Early Safety and Efficacy Data in Cynata’s Phase 1 Trial of CYP-001 in GvHD

Encouraging Early Safety and Efficacy Data in Cynata’s Phase 1 Trial of CYP-001 in GvHD; DSMB Recommendation to Initiate Enrolment of Second Patient Cohort

Australian stem cell and regenerative medicine company, Cynata Therapeutics Limited (ASX: CYP) announced that the independent Data Safety Monitoring Board (DSMB) has recommended that Cynata’s clinical trial of its lead Cymerus™ mesenchymal stem cell (MSC) product CYP-001 should progress to the next stage as planned.

Key Highlights:

• All eight participants in Cohort A (lower dose cohort) have demonstrated at least a Partial
Response (defined as an improvement in the severity of GvHD by at least one grade compared
to baseline)
• No treatment-related serious adverse events or safety concerns have been identified
• DSMB recommendation to progress clinical trial to second cohort (Cohort B)
• Patient enrolment in Cohort B (higher dose cohort) now open at seven trial sites in the U.K.
and Australia

Cynata’s clinical trial, which is the first clinical trial in which patients have been treated with an allogeneic, induced pluripotent stem cell (iPSC)-derived therapeutic MSC product, consists of a planned total of 16 patients with steroid-resistant acute graft-versus-host disease (GvHD). The recommendation to progress to the next stage (Cohort B) followed an independent review by the DSMB of the eight participants in Cohort A. Recruitment for Cohort A commenced in May 2017, and there are currently seven trial sites active and ready to enrol participants into Cohort B.

Steroid-resistant GvHD patients today have a dismal prognosis, where mortality rates are very high. At this time, seven of the eight participants in Cohort A are alive. One participant died after developing pneumonia, which is a common finding in recipients of bone marrow transplants and similar procedures.1 This death was not considered to be treatment-related. Participants enrolled in Cohort A of the dose-escalation trial received a dose of CYP-001 that was anticipated to be at the lower end of the effective dose range (one million cells per kilogram of bodyweight, up to a maximum of 100 million cells per infusion). In Cohort B, a further eight participants will receive two infusions of CYP-001 at a dose of two million cells per kilogram of bodyweight, up to a maximum of 200 million cells per infusion.

Dr Ross Macdonald, CEO of Cynata Therapeutics, said, “We are thrilled to report this encouraging early review of the Phase 1 trial of CYP-001, which marks the first time that patients have been treated with an allogeneic, induced pluripotent stem cell-derived therapeutic MSC product. The improvement in GvHD grade observed in 100% of these gravely ill people is very promising, especially given the low dose administered in Cohort A. The positive DSMB recommendation is an important milestone that enables us to begin enrolment in Cohort B, and advance toward our goal of completing the trial later this year. A successful outcome will support the application of CYP-001 in many medically and commercially significant targets where therapeutic MSCs have shown promising results.”

Next Steps:

Patient enrolment into Cohort B is now open at seven active sites across the U.K. and Australia. Cynata looks forward to providing further updates to the market as the study progresses.

Ref: Cynata PR

Cynata & The Rubik of Cell Science

As with the sun rising in the East so have the first two pioneering programs using Induced Pluripotent Stem Cell (iPSC) technology for human clinical study. Independently initiated, but now strategic brethren, the Japanese and Australian efforts to provide a next gen proof-of-concept foundation have all the makings of a new dawn in Stem Cell Science, one that many hope will deliver on unfulfilled expectations for the field.

Methods and mechanics, protocols and parameters - these are but a few of the myriad of defining characteristics that a commercial cell product needs to elucidate in the highly complex rubik of molecular innovation and translational steps. Barcodes if you will of cell product definitions underlying the very nature of scientific clarity and positioning that will pave the road moving forward and deliver safely on The N Factor of human trials with data.

To highlight movement in this direction I’ve addressed a few questions to Dr. Ross MacDonald, CEO of the Australian stem cell company Cynata Therapeutics, on recent progress with their iPSC programs and business plan for this update review piece on the previous conversation I posted last year.


M - Cynata is poised to begin an important sector accomplishment with a first-in-man clinical trial involving a therapeutic product derived from Allogeneic Induced Pluripotent Stem Cells (iPSCs). Can you kindly provide a brief refresh for us on the cell type/technology being used, the target indication and the clinical trial sites prep/patient application/data timelines?

