturers are betting on decentralized or “point-of-care” model of cell therapy manufacturing/ delivery. You can read more about pros and cons of each model in the recent reviews – here and here. But I’d like to focus today on potential catalyst for shifting from centralized to decentralized model.

Proponents of decentralized model of cell therapy delivery would like to use relatively simple/ user-friendly, automated, closed system-based device, which can do many manufacturing processes at once. We call this type of devices “all-in-one”. Of course, “all” is not equal 100% , but combining many major processes, which are usually described in bioprocessing as separate “unit of operations”. Three years ago, German company Miltenyi Biotec has launched new device CliniMACS Prodigy (CE mark in Europe). I’d consider Prodigy’s launch as the first attempt to introduce a prototype of “all-in-one” device to clinical cell therapy world. Unlike previous generation of devices with capability to do more than one process, Prodigy went as far as integration of cell separation, magnetic cell sorting and cell culture.

Since launch, seem like Prodigy is doing well on the market (as much as I can say from attending conferences). Prodigy clinical validation reports are available now for CAR T-cells, mononuclear cells from bone marrow and peripheral blood, CD34 cell selection, NK cells and virus-specific T-cells. The main advantage of Prodigy, of course, is process integration capability. Importantly, it is fully automated, closed system device, which can save a lot on time and labor. I’d like to highlight few disadvantages of Prodigy:

  • capability to produce only one batch at time (1 patients –> 1 device)
  • high complexity and absence of backup device (equal alternative) underlies high risk
  • low flexibility of cell incubation unit (limited volume/ cell concentration)
  • relatively high cost.

Now, I’d like to discuss the main potential impact of Prodigy and devices alike. I think, Prodigy could be a catalyst for shifting from currently widely accepted centralized model to “point-of-care” model of cell manufacturing/ delivery. Devices like Prodigy is exactly what most proponents of decentralized manufacturing model were dreaming about. It could, potentially, “democratize cell therapy” by making clean room facilities obsolete and simplifying whole manufacturing process by pushing few buttons and hanging the bags. Single use disposable of multifunctional device is a replacement of class 10,000 clean rooms. Full automation is replacement of labor. Importantly, it will work nicely only for autologous (personalized) cell therapies, where cost of manufacturing is very high and starting material is very variable. In this case, cost of auto- cell product will be equal cost of manufacturing, no profit. Hospitals and patients will love it and jump on it! Allogeneic cell products manufacturing will be taken (almost entirely) by industry into centralized plants.

I think, it may work especially nicely for few processes and few indications (for example, CAR T-cells in B-ALL). If your hospital wants to have multiple cell therapies for multiple indications, Prodigy may not be universal answer. Ideally, big multidisciplinary hospital would have cell therapy facility with both types devices “all-in-one” and “plug-and-play” (multiple devices for multiple processes). But if you’re looking only for getting your CAR T-cell program going in hem/oncology on a budget, Prodigy alone could be the solution.

Finally, I’d like to notice that Prodigy is just at the beginning of its way in clinical cell therapy. We may see more and better “all-in-one” devices in the future. We don’t know for sure if fundamental shift from centralized to hospital-based model will finally happen for some autologous cell products in some indications. Miltenyi’s people firmly believe (based on what I’ve learned from few talks on different conferences) that it may take years, but finally decentralized “point-of-care” model will prevail for autologous cell therapies.

What do you think? Will Prodigy change everything?

Disclaimer: This post is neither advertisement nor endorsement, but invitation for discussion. I’m not a user of CliniMACS Prodigy. I do not have any conflicts, related to Miltenyi Biotec.

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Cells Weekly – July 31, 2016

by Alexey Bersenev on July 31, 2016 · 0 comments

in notes

Cells Weekly is a digest of the most interesting news and events in stem cell research, cell therapy and regenerative medicine. Cells Weekly is posted every Sunday night!

1. Dispelling the myth of premature aging of cloned animals
Very important study, proving that cloned animals don’t have serious health problems with age, was published this week. Researcher from University of Nottingham, analyzed health condition of 13 cloned sheep, including 4 sisters of famous Dolly the Sheep. Because Dolly had some health issues before death, the scientists believed for long time that cloned animals do not age normally due to development diseases and cloning-related abnormalities. It is the first study “to assess the long-term health outcomes of somatic cell nuclear transfer in large animals”. This news was massively covered by the media and blogs. From New York Times coverage:

Similar evidence disproving premature aging in cloned animals was previously found in mice and cows, said Jose Cibelli, who studies reproductive cloning at Michigan State University. The study of the sheep confirms that once cloned animals survive the first few years of life, they won’t die any sooner than other animals.
“It really changes the perception of how people look at cloning,” said Charles Long, a scientist who studies artificial reproduction at Texas A&M University and was not involved in the study.
Many scientists hope that changes in perception will lead to advances in reproductive technology that will enable us to provide food for a growing global population, save endangered species and develop advanced therapies. Scientists involved in and separate from the study don’t think it will mean we might clone humans anytime soon, nor do they condone it, but they can’t say someone won’t try.

2. Results of Phase 3 stem cell trial in Crohn’s disease fistulas
Belgian cell therapy company Tigenix this week published results of Phase 3 trial, assessing adipose tissue-derived mesenchymal stromal cells in perianal fistulas of Crohn’s disease patients. It was one of the biggest stem cell trials in Europe, conducted in 49 centers. The study was designed as randomized, double-blind and placebo-controlled. As announced by company last year, the study met primary end point – combine remission. (51% in experimental group versus 36% in placebo). Tigenix submitted marketing authorization application to EMA earlier this year and expecting approval by the beginning of next year.

