Some thoughts on US Cell Manufacturing Roadmap

by Alexey Bersenev on June 23, 2016 · 1 comment

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As you may know, last week US-based National Cell Manufacturing Consortium issued very interesting report – Cell Manufacturing Roadmap. What is it all about? Here is a quote from the report, which gives background information:

The Georgia Research Alliance (GRA) and Georgia Institute of Technology (Georgia Tech) recognized the opportunity to advance innovative technologies and techniques that can overcome current cell manufacturing challenges and support long-term growth of the cell manufacturing industry. Together, GRA and Georgia Tech established the National Cell Manufacturing Consortium (NCMC) and led the development of this roadmap, with funding from the National Institute of Standards and Technology (NIST) Advanced Manufacturing Technology Consortia (AMTech) program. This roadmap identifies challenges that currently constrain cell manufacturing and provides a pathway for developing, advancing, and implementing advanced technologies over the next 10 years to enable large-scale, cost-effective, reproducible manufacturing of high-quality cells.

You can also learn more from Georgia Tech press release. The report makes a point for necessary development of cell manufacturing technologies in US as national interest. The bulk of Roadmap is composed of actions plan for development of cell manufacturing technologies in the next 10 years. By some reasons, it gives confusing definitions, for example – autologous cells:

– cells harvested, expanded, and later administered to the same patient as a point-of-care cell-based medical product

Why narrow it to point-of-care? What about central manufacturing of commercial autologous cell products – the thing that many big industry players are trying to accomplish?

In general, plan of actions for the next 10 years, described in the Roadmap, is very good, I like and I agree with almost all of it, but… it left me with two big questions.

First, the Roadmap highlights the necessity for development of new tools and technologies, but it does not mention a great variety of currently existing tools. By some reasons, the Roadmap’s authors have ignored all that technological wealth, which was created by variety of manufacturers specifically for cell therapy industry or adopted from Biotech. Why so? I didn’t get it, guys. For example, Cell Processing Roadmap plan for the next 10 years –

* Define methods for growing autologous products in the absence of antibiotics
* Develop automated, closed systems that allow for parallel manufacturing of multiple patient samples
* Develop a reagent and method for large-scale T-cell activation

All of these have been done already! If currently available tools are not perfect, why not assess them in report, highlight advantages/ disadvantages and give expert’s opinion on necessity of developing new ones or improvement of existent ones?

I’ve picked only 3 examples, but the same thing applies to cell expansion, separation, storage, tracking, cryopreservation, monitoring, quality control… There are hundreds of tools available right now! I think, we actually have the opposite problem – too many tools to try and play with! Not enough time, money and manpower to try them all and pick a few!

My second question is who and how will execute the Roadmap’s proposed plan? Yes, a lot of things must be done in order to get US to the next level in cell manufacturing, but who will do it all and how will it be monitored? Some positions from 9-years plan in the Roadmap look too ambitious to me. They could be accomplished only with great financial support, strong leadership and sophisticated management system. The Roadmap is a request for financial support, but we don’t know for sure how well it will be funded by government. Also, there is no NCMC org chart to monitor plan execution and efficiency.

It’s very hard to imagine how all positions in cell manufacturing technologies roadmap could be executed in the next few years. For example, who will search for manufacturers and tell them what to do? Who will ask FDA to create working groups and who will ensure their function? I have the same questions about creation of workforce and training. Examples from training roadmap:

* Launch graduate and postdoctoral industry internships that include preparatory curriculum with instruction on industry skills for productivity (e.g., how to keep a laboratory notebook, how to manage intellectual property), case studies of successful and failed processes and products, and rapidly changing guidance documents such as those from the U.S. Food and Drug Administration (FDA)
* Create a university training model with continuous industrial engagement (e.g., survey industry on needed skills and knowledge gaps) in areas of cell manufacturing knowledge, including logistics, revenue, intellectual property, and confidentiality
* Engage local community and technical colleges to help train the entry-level workforce in the skills that industry has identified as critical to advancing cell manufacturing

All these must by accomplished by 2018, according the plan. I love the idea, but is it realistic to accomplish in 2 years?

Overall, it is very interesting document. Even if only half of proposed plans will be accomplished in the next 9 years and if it will be funded, I’ll be very happy. I hope, some authors of the Roadmap will read this post and clarify my questions.

