NOVEMBER CELL THERAPIES: PART ONE
NIH link participating in clinical trials
Depending on the stage of the disease, we know that to cure type 1 diabetes (T1D) we need to identify who is at high risk of developing diabetes. In knowing this, we can work through disease-modifying therapies to delay, reverse or stop the progression of T1D. JDRF is working to replace lost beta cells with new functional cells. There are many people working to make this a reality and several approaches are being researched so we can be successful on this path to a cure. The first item is to discuss the breaking news out of the company Vertex Pharmaceuticals. Vertex announced that the first patient in their safety trial with the VX-880 cells had several positive changes to their T1D in the first 90 days of this trial. This patient received half of the dose of insulin-producing cells. This half dose resulted in a 91% decrease in daily insulin usage, a marked improvement in their A1C and detectable C-peptide in the fasting state along with an increase in C-peptide when challenged with a meal (or, an increase in insulin needs). There were no significant adverse events that were connected to these transplanted cells. Participants in this trial are taking immunosuppressive drugs, making this similar to participants who qualify for a cadaveric islet cell transplant. Vertex plans to file an investigational new drug (IND) with the FDA for the encapsulated product containing these cells. JDRF, along with the National Institute of Health (NIH), has had a huge role in getting this therapy to this point by funding Dr. Douglas Melton at Harvard University. Dr. Melton is the one who figured out how to create these insulin-producing cells and have them succeed. He started the company Semma Therapeutics in 2015 to produce these sells. Vertex Pharmaceuticals acquired Semma Therapeutics in 2019.
This trial is enrolling a small number of participants in sites across the United States and in Canada. Here is the link for more information for the Vertex trial.
This cell therapy article will go into a little more depth than last year’s article on cell therapies, as there has been a lot of progress and movement forward to date. JDRF is funding and developing therapies which use live cells to treat or reverse T1D. The delivery of externally derived beta cells or islets will be used to restore insulin independence and provide glucose control. JDRF is working to get these therapies to the T1D community by supporting pre-clinical and clinical testing and helping to also move them through the FDA regulatory approval process.
Currently, there are limitations to getting islet cell transplant from a donor source. One is that donor islets are very scarce when compared to the number of patients who need them. This procedure requires broad immune suppression, which has unwanted side effects. Patients who qualify for donor islet cell transplants usually have life-threatening hypoglycemic events or hypoglycemia unawareness. In looking for unlimited sources of islets cells, there are two categories: the first is called an allogenic source, which would be human-derived stem cells; the second would be a xenogenic source, such as porcine (pig) islets. The strategy is to deliver the cells and ensure that they stay alive and functional without broad immune suppression. This will require validating alternative sites for implantation, ensuring cells have an adequate oxygen supply to survive, a way to protect the cells from immune rejection, and that the cells are able to sense changes in glucose levels and secrete insulin as needed.
Islet cell transplants done at this time are placed in the portal vein of the liver. This does result in insulin independence as seen in the above graph. The control achieved through replacement of the islet cells is much better than any technological options that are available. What we have found through islet cell transplantation is that the liver is not an ideal site for these cells. The liver is where drugs and other substances are broken down. This can create a toxic and inflammatory environment that can cause the rejection of these cells. Different sites continue to be researched. There are many companies that are and have been working on this, such as Advanced Regenerative Manufacturing Institute (ARMI), Novo Nordisk, Vertex Pharmaceuticals, Evotec SE, Semma Therapeutics, and ViaCyte, Inc. There were many steps involved in getting these cells to be functional. We now have renewable sources of cells. These are stem cell-derived insulin-producing cells. Different companies are working on cells at different stages, as some are fully developed, some are progenitor cells that can mature into the islet cells found in a healthy pancreas after they have been transplanted.
The next step is delivery and protecting these cells after transplantation. There are several strategies now being considered. There is encapsulation – both macro and micro – which will be explained further. This provides a physical barrier that blocks the immune attack while ensuring cell survival and rejection. Another method is using a scaffold. Using a scaffold to improve the local environment may help to keep these cells alive and provide more functionality in local drug delivery and better oxygenation. When it comes to protection tactics, the strategy is to modulate the immune response so the implanted cells and/or device are not attacked, thereby allowing the cells to thrive. The hope is to create a localized immune-protected site instead of needing to address the entire immune system. Lastly, concerning protection tactics, is the idea of gene editing. JDRF and other companies are working to use gene editing tools to enhance the survival of implanted cells.