R - We are using a clinical grade, human iPSC as the starting material.  The iPSC cells were obtained from Cellular Dynamics International (CDI).  From these cells we manufacture our finished product, a therapeutic mesenchymal stem cell (MSC) preparation, using our proprietary Cymerus™ manufacturing process.  The target indication is steroid-resistant acute Graft versus Host Disease (GvHD) and the Phase 1 clinical trial is entitled: “An Open-Label Phase 1 Study to Investigate the Safety and Efficacy of CYP-001 for the Treatment of Adults With Steroid-Resistant Acute Graft Versus Host Disease”.  The trial will aim to recruit approximately 16 participants who have undergone a bone marrow transplant or similar procedure, and were subsequently diagnosed with steroid-resistant Grade II-IV acute GvHD.  The study centers are located in the United Kingdom and in Australia and we expect the study should conclude by the end of 2017. GvHD is a potentially fatal disease that often follows a bone marrow transplant procedure and occurs when the immune cells in the donor material (the graft) attack the recipient’s tissues (the host) as “foreign”. 

M - Your recent validating announcement that Cynata has signed a definitive License Option and Equity Investment Agreement with FujiFilm reiterates your strategy to develop and partner development programs with leading sector players. Could you review for us this strategy, the determining factors involved in the decision to sign a partner to your lead program at this stage and the synergy with FujiFilm’s Regenerative Medicine divisions moving forward.

R - Cynata’s Cymerus technology enables the economic manufacture of a consistent and robust therapeutic MSC product.  Given the very many potential therapeutic applications for MSCs (noting the >600 clinical trials underway using MSCs) it would not be possible for Cynata on its own to adequately exploit even a small fraction of the potential commercial opportunities.  Moreover, the Australian environment for biotech companies is challenging for those seeking to become a fully integrated, sales and marketing enterprise.  Accordingly, we believe the best path to ensure shareholders derive stellar returns is to partner our technology with those companies that have the resources, expertise, enthusiasm and global exposure to drive commercialisation of our products.  Clearly Fujifilm is a very active participant in the regenerative medicine sector and has shown a willingness to invest very heavily to maximise the chances of success.  They are an ideal partner for Cynata.  We have however left open the opportunity to work with other companies as well.

M - In your press release on the deal with FujiFilm you mentioned that the arrangement included “certain rights to other Cynata technology.” Are you at liberty to detail somewhat the nature of the technology and the rights granted.

R -  No.

M - Currently Cynata has targeted UK/Europe and Australia as its initial trial territories and has received favorable green light feedback from the respective regulators. Could you comment on the developing regulatory framework to commence these types of pioneering iPSC studies in the US and Cynata’s plans for clinical work in the US market.

R - We have already had very positive initial dialogue with the US FDA. We plan to progress these interactions this year, and we will certainly seek to include US centres in our clinical trials as we move forward. The Regenerative Advanced Therapy Designation process, which the FDA has recently introduced, is of great interest to us and potentially has numerous advantages, including accelerated approval, greater interaction with the FDA, assistance with study design, smaller trials, and ability to rely on real world evidence rather than solely data from formal clinical trials.

M - As Cynata is a leader in the development of Pluripotent derived Allogeneic iPSC treatment technology is there a perspective you could share that puts into context the application specific potential for programs that seek personalized treatment options with Autologous iPSC technologies versus Allogeneic iPSC approaches. Is there a case for both, putting aside the cost issues for a moment, with regard to targeted therapeutic potential, safety and immunogenicity?   

R - I do think there is a case for both, but as always it will come down to (i) the weight of clinical evidence and (ii) cost. Autologous iPSCs may have a greater role to play in tissue engineering applications, where the aim is directly replace or repair damaged tissue at a site of injury or disease.  With our Cymerus technology we have sought to provide a solution to the practical shortcomings associated with manufacturing an “off-the-shelf” allogeneic MSC product.  We firmly believe that our approach, ie using iPSCs, will yield a huge cost and regulatory advantage, at least insofar as MSC therapeutics are concerned.  The broader applications of iPSC-derived cell therapy products is being hotly debated and much research capital is being expended on developing the “super haplobanks” to make allogeneic products more practical. 