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Cells Weekly – June 19, 2016

by Alexey Bersenev on June 20, 2016 · 0 comments

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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. Cell manufacturing roadmap
US-based National Cell Manufacturing Consortium issued this week the first document – Cell Manufacturing Roadmap. The roadmap is a collaborative project, which outlines the future directions for development of cell therapy manufacturing infrastructure as national priority in US. that can enable large-scale, cost-effective manufacturing of therapeutic cells. From Georgia Tech press release:

… the Georgia Research Alliance (GRA) and the Georgia Institute of Technology (Georgia Tech) have launched the National Cell Manufacturing Consortium (NCMC), an industry-academic-government partnership that recently released the National Roadmap for Advanced Cell Manufacturing. Establishment of the consortium and development of this 10-year national roadmap was sponsored by the National Institute of Standards and Technology (NIST).

2. Gene therapy of metachromatic leukodystrophy – interim report
Researchers from San Raffaele Scientific Institute (Italy) reported results of ad-hoc analysis of gene therapy trial for fatal demyelinating disease – metachromatic leukodystrophy. Preliminary results are great:

At the time of analysis all children had survived, with a median follow-up of 36 months (range 18–54).

A progressive reconstitution of ARSA activity in circulating haemopoietic cells and in the cerebrospinal fluid was documented in all patients in association with a reduction of the storage material in peripheral nerve samples in six of seven patients. Eight patients, seven of whom received treatment when presymptomatic, had prevention of disease onset or halted disease progression as per clinical and instrumental assessment, compared with historical untreated control patients with early-onset disease.

This trial is one more “licensing targets” of GSK.

3. New method for expansion of adult stem cells
New method for long-term expansion of epithelial stem cell was described this week in Cell Stem Cell. Using dual inhibition of SMAD signaling pathways, researchers were able to expand “airway basal stem cells from multiple species”. The senior author said:

“This new methodology opens up new avenues for research in any airway disease, such as asthma or COPD,” says Jayaraj Rajagopal, MD, of the MGH Center for Regenerative Medicine and the Harvard Stem Cell Institute, senior author of the report. “While in the past we could only expand stem cells for a few generations, now we have the ability to generate enough cells to last multiple laboratories for years of experiments. Our system is also very simple, avoiding the complexities of former culture systems and making it more accessible to many labs.”

“We also found that the same methodology works for many tissues of the body — from the skin to the esophagus to mammary glands. Many of these organ tissues cannot currently be cultured, so it remains to be seen whether scientists in these areas will be able to grow stem cells from samples acquired from other minimally invasive procedures, including the collection of secretions. If all this becomes possible, it would represent a big step forward for personalized medical approaches to disease,” he says.

4. A decade of iPS cell discovery
Nature posted nice news feature article on “iPS cell decade” – How iPS cells changed the world. The article emphasizes clinical translation of iPS cell technology:

Developing and testing a therapy in even one person has been educational, says Yamanaka: it took one year and US$1 million. He expects future therapies to use donor-derived iPS cells from a cell bank, rather than making them for each patient.

Takahashi plans to compare banked iPS cells side-by-side with those derived from patients, to observe any differences in immune reaction. She intends to apply to the Japanese government to resume her macular-degeneration trial “very soon”, but when asked, would not specify a timeline.

5. About F-class cells discovery
Jovana Drinjakovic of the Signals blog wrote a nice piece about discovery of F-class cells by Andras Nagy lab.

“Some scientists have a paranoia trying to show that what we are creating is the same as what naturally occurs in our bodies. But what’s natural? Everything that we have created, including embryonic stem cells, is just as artificial as our F-class cells,” says Nagy. Despite scientists’ best efforts to imitate the body’s environment, tweaking the nutrients, growth factors or oxygen until they’re just right for growing cells and tissues in the lab, these conditions are man-made and, according to Nagy, could clearly be considered artificial.

6. New methods and protocols:
Large-Scale production of neurons from human pluripotent stem cells in 3D culture (Stem Cell Rep)
Isolation of murine embryonic hemogenic endothelial cells (JoVE)
Generation of functional podocytes from human iPS cells (Stem Cell Res)
Lentiviral gene transfer into human and murine hematopoietic stem cells: size matters (BMC Res Notes)


Cells Weekly – June 12, 2016

by Alexey Bersenev on June 13, 2016 · 0 comments

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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. Genomic analysis of multiple pluripotent stem cell lines sets quality standards
Scientists of NIH-funded “Progenitor Cell Biology Consortium” reported first results of genomic analysis of 64 human iPS/ES cell lines from 10 laboratories. Interestingly, only 64% of lines met “basic quality criteria”, some of them were contaminated. Raw data from this ongoing analysis are accessible via Synapse platform.

The resource presented here provides a standardized and annotated dataset for the characterization of hESC and iPSC that can be applied to the discovery of molecular determinants underlying specific biological properties of iPSC and their use for future clinical applications.