JDRF sees a road map to getting to successful cell therapy. The first step, where we are currently, is islet cell transplantation, requiring a person is experiencing hypoglycemia unawareness. These transplants require donor/cadaver islets and broad immunosuppression (IS). The next move will be to have a renewable cell source, which will still require broad IS. The renewable cell source will enable many more who need a transplant due to life-threatening hypoglycemia to have one. The third step down the road is the first generation that requires no broad IS. This will first be available for adults using a renewable cell source, some form of encapsulation, immune modulation, and/or gene editing. The final goal in cell replacement from an outside source is to have no broad IS, which would be made available to both adults and children. Consider this a second- or third-generation product also with a renewable cell source, encapsulation, immune modulation, and/or gene editing. In moving through these steps JDRF will be providing therapies to more T1Ds improving A1Cs, decreasing hypoglycemic events, and facilitating better time-in-range (TIR).
Encapsulation goals are to protect implanted cells from immune rejection without the use of broad IS. The idea to is protect these cells from the immune attack while allowing the exchange of nutrients, glucose, and insulin to achieve therapeutic benefit. There are two forms of encapsulation being researched: one is the macroencapsulation that you may be already familiar with; the second is microencapsulation. Macroencapsulation can house a large number of islet cells and is implanted where cells can function and be retrieved if needed. Microencapsulation is where a few clusters of cells can be protected and implanted where they can perform their function. Fewer cells provide a higher surface volume, therefore making it easier for nutrients to get to these cells. This will provide a healthier transplanted cell. In having smaller encapsulation devices such as capsules, there will need to be more of them and then the retrieval may be more challenging. The encapsulation field is also moving toward a third choice, which is nanoencapsulation that will enable the coating of clusters of islet cells. These will be much thinner than microencapsulation, which makes it better for the diffusion of nutrients and insulin in terms of implant volumes and sites where they can be transplanted. This will involve using materials shown not to elicit a fibrotic response. This response occurs when the body thinks there is something foreign and tries to wall it off in response.
Both Sigilon Therapeutics and Eli Lilly are working on creating better biomaterials that prevent scar tissue formation. They are currently getting this cell therapy into the clinic. This research will also be useful to others in the field that are looking for novel biomaterials for devices such as pacemakers, stints, or sensors. JDRF has funded Dr. Robert Langer at MIT who is addressing the biomaterial issue to prevent the fibrotic response. JDRF continues to fund different approaches in order for us to have many shots on goal.
IMMUNE MODULATION
JDRF is funding work on several strategies in the field of immune modulation:
*Work to alter the immune response to the implanted cells and/or device,
allowing cells to thrive
*Employ biomaterials for controlled delivery of drugs and work on the
presentation of helpful immune signals at the implantation site
*Research whether we could suppress rejection of implanted cells and/or reeducate the immune system to accept them
The next step is to combine work on immune modulation and tissue engineering to cure T1D. This is being accomplished with academic collaboration developing a biomaterial-based immune modulation approach. This approach includes:
*Using biomaterials for local delivery of immune signals to suppress immune rejection and obviate broad immunosuppression
*Demonstrating that prolonged survival of implanted cells that are accepted have long-term function when they are combined with short-term immunosuppression
*These collaborations have led to the founding of iTolerence, Inc., a biotech
company which is pursuing clinical development of this technology
*New potential platform technologies to help with additional immune-
modulators; these are microgels which will not need encapsulation.
GENE EDITING
Employing gene editing tools will enhance the survival and function of implanted cells. DNA is basically the plans and instructions that encode for certain proteins and how they are expressed. Proteins are made and then go on to perform whatever their function is in the cell. By editing the genes, we can modulate or affect how the cells function. This is how we can change immune activation that would result in tolerance. These are some of the important points as to why we would employ gene editing:
*Genes control cell function by controlling protein production
*Can intervene by targeting genes/proteins involved in immune recognition, autoimmunity and tolerance immunity
*Can also target genes/proteins that make cells more robust and enhance
their function
There are several JDRF Centers of Excellence that are working on immune modulation.
At the Northern California Center of Excellence, Stanford and the University of California San Francisco (USCF) are working on the immune mechanism in T1D that involves genome editing of beta cells. Work is being done to adapt the host immune system to care for the donor beta cells by genome editing of T-cell subsets. This site is also working to validate a clinical approach to induce immune-tolerance for islet transplantation.
At the New England Center of Excellence, The Harvard Stem Cell Institute (under Douglas Melton), Harvard Medical School, UMass Chan Medical School, and Joslin Diabetes Center, are working to identify genetic factors controlling auto- and alloimmunity. Alloimmunity is a type of immunity that produces an immune response against antigens from members of the same species. An example of this is when the body attacks transplanted tissues resulting in graft rejection. This is different from autoimmunity, which is the immune response attacking one’s own cell components, cells, or tissues. They are working to generate immune-evasive beta cells for transplantation through genome editing of beta cells. They are also working on better in vitro and in vivo models to test these concepts.
The University of Michigan Center of Excellence is working to improve beta cells by increasing their energetic and metabolic capacity for better function. This also will help them to survive during transplant stress.