M - As previously reviewed, the IP surrounding your technology was invented by scientists at the University of Wisconsin and exclusively licensed to Cynata by the University’s IP management arm, WARF. You note that that these foundational patents are being expanded upon by the filing of additional Cynata patent applications related to progressive discoveries to the underlying technology. Could you provide some specifics at this stage as to the substance of the novel and unique aspects of the invention mentioned, given, I believe, these innovations are as yet unpublished.

R - Indeed we are seeking to build the IP platform with additional patents around new inventions in our Cymerus technology.  As these applications are in the early stages of prosecution we are unable to provide details at this stage.

M - In respect to your other program assets, could you highlight recent developments that pertain to Cynata’s pipeline and any news on initiated research into new indications, such as the positive impact Cymerus™ mesenchymal stem cells (MSCs) could have for Asthma suffers.

R - The data we reported late last year in the well-established chronic allergic airways disease model was certainly very exciting and accordingly we have been encouraged to further study the effects of our Cymerus MSCs in related models and potentially into the clinical setting.  We also have active programs underway in cancer (through Harvard/MGH) and in cardiovascular disease (with Westmead Hospital/University of Sydney).  With the success of our recent capital raising the company is now very well positioned to accelerate these ongoing programs as well as to consider other areas where we might be able to quickly build value.

M - Finally, at present Cynata is a publicly traded entity on the Australian securities exchange (ASX). Do you have any plans in the near term to reach out to more investors through a UK or US listing?

R - This is a question that stimulates much discussion around the boardroom tables of Australian biotech companies.  Certainly US and European investors have a very high level of understanding of the potential risks and rewards of biotech and the availability and quantum of capital is typically higher than in Australia.  However, an offshore listing is not for the faint hearted and some recent spectacular fails have made Aussie’s very circumspect. We have an open mind, but would prefer to really build a solid and supportive shareholder base in Australia first and thus have a solid foundation beneath us before we would contemplate a foreign exchange.

M - Thank you Ross for your time and all the best for the upcoming trial. Cheers

UPDATE: See latest Cynata program news at "Cynata's iMSCs" blog tab.

The N Factor

The mere mention of a possible stop-gap option to the grave medical realities of those that suffer, let alone a lifeline to a solution, is enough to get most patients and their families/friends talking. Clinical trials however are relatively few and far between for specific diseases and those that are available are currently akin to drawing the lottery where circumstances such as referral, timing, scale, proximity and onerous inclusion criteria set a very high bar to entry.

The vast majority of patients don’t have any options.

I’ll relay a representative case in point - a friend of mine was diagnosed recently with Stage 4 Melanoma, an advanced skin Cancer which is all but fatal in relatively short order. His doctors gave him the ticking clock and little hope. However, given his wish to live and determination to see his young son grow up he studied, turned over every rock and reached out. He landed a very rare spot as a tag along to a new immunotherapy trial. He was lucky, most are not, given he didn’t meet the strict criteria for official entry. The trial treatment saved his life.

T-Cells in Action
Hope is a cruel bedfellow with its constant draw of energy and resources from the very reservoir it seeks to fill. Yet without that flicker of a flame gasping for oxygen the very medical system built upon empirical data derived from clinical trials designed to advance knowledge wouldn’t exist.

The system needs patients and patients need the system - both rely on the other and as such require inclusive practices to further the agenda of progress towards real solutions.

Emily Whitehead
N is a strong and decisive letter in our everyday language but in investigative medicine it’s a defining research statement which confers status and validity where quantitative analysis imbues significance and wields judgement on meaningfulness. For those not on the in, the N is translational science parlance for the number of patients treated and their data sets. The lower the N the more likely there will be variability in the eventual safety and benefit outcomes when applied to the patient population at large. While the larger the N the more significant the potential correlation in delivering a safe option and potentially treating the targeted disease indication. 

As fundamental as the N is to applying the scientific method to proving the safety and potential for wide scale application, it cannot be suggested to be devoid of meaning at any level, especially considering the human impact and nascent development of promising new therapeutic modalities for treating previously unmet medical needs.

The mere fact that we will all suffer in one form or another from the debilitating conditions of age is enough to warrant more attention to the secondary benefits in N data given the lack of achieved endpoints of trialed drug interventions to-date. Combine the natural degenerative conditions of the aged with a population rife with chronic and acute medical issues that continue to overburden the system, leaving a significant population of those in need without a solution, and you have the argument for considered change.