Senior author said:

“It was very surprising to us the high number of unstable cell lines identified in the study, which highlights the importance of setting safety standards for stem cell therapies,” said Carolyn Lutzko, PhD, senior author and director of translational development in the Translational Core Laboratories at Cincinnati Children’s Hospital Medical Center. “A good number of the cell lines we studied met quality standards, although the unexpected number of lines that did not meet these standards could not be used for clinical therapies.”

2. Clinical trials update
I’ve picked two clinical trials, results of which were published this week. First, Canadian Ph2 study, which assessed hematopoietic cell transplantation in multiple sclerosis. Some patient stories and mass media reporting made a big buzz about positive results of the trial. The study was small (n=24), uncontrolled, but results are really impressive. Cautionary note:

The lead author, Mark Freedman, of the University of Ottawa, was cautious about how the results should be interpreted, saying, “The sample size of 24 patients is very small, and no control group was used for comparison with the treatment group. Larger clinical trials will be important to confirm these results.
“Since this is an aggressive treatment, the potential benefits should be weighed against the risks of serious complications associated with aHSCT, and this treatment should only be offered in specialist centres experienced both in multiple sclerosis treatment and stem cell therapy, or as part of a clinical trial.”

The second study, assessment of commercial Tigenix product-candidate (Cx611) in refractory rheumatoid arthritis. Allogeneic adipose tissue-derived mesenchymal stromal cells were infused intravenously in 3 different doses (3 cohorts of patients). 141 adverse events were observed in 53 treated patients, but the authors deemed it as “non-toxic, well tolerated” intervention. Interestingly, there was no direct dose – clinical effect correlation observed. The lower dose was the most efficacious.

… a trend for clinical efficacy was observed. These data, in our opinion, justify further investigation of this innovative therapy in patients with RA.

3. Advance in antibody-based bone marrow conditioning
Researchers from Harvard described a new experimental method of condidtioning preparation for hematopoietic stem cell transplantation. Unlike conventional toxic radiation and chemotherapy, the authors used antibody for precise depletion of hematopoietic cells in bone marrow:

Here we report an internalizing immunotoxin targeting the hematopoietic-cell-restricted CD45 receptor that effectively conditions immunocompetent mice. A single dose of the immunotoxin, CD45–saporin (SAP), enabled efficient (>90%) engraftment of donor cells and full correction of a sickle-cell anemia model. In contrast to irradiation, CD45–SAP completely avoided neutropenia and anemia, spared bone marrow and thymic niches, enabling rapid recovery of T and B cells, preserved anti-fungal immunity, and had minimal overall toxicity.

The idea of using antibody-based conditioning is not new and it has reached the clinical trials. However, CD45 antibody in a form of immunotoxin, seem like more precise and less toxic approach.

4. New method for in vivo selection of gene-modified cells
Markus Grompe’s lab reported a methodology for efficient selection of gene-modified liver cells in vivo. How it was done:

Alongside the therapeutic transgene, the authors inserted into hepatocytes a short hairpin RNA targeting an enzyme that, when knocked down, made the cells resistant to a drug called CEHPOBA. Healthy animals received liver-specific vectors to express a model gene, human factor 9, and then were given CEHPOBA or saline for several weeks. The animals receiving saline control saw no change in gene expression in hepatocytes, whereas animals receiving the drug CEHPOBA saw an order of magnitude increase in factor 9, indicating that the gene-corrected cells were pharmacologically selected in a living animal.

Great model, but maybe very toxic. Comments on potential toxicity:

But what about the dangers of using a drug to deliberately injure liver cells? Grompe says that is not as risky as it sounds because babies are sometimes born with a condition that mimics the liver-damaging effects of the CEHPOBA drug. Yet they can fully recover if treated.

Kathy High, president of Spark Therapeutics, a gene therapy company in Philadelphia, Pennsylvania, calls the new strategy “clever,” but she’s wary of injuring any liver cells deliberately.

5. New methods and protocols:
Isolation and expansion of human MSC from placenta (JOVE)
In vivo tracking of human hematopoiesis using vector integration sites (Cell Stem Cell)
Influence of factors of cryopreservation and hypothermic storage on MSC (PLoS ONE)
Adaptation of a low-cost 3D-printer for precise cell placement (Biofabriacation)
Culturing human pluripotent and neural stem cells in an enclosed cell culture system (JoVE)
Quantitative lineage tracing to identify multiple lineages of tissue-specific stem cells (Gen Dev)


10 companies to watch – part 7

by Alexey Bersenev on June 11, 2016 · 0 comments

in RegenMed digest

This is 7th issue of Ten Companies to Watch. Here I pick and overview the most interesting companies in stem cell/ cell/gene therapy/ regenerative medicine field. I’m focusing on new startups, but considering any other “under-appreciated” companies. As always – I’m open to your suggestions.