The University of Wisconsin Center of Excellence is working on immune-evasive beta cells. Dr. Jon Odorico and his team are genetically modifying beta cells to evade the immune-response. In an earlier JDRF grant, they created cells that overexpress immunoinhibitory molecules and can be transformed into islet-like structures.
Centers of Excellence have some overlapping but different strategies to this immunity issue. As we are at the beginning of tackling the immunity issues, we will move forward faster by having more strategies at the same time.
SCAFFOLDS
The development of a scaffold containing islet cells will enable engineering of the local environment to keep cells alive. Here are some of the features that are being researched:
*A porous matrix that distributes and houses cells
*An open structure that allows filtration of blood vessels for nourishment
and that allows glucose sensing and absorption
*Delivery of oxygen to support cell survival and drugs to promote blood vessel growth
*Immune protection by providing local delivery of drugs that can help with
the presentation of immune signals
*Providing a scaffold that can contain cells that are in a micro- or nanoencapsulation device
The scaffolding will be engineered to keep these cells alive. It also will help to have the cells not be so close together, and this will help to lower the amount the cells will have to compete for nutrients such as oxygen. This will also help insulin to be able to get out into the bloodstream.
JDRF is in partnership with Sernova Corp, a company in Canada. This company is pursuing a scaffold-like approach. The approach also involves priming the skin prior to cell implantation to enhance survival of the cells. There was a promising preliminary trial result from January 2021. No adverse events were observed, the device was safe and well tolerated, the device integrated well and demonstrated ingrowth of blood vessel networks, there were indications of clinical benefit such as reduction in daily insulin requirement, and C-peptide in blood was observed.
JDRF has a part in funding all the research in this article. JDRF was also instrumental in creating the Beta Cell Consortium years ago that has been critical in moving this research forward. Below is an example of all who are working on T1D cures and therapies. This also involves equity investments in high potential pre-clinical and clinical stage companies with T1D programs that provide additional investments.
The role JDRF plays in regulatory activities for new T1D therapies is very important. All the therapies that are becoming a reality need to be approved by the FDA and accepted by the T1D medical community for patients to have access to these therapies. JDRF has been engaging the FDA since 2007 and sharing the science and technologies being developed for T1D beta-cell therapies. Seminars were developed in conjunction with the FDA on topics such as novel biomaterials, scaffolds, conformal coatings, oxygenation and nutrient supply, immunomodulatory components, and xenotransplantation.
Here you can see the breakdown on the funding for FY22 for cell therapy:
Clinical Trials:
*ViaCyte, Inc. – VC-01 (PEC-Encap) and VC-02 (PEC-Direct trials)
*Vertex Pharmaceuticals – VX-880
*Sernova Corp – Cell Pouch
*UCSF – Parathyroid gland/islet co-transplantation
*University of Alberta
*Polyclonal Tregs
*Anti-CD40L, immunotherapy
*Deviceless site (new)
Two Cell Replacement Trials available in the JDRF Minnesota and Dakotas Chapter:
Please check out other trials in our area including those for those newly diagnosed at JDRF Clinical Trial Connection
A couple of these trials are accessible in our chapter area; one which may be able to enroll someone at one of the trial sites is Vertex. Then there are others in different locations that are also listed below. Please check the JDRF Connection tool to access these trials along with many others. You may notice the UCSF trial that says parathyroid gland/islet co-transplantation. This trial comes out of the knowledge that current parathyroid gland transplants do very well and this tissue engrafts well. The trial will see if a knowledge from this type of transplant can also help with islet cell engraftment.
These statements encompass all that can be taken from this article that shows the incredible work that JDRF has funded and is funding to get us to a cure:
- Clinical Islet cell transplantation demonstrated beta cell replacement can provide a functional cure for T1D
- We are limited by scarcity of donor tissue and reliance on broad immunosuppression
- We now have a renewable source of cells – insulin-producing cells made from stem cells – which are being tested in clinical trials
- The current focus is on methods to deliver the cells that ensure they remain viable and functional, and on methods to protect them from immune rejection without the use of broad immunosuppression
- JDRF is supporting research exploring alternative sites of transplantation and methods to deliver oxygen and enhance cell vascularization
- JDRF is exploring multiple avenues to protect the cells from immune rejection – encapsulation immune modulation and genetic modification
- JDRF continues to catalyze progress through the Beta Cell Consortium and ongoing clinical trials
- Due to the investments that JDRF has made, it has significantly increased the additional investments from the private sector to develop beta cell replacement technologies
Please feel free to reach out to me with any questions to you have about the research that is currently going on along with questions about clinical trials in our area. Even if it is to have a chance to talk through the concepts so you can understand them more, and be able to share the promise we are now seeing for the future of T1D. I can be reached at debbieaevans1@gmail.com. I can also be reached at 612-810-1933 – please leave a message and I will call you back as soon as possible.