Breakthroughs in medical science indeed offer a real opportunity to effect change and the more that can be done to allow for inclusion and support for that transformative process to occur the more representative the N will be that correlates to real tangible wellbeing data logged for the betterment of the science as well as the patient. 


Ref: Related Cancer Blog on Emily Whitehead

The Coming of Age of Pluripotent Science & Musings on a Sonogram

One of the most memorable images I can recall on the effect of catalytic dynamics for me during these years of scientific curiosity was the explosive result of sperm enzyme successfully impacting a human egg - almost Big Bang like in all its microscopic potential.

One can now extend that impact phenomena analogy to the very pertinent research and translational effect Induced Pluripotent Stem Cell (iPSC) technology has had on the field of molecular biology and regenerative medicine.

Nature - Andy Potts
It’s been ten years since Shinya Yamanaka and Kazutoshi Takahashi opened the portal to a whole new way of thinking and practicing the Art of Stem Cell Science by announcing that embryonic like properties could be regained in adult cells through molecular reprogramming.

Royal Society
Much has been written about this apex moment of foundational innovation which ushered in the era of mainstream adoption of reverse engineering techniques on human cells but as we celebrate the ten year anniversary of iPSCs the opportunity presents itself to reflect and celebrate the coming age of Pluripotent science, specifically iPSCs.

Signals of Canada, a leading destination for "insiders’ perspectives on the world of regenerative medicine and stem cell research, written by scientists and professionals in the field" is hosting a "Blog Carnival" of which this article is one of a number being written covering the iPSC anniversary topic. Please click here to read what other bloggers think.

Inherently complex the various Pluripotent states and the multitude of their progressively differentiated descendants, as they relate to human biological microsystems, have only begun to be explored and understood. The inherent processes by which these interconnected derivative cells work and communicate are by and large just now being decoded and mapped. Although it’s been only ten years since the discovery of iPSCs and nearly 20 years since the human embryonic stem cells were first isolated the progress made to-date in translating Pluripotent science into real world clinical programs is very much the focus now of countless labs in the field, thanks in large part to the advent of “open source” iPSC technology. 

Prior to iPSCs the use of hESCs and the technology associated with its clinical translation was largely a specialty area limited in scope by funding, rules, regulations and IP. The advent of iPSCs changed that and with it the stem cell industry added a universal layer of potential. Whether it be using Pluripotent derived cells as tools or more notably to develop therapeutic cell candidates for clinical use those researching and developing applications using these cells are pioneering the way forward for the emerging era of next generation stem cell products.

To put not too fine a point on it, we have only scratched the surface and in the next ten years I expect there will be a number of Pluripotent treatments on the market in various countries and many many more still in the clinic moving towards approval with positive results over standard of care or filling-in where there is currently nothing to offer patients in need.

The topic of what can we expect to see on the frontline of the developing therapeutic market using Pluripotent derived cell products is often highlighted as a discussion point and rightly so given the limited public depth of awareness on the subject and the long standing promise by the sector as a potential basis for effective treatments.

Below are some of the targets and iPSC programs representative of the state of play in the field to look out for:

Riken/HealiosMasayo TakahashiiRPE++Wet/Dry AMD++Auto>Allo
     Notes: Program will address many disease states of Retina/Eye
Astellas RegMedLanza/MacLareniRNP++Dry AMD/RP++Allo
     Notes: Program will address many disease states of Retina/Eye
UWisconsin WaismanGamm/MeyeriRNP/RPEStargardt+Allo
     Notes: Representative of next gen concept using eye "organoids" 
NEI/CDI-FujiBharti/MilleriRPEDry AMDAuto
     Notes: US Govt backed program 
Cedars Sinai/CIRMShaomei WangiRNPRPAllo
     Notes: Advanced status w/ IND enabling studies 
Kyoto UnivJun TakahashiiNCPakinsonsAllo
     Notes: Leading iPSC Parkinson program due to start in 2017
Sloan KetteringLorenz StudereNC/iNCPakinsonsAllo
     Notes: Top tier US hESC/iPSC lab moving to clinic
Scripps/CIRMJeanne LoringiNCPakinsonsAuto
     Notes: Bringing it home full circle w/ CIRM onboard 
CynataSlukvin/U WisconsiniMSCGvHD++Allo
     Notes: Entering clinic later in 2016 w/ solid pre-clinical data
Astellas RegMedRobert LanzaiMSCSepsis, Lupus++Allo
     Notes: Multiple targets across board w/ pre-clinical hPSC data
     Notes: Leading Japanese program poised to enter clinic in 2017
Novosang-Roslin/SNBTS++Marc TurneriRBCThalassaemia++Allo
     Notes: Leading UK Consortia looking to clinic in 2017
Inserm/PlatODDominique BaruchiPlateletsCancer/Surgery++Allo
     Notes: Leading French program nearing clinic in 2017 
Astellas RegMedRobert LanzaiPlateletsCancer/Surgery++Allo
     Notes: Had a leading program using research grade iPSC line in 2013
Players in CAR/Immuno SpaceiBloodCellsCancer/ImmuneAuto>Allo
     Notes: Auto/Allo B, T, NK, DC+ benefits 4 immuno product requirements