Here is my new list without particular order:

1. Cell Design Labs
This startup is aiming to commercialize approaches for therapeutic cell engineering, developed by Wendell Lim’s lab. With the first switch-on CAR T-cell study, cell therapy community got very excited about Lim’s work. Two more studies on engineering of CAR T-cells came up earlier this year. Recently Kite Pharma struck a deal with Cell Design Labs.

2. Vitruvian Networks
Recently launched company by GE Ventures in partnership with Mayo Clinic. The company is developing the first of its kind software, which will connect and provide a network of cell/ gene therapy tools manufacturers via digital cloud. This is the first concept of “internet of things” for cell/ gene therapies.

3. OxStem
University of Oxford spinout, which commercializes a concept of “in situ cell programming therapy”. This pre-clinical company is identifying small molecules, which will stimulate or “reprogram” tissue resident stem/ progenitors cells with therapeutic outcome. The company has raised £16.9 million this year, which is a record amount for academic spinouts in UK.

4. iCELL
Japanese company, which is developing approaches for creating organs from iPS/ ES cells in the animals via blastocyst complementation. Company was founded 6 years ago by famous stem cell scientist Hiro Nakauchi.

5. TxCell
French clinical-stage company, developing cellular therapeutic products, based on regulatory T-cells. The company was founded in 2001, but recently captured my attention, because of their new platform – ENTrIA. CAR-Tregs is the first attempt to use CAR T-cells outside of oncology. This year, the company has launched collaborations with 2 academic institutions for development of CAR-Tregs for therapy of autoimmune diseases.

6. AvroBio
Launched this year, startup from Canada/US has a stellar team behind. The company is developing cell/ gene therapy approaches for rare diseases (Fabry disease) and immunotherapy for cancer.

7. BioCision
US-based company, which provides tools for standardization of cold chain logistics. In the recent years, Bioscision developed and introduced to the market a number of innovative award-winning products. I’d also highlight a great stylish design of Biocision’s products.

8. WindMIL Therapeutics
Very new startup company, which is aiming to commercialize marrow-infiltrating lymphocytes (MIL) product in some hematological malignancies. The technology was developed by Johns Hopkins University’s researches. Last year, results of the first clinical trial were published.

9. Recombinetics
US-based company, which uses gene editing techniques in livestock. The company captured my attention, because it started to team up with academics in creation of human-animal chimeras and humanized pigs for organ bioengineering.

10. Homology Medicines
Newly launched gene editing/ therapy stratup from US. The company’s technology of gene editing is based on homologous recombination. The company recently raised $43.5M.

Disclaimer: This list reflects solely my opinion and sympathy. I have no financial interest in companies, mentioned in this post. This information should not be considered as financial advice.


Cells Weekly – June 5, 2016

by Alexey Bersenev June 6, 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. Recent cell-gene therapy products approvals Starting from good news – two new cell therapy drugs were recently approved on a market. First, UK-based GSK scored EMA […]

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Cells Weekly – May 15, 2016

by Alexey Bersenev May 16, 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. ISSCR Guidance for translation of stem cell research It was probably the most discussed news this week. The International Society for Stem Cell Research (ISSCR) has […]

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Not Lost in Translation: ISSCR Guidelines 2016

by Alexey Bersenev May 15, 2016 regulation

One of the biggest news this week was a release of final updated 2016 version of the Guidelines for Stem Cell Science and Clinical Translation (you can download pdf version here). Everyone who involved in stem cell research and/ or clinical translation of stem cell-based interventions should read this document! I think, ISSCR did a […]

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Cells Weekly – May 8, 2016

by Alexey Bersenev May 9, 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. Advances in growing human embryos in vitro and 14-days rule debate This week researchers from Rockefeller University and U of Cambridge reported improved in vitro system […]

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New generation has no problem with gene editing applications

by Alexey Bersenev May 8, 2016 notes

Results of very interesting survey were published in the latest issue of Cell Stem Cell. It was the first big social media survey about attitudes to human genome editing technologies, performed by researchers. Here is methodology of the study: We developed an online survey about attitudes to the application of genome engineering in different contexts […]

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Cells Weekly – May 1, 2016

by Alexey Bersenev May 2, 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. Vitamin increases mice lifespan via stem cells modulation mechanism International group of researchers have published very interesting study this week, where demonstrated that nicotinamide adenine dinucleotide […]

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