3. Controversy around new gene editing technique NgAgo
New gene editing technique NgAgo was described by Chinese researchers this year. Since the publication, some doubts about reproducibility were expressed on the Niche blog. Since more and more labs were trying to reproduce technique, the controversy came out. Paul Knoepfler covered reproducibility of NgAgo on his blog in details here and here. You can also join and follow PubPeer discussion.

4. American poll on human enhancement
This week U.S. Pew Research Center released results of large poll about human biomedical enhancement technologies. There were specific questions about such technologies as gene editing, brain chip and synthetic blood. The short conclusion:

Americans are more worried than enthusiastic about using gene editing, brain chip implants and synthetic blood to change human capabilities.

But, of course, devil in details. First, worried majority is only about 60%. Second, about 90% of surveyed knew almost nothing about such thing as gene editing. Third, (quote) “those familiar with gene editing are more inclined to wont it for their child” in case of risk of serious disease.

5. Impact of cryopreservation on T-cell subsets
SamplingScience blog posted a snapshot of the study about impact of cryopresevation on composition of human T-cells from PBMC.

T cells were more sensitive to cryopreservation than other cells. Our results indicated that submitting the thawed cells to a 1 h rest period improved the detection of some cell markers when compared to fresh samples. In contrast, cells submitted to a 24 h rest period, or to none, were less representative of fresh sample distribution.

6. Fresh reviews:
Senescence in Human Mesenchymal Stem Cells – Implications in Stem Cell-Based Therapy (Int J Mol Sci)
Cellular GFP Toxicity and Immunogenicity (Stem Cell Rev Rep)
Bioengineered Livers (Eur Surg Res)

7. New methods and protocols:
Generation of induced pluripotent MSCs from human dermal fibroblasts using recombinant proteins (Stem Cell Res Ther)
Production of tissue-engineered intestine from expanded enteroids (J Surg Res)
In vitro generation of fertile oocytes from mouse primordial germ cells (PNAS)
cGMP production of patient-specific iPSCs and photoreceptor precursor cells (Sci Rep)
Isolation, characterization, cryopreservation of human amniotic stem cells (PLoS ONE)
In vivo testing of iPS cell-derived 3D cardiac tissue (Sci Rep)
Depletion of mouse cells from human tumor xenografts to improve downstream analysis of target cells (JoVE)
Tissue-like microgel arrays for evaluating stem cell differentiation (Sci Rep)
3D cryo-imaging for studying of biodistribution of human MSCs (Stem Cells TM)
Comparison of a xeno-free and serum-free culture system for human ES cells with conventional culture systems (Stem Cell Res Ther)
Comparison of KnockOut™ serum with FBS for culture of limbal epithelial cells (J Ophtalmol)

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Cells Weekly – July 24, 2016

by Alexey Bersenev July 25, 2016 notes

Cells Weekly is a digest of the most interesting news and events in stem cell research, cell therapy and regenerative medicine. Cells Weekly is posted every Sunday night! 1. CRISPR clinical trial in China Nature reported this week about the world’s first clinical trial, involved CRISPR gene edited cells. The trial is planning to start […]

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Cells Weekly – July 17, 2016

by Alexey Bersenev July 18, 2016 notes

Cells Weekly is a digest of the most interesting news and events in stem cell research, cell therapy and regenerative medicine. Cells Weekly is posted every Sunday night! 1. Resolving Betatrophin controversy I’ve followed controversy around pacreatic beta-cells growth factor betatrophin, described by Harvard’s Doug Melton (read here and here). This week, “controversy resolution” report […]

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Fibroblasts versus mesenchymal stromal cells – lost identity

by Alexey Bersenev July 16, 2016 mesenchymal

I’ve written before about Pieman Hematti’s opinion piece on Similar identity of mesenchymal stromal cells (MSC) and fibroblasts. Recently, Hematti’s lab published results of new study, which attempted to find any phenotypic and immunological differences between fibroblasts and MSCs. Four well-established, widely used fibroblasts cell lines from 3 different original tissues were compared with adipose […]

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Cells Weekly – July 10, 2016

by Alexey Bersenev July 10, 2016 notes

Cells Weekly is a digest of the most interesting news and events in stem cell research, cell therapy and regenerative medicine. Cells Weekly is posted every Sunday night! 1. The end of Chondrocelect Beligian cell therapy company Tigenix announced plans for withdrawal of their autologous chondrocytes implantation product Chondrocelect from European market. This is business […]

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Cells Weekly – July 3, 2016

by Alexey Bersenev July 4, 2016 notes

Cells Weekly is a digest of the most interesting news and events in stem cell research, cell therapy and regenerative medicine. Cells Weekly is posted every Sunday night! 1. Proliferation of “unproved stem cell clinics” in US The biggest buzz this week was a study by @LeighGTurner and @pknoepfler on “stem cell clinics” in US. […]

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Clinical Cell Processing News – part 3, 2016

by Alexey Bersenev July 2, 2016 clinical lab

Clinical Cell Processing News is a series about new protocols, products and techniques for clinical-grade cell processing and manufacturing. Cell processing devices, cultureware, bioreactors, GMP-grade reagents, cell separation techniques. This series is posted every 2 months. FEATURED: Protocol: PBMC isolation protocol using SynGenX-LAB System (SynGen) Validation of CliniMACS Prodigy for clinical CAR T-cell manufacturing (Cytotherapy) […]

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