*The above listing is representative of the sector and is not at all comprehensive. Apologies to the many great programs that should be there also.

hiPSC science has industry wide support globally and is a mainstream technology acceptable in jurisdictions in which other ES methods face challenges. Translational hurdles for hiPSC are specific to their reprogramming and to the adult to youthful conversion which forms the basis of the applied technology. This presents an additional safety component to the already strict regulatory oversight applied to the clinical translation of Pluripotent programs now and in the future. 

Will they be highly successful and achieve revolutionary paradigm shifting status and establish new standards of care in their go-to-market quests? 

That is a subjective question for each and every program and one which you could speculate on, yet it would be Hype to suggest definitively without established patient data. However, the indicative MOA and technology basis of those programs on the list point to a sound foundation to work from. 

In my opinion, Pluripotent science, specifically hiPSCs as a universal technology, has the very best chance to score across the board wins for the patient in areas of unmet medical needs. 


Some of the reasons I have doggedly believed that lie in the very nature of the plasticity of the sources, youthful phenotypes, cell expression and innate modulatory properties. Other reasons specifically relate to the field’s capacity to precisely derive and modify them in-vitro while perfecting their required derivative purities and expandability to consistently replicate them indefinitely in volume under strict quality control for regulated mass market applications. 

This potential, if successfully delivered together, will usher in a new Pluripotent Era in the Stem Cell Story. 


Are we at an inflection point?

Certainly the perceived slow pace of translational activities has been a media drag on the sector, irrespective of the actual comparative timelines to move from bench to bedside. In retrospect there are still only a surprisingly small number of clinical programs in trials worldwide using Pluripotent derived cells, due in large part to stricter preclinical and regulatory standards applied to safety issues associated with these cell sources. So one would say we’re definitely due some momentum building inflection points….  

Human embryonic stem cell trials were initiated in the US some 6 years ago on the basis of only research cell lines after lengthy preclinical research and safety checks. Subsequent small studies in Europe and Korea using hESCs added additional safety data. These trials paved the way for iPSCs yet still today the only enrolled clinical trial for iPSC derived therapeutics is in Japan. This pioneering trial had been on hold for over a year as the cell source analysis flagged possible genetic instability issues and was switched out from an autologous approach to a recently approved allogeneic cell line and is due to resume in 2017. The one patient to-date receiving the iPSC based iRPE cell sheet for Wet AMD has been reported to be in good condition with no apparent safety issues associated with her procedure.

The rigorous standards of the need to use an NIH approved clinical grade cell line in the US has delayed the start of US trials on iPSCs and only just recently has one been announced as available. Pre-clinical lab work one would assume would now need to be done using that line for the clinical trial programs wishing to enter the clinic sometime in the future (yrs) or approval sought and granted for proprietary lines already used for clinical prep on existing developmental programs. This safety issue, albeit necessary and prudent, has forestalled the advancement of Western work and raised the bar from where hESCs entered the clinic.

When discussing timelines and where this segment of the sector is headed it’s important to factor in these types of regulatory hurdles one must overcome on the road to a Pluripotent IND, clinical trial approval and human phased testing. Trial design considerations require stringent oversight monitoring of Pluripotent trials and have and will slow down the translational best efforts of those academic and commercial players entering the space.

Generally if it takes longer that the average drug development process to see stem cell based products enter trials and progress through the Phases and a therapeutic emerge from any stem cell specific regulatory approval pathway people will continue to be disappointed. A scaled approach to the sector’s product entry and exit criteria seems reasonable given the variance of risks associated with different stem cell products under some form of adaptive umbrella.

Safety is of the essence and the nascent SC sector requires everyone err on the side of caution. This is the mantra I hear regularly and I can’t really say it’s not appropriate to a great extent. However, it is this writer’s opinion that the priority should not be overly weighted towards the slowest approach to protect the sector at the expense of patients willing to engage in regulated, open and comprehensive phase development programs designed to enroll and prove the science. Sufficient data can only be generated from a participatory system that is adaptive and accommodating not restrictive and burdensome by design or intent.

A Quad Pregnancy demands care & attention.

Ashley Gardner Quad IVF Reaction cnn
When I recently scanned the Pluripotent sonogram I saw some Art where 4 heads appeared! Unlike our shock horror double take when 2 appeared in my wife’s scan, I was glad to see the 4 represented there, happily squished together and well. One seems to be growing bigger at the expense of a couple of the others but by and large it’s a Bridge Gang willing and able to take on the challenges when alive and kickin. I personally look forward to seeing them all born healthy and grow, in addition to their Olympic caliber Adult cousins. That would give us semi-oldies the best chance when it´s our turn to ask for help from those wise and experienced in the Jedi ways of healing. This is where Advocacy for Cures comes in. 

Hope is a powerful force and will always be there for patients in need. Unfortunately the reality is that most next generation Pluripotent cell solutions are still a few steps away, if not more, for those that suffer. High science, low science, no science - too many people continue to be excluded, lack alternatives, suffer & die from disease. Stem Cell Science offers potential solutions and requires stakeholders to rally around programs and data that deliver real world results, even marginal benefits over existing options while awaiting more advanced solutions.

To conclude I have reported on the stem cell industry, specifically the Pluripotent segment for many years, and it has been easily influenced by sentiment and competitive currents rather than sharpening its aim on achieving sector growth. What we all care about most are real solutions for the long list of conditions that continue to ail us and for those that we love. Rather than future technology leading, current programs built on the foundation of pioneering efforts in both the Adult and Pluripotent fields need to be clinically accessible and then successfully delivered widely. Supporting and driving all safe and effective stem cell solutions will propel the entire sector forward.

Safety with pace, open and inclusive. Driving patient centric solutions forward as a community, in a modernized regulatory environment, by design and for the people.

Advocacy for Cures. 



Cell Press Nucleus - "iPSCs: A Decade of Discovery" (comprehensive review issue)

Cell Stem Cell Editorial: "10 Questions: Clinical Outlook for iPSCs" Cell Stem Cell, Vol 18, Issue 2, 170-173, DOI: 10.1016/j.stem.2016.01.023 (included in review issue ref above)

Ilic, D. and Ogilvie, C. (2016), "Human Embryonic Stem Cells — What Have We Done? What Are We Doing? Where Are We Going?". Stem Cells. doi:10.1002/stem.2450

The Niche, P.Knoepfler: "Yamanaka's baby turns 10 so here's a top 10 list of IPS cell hot button bullet points"  

Balancing Paradigms with Mesenchymal Stromal Cells

Steve Gschmeissner/Science Photo Library
Innovation isn't uniquely devoid of commonality of adoption by discipline. Rather the likelihood of acceptance generally tracks evenly to historical norms in parallel with society's openness to progress and the search for solutions. However, the impact of technological change is variable and dependent on societal factors related to income and health. One could argue the greatest benefit comes when change drives both economic prosperity and improved health standards.   

While the average pace of technological innovation slowed some decades ago the recent rapid rise of medical science has taken on the mantle of sustainability for growth. The dramatic impact potential of fundamentally transformative practices in healthcare is being fueled by access to new knowledge and a greater sharing of insight. 

Today, due to the convergence of various technology led disciplines, there are many important catalysts for paradigm shifting change. A key criteria common to all are the Drivers - fundamental products or processes that opens up the gates to new realms of understanding and acceptance. At each juncture a bridge must span the divide and a stake ground into new terrain. 

Are MSCs a Driver that can forge a paradigm shift in stem cell healthcare & how did we get here?
The investigation of bone marrow (“BM”) stem cells led to the establishment and widespread clinical practice using cells of the mesodermal blood lineage via bone marrow transplantation – known as hematopoietic cells (“HSCs”).
The first use of these BM  stem cells as therapy was pioneered over 50 years ago when transplants were first introduced experimentally to treat leukemia. However, as with most donor tissue the understanding of immune rejection of foreign non-self cells was and still is of major concern for the successful treatment of disease using allogeneic (donor) tissue. This is even the case when immuno-histocompatibility is done via matching of the cells to the host. This complication has stymied the field of cellular therapeutics due to the severe adverse events that can result from the administration of donor derived cellular treatments. In the case of BM transplantation they routinely cause Graft versus Host Disease (“GvHD”) as a result of the treatment, with approximately 50% of all such patients reporting complications. The percentage of mortality as a result of this last resort treatment intervention even today is staggering with up to 17% of all severe liver/gut GvHD cases resulting in death(1).
As a field the discovery and isolation of Mesenchymal Stromal Cells (“MSCs”), a small subset of BM niches representing less than 0.01% of all HSCs, was a watershed moment. It was a true breakthrough as these cells were found to be able to replicate as multipotent precursors and can be differentiated into fat, bone and cartilage. The isolation and clonal nature of these MSCs opened up a whole new avenue for cellular investigation. Further sources of MSCs were discovered in a range of bodily tissues, including fat, perinatal tissue and dental pulp. The technology for human application of these adult cells gave rise to the stem cell industry we know today. Upwards of 500+ clinical trials using MSCs are registered currently in the US central database clincaltrial.gov for a variety of unmet disease indications (2).
In addition, there is a large growing trend of undocumented cases using MSC products in private medical offices as marketed treatments via autologous (self-to-self) therapies (3). These unlicensed medical practitioners using MSCs products are the subject of considerable debate as to where the line should be drawn between required regulatory oversight and freedom of medical use in private clinics for autologous treatments. The US FDA is currently reviewing draft guidelines (4,5,6,7) for treatment products using MSCs. They are preparing to define what constitutes more than minimal manipulation and cell use parameters. This is with a view to determining clinical trial requirements for MSC biologics, in keeping with current drug development procedures already in place.

Safe and Effective?   
The prospect of MSC utility for therapeutics has been due in large part to the evident immunological privileged nature of MSCs and their potential for universal application without immunosuppressive drugs – unlike HSCs themselves. Although MSCs have an antigen profile they lack major class antigens which makes them relatively immune-privileged to the host system thereby allowing for donor derived cell treatments without treatment rejection in low dose regimes.      
The Scientist - Keith Kasnot
The properties of MSC have been appropriately described as “ambulatory” and “paramedic” – i.e. they’re built to respond to injury in the body and assist in its repair. How they detect, migrate and signal, in addition to what biological manner they act, and what way in different circumstances, is a source of considerable study. It seems clear though now that their “method of action” (“MOA”) is modulatory in nature via complex regulatory mechanisms (8). One such mechanistic attribute is via the excretion of bioactive factors (vesicles, exosomes et al) and work to facilitate cell to cell communication networks (9).
Much has been written about the potential of tissue derived MSCs as a treatment option for a host of acute, immune and degenerative conditions. However, the field is still developing and protocols are being tested and adjusted to maximize possible outcomes. I’ve added an overview video below on the challenges and issues faced by MSCs product developers’ to-date by a leading expert in the field Dr. Jacques Galipeau of Emory University. The presentation highlights a number of findings on research and data in this sector and is well worth watching
Dr. Jacques Galipeau of Emory University

As mentioned, and referred to in the video, numerous clinical studies are underway on the use of MSCs and case reports have been published on both the potential benefits and in certain cases a lack of statistical benefit in patients receiving these cells from a variety of tissue sources.
With regard to the clinical trial results there is clear validation of MSCs safety profile, which is fundamental to their successful translation. Potential treatment efficacy of MSCs is suggestive to-date of positive activity on various outcome measures in a number of reported studies. These positive results are counter-balanced with questions on method of action (“MOA”) and some failed studies. This somewhat mixed picture generally points to issues relating to the development of medicinal products and cellular biologics should be viewed as no different.
A few of the better known company examples of MSC sector developments in the sector are briefly summarized below with links to the company for further details on the data.
  • TiGenix (adipose/fat) – has moved on from the 1st EU approved and marketed autologous (“auto”) MSC cell therapy called ChrondroCelect for cartilage repair to an allogeneic (“allo”) product strategy with solid Phase III results in hand for Cx601 in Crohn’s Disease. This will mark their first allo indication nearing approval with other adipose stem cell products in the pipeline. 

  • Mesoblast (BM) – bought the first approved western auto cell therapy Prochymal for GvHD from Osiris which had mixed results and was never released. They are developing a full in-house line-up of allo product candidates with good support data and are partnered with a Teva Pharma. Notable pipeline news include marketing approval of TemCell in Japan for GvHD with local partner JCR Pharma (repackaged Osiris product) and solid data in late stage trials (MSC-100-IV for GvHD also, MPC-150-IM for heart and MPC-06-ID for back pain, amongst others).

  • Athersys (BM) – lost Pfizer as a program partner for MultiStem after releasing mediocre data in ulcerative colitis. A second Phase II read-out, this time in stroke, also failed to meet endpoints. However, newly released interim data in its ongoing stroke study is now suggestive of positive results from the homing-in strategy on potential earlier treatment window benefit. Also of note are the additional clinical programs in development for cardiovascular and inflammatory/immune indications. In addition there’s a solid validation deal with Healios of Japan for MultiStem in that market and use of the product for Healios’ ongoing development programs.

  • Pluristem (placenta) – “PLX” product line for vascular, muscular and immune indications in early stage clinical trials (PI & PII) with solid data in muscle and critical limb ischemia. Promising preclinical results for bone marrow repair with government sponsorship for rapid route to market in acute radiation syndrome.

  • Vericel (BM for heart program) – previously known as Aastrom with a long history of development of auto MSCs for heart and CLI indications with poor accumulated data continues to develop the heart product in clinical studies with recent positive data after previous endpoint failure, indicative of statistical benefit. In 2014 they secured additional auto cell therapy products from Sanofi (Carticel & MACI – cartilage and Epicel – skin) which had previously received certain market authorizations and are generating revenue with patient benefit.

Indicative data sets for comparative analysis and ratio breakout are yet to be tabulated with regard to which conditions and methodologies the cells work well for and in which cases they don’t help all that much or at all. However, one must be cautious when assessing the efficacy value of cellular products as they are biologics and there are many issues relating to their degree of effectiveness, such as: their source; derivation method; inherent donor variability; passage potency; culture conditions & scale-up manufacturing; cold chain methodology; target indication; patient population; disease states and application methods, amongst others. As a result not all cellular products will perform well in human studies. These issues play a significant role in whether they achieve benefit in tests on patients, and to what extent in relation to standard of care. Although the jury is still out there is a general agreement based on empirical data that these cells are on the whole safe, when developed and used appropriately. Where they have been shown to have positive outcome and biological activity there is acknowledged room for improvement with regard to enhancing efficiency, potency and cell mechanistic action, which is encouraging.
One aspect of the development of industrial scale cellular therapies speaks to the need for increased replicative capacity, lower passaged products and standardization via use of optimization technologies and shifting to pluripotent cell sources instead of donor derived batch processing of multipotent cells.
Octane Bioreactors
As a result of this progressive development culture method adjustments gleaned from the early pioneering work of MSC development are giving rise to efficiencies of process and improved manufacturing protocols for next generation methods in both multipotent and pluripotent products. The above mentioned early leaders in MSC product offerings are beginning to line up their treatments for entry to the market, while the sector looks to prepare and trial the more advanced cell factories of the future.

UC Davis MSC Investigators
This momentum is also being driven by the rise of synthetic constructs using MSCs - the personalized tailoring of targeted medicines for improved performance. MSCs possess inherent homing and immunomodulatory properties and therefore are ideal for use in combination with gene and nano technologies. In addition, the extraction of the inherent cell properties of MSCs for standalone biologic products adds to the overall picture and excitement in the field.

MSC products are representative of the wider cell therapeutic field and are the standard bearers in the effort to bridge the shifting paradigms of new treatment modalities for patients in need.

Ref: Sector Update on Asian Market for MSCs > "Cell Therapy in Asia Erupts with Partnerships and Joint Ventures"