There is a growing need for improvements in synthetic assembly techniques aimed at constructing artificial tissue constructs both for therapy and further research. In recent months, we highlighted recent work on combinatorial assembly approaches for vascular tissue scaffold assembly, as well as 3D scaffolds for iPSC differentition – a drop in the bucket of the ever-increasing body of work in a field that is, despite significant medical impetus, still for many of its applications, in the development stage.
Since our entry last year, “Towards ‘Smarter’ 3D Scaffolds,” which highlighted improvements in biomaterial design that are introducing innovative combination and hybrid materials coated with biomaterials such as growth factors or cells for improved in vivo behavior, the field has seen some remarkable progress in the form of innovative research surface thereby expanding the existing capabilities for tissue regeneration using such combinatorial techniques.
Just a few months ago, work by David Mooney’s lab at Harvard University, published in Nature Biotechnology, disclosed an innovative, injectable scaffold/drug hybrid that self-assembles in the body into macroporous structures that, once delivered to the target tissue, alongside delivery of the drug, recruit host cells to provide a substrate for adhesion and tissue regeneration. The structures, based on mesoporous silica rods, were tested in mice and shown to be able to recruit dendritic cells in the host whose behavior can be further modulated by sustained release of inflammatory signals from the scaffold. The authors tested the delivery of vaccines from the scaffold with promising results based on the effect on systemic helper T cells and cytotoxic T cell levels evaluated after injection.
Elsewhere, further evidence was presented that particular tissues require very specific and tailored three-dimensional surfaces for optimal behavior. Work by Laura Ballerini’s lab at the University of Trieste, published in Nature Scientific Reports, highlighted a hybrid scaffold system which was based on porous scaffolds made of PDMS (polydimethylsiloxane) mixed with carbon nanotubes for enhanced growth and function of primary neurons. The scaffolds were fabricated with multi-walled carbon nanotubes, which are thought to improve interaction with dendrites owing to their high electrical conductivity and large surface area. Their results showed that such scaffolds allowed improved interfacing of neuronal cells with the nanomaterial structure and thereby enhanced the activity and function of cellular network dynamics.
Amidst the growing body of work, some of which was highlighted here, is the reality that the field is steadily moving in the direction of tailor-made scaffold constructs that reflect the specificities of the particular tissue that the construct is aimed at. This is hardly a surprise, but a realization that researchers are increasingly embracing.
As of today, there are over 8,600 ongoing trials related to cell therapy listed on clinicaltrials.gov, most of which are in phase 2 (~4,000) or phase 1 (~2,500), with more than 1,000 in phase 3, although only a handful of products have reached the clinical approval stage.
The primary reasons why the maturation of cell therapy trials to commercial stage is slow, and why only a very small fraction of trials reach clinical approval, are thought to be, broadly, the following:
- Product development and characterization. Cell therapies are complex: different cell types, various tissue sources and treatment type (allogeneic vs autologous) introduce significant levels of complexity to the development of CT products. This also includes raw material sourcing.
- Manufacturing and scale up. Manufacturing and scale-up to clinical stages is marred with difficulties for reasons which include the need to tightly ensure reproducibility, consistent potency, a control of manufacturing costs, process and environmental controls (e.g. closed systems, batch-to-batch variations etc.)
- Regulatory landscape. Not fully defined regulatory guidelines.
Regulatory landscapes are, moreover, set up differently in different markets: the Japanese regulatory landscape follows different regulations than doesthe FDA in the USA. For that reason, some US companies are engaged in trials in foreign markets (for example, Japan), due to more favorable approval hurdles than those in the USA.
As far as product development is concerned, process controls start with raw material sourcing. The cellular starting material is an integral part of the living, functional cells that constitute the active drug substance of cell therapy products. It is for that reason that tight controls must be in place to ensure traceability and quality control of raw material for cell therapy products. Moreover, special considerations in starting material qualification for patient-specific products (autologous or allogeneic) vs. off-the-shelf allogeneic products (multipotent or pluripotent stem cell-derived) are of significant importance too.
Manufacturing considerations also relate to closed systems (cell therapy products cannot be manipulated after manufacturing and must thus ensure aseptic processing during the manufacturing and formulation stages), environmental controls and scaleability.
Finally, logistics in relation to transport, shipping and storage during these steps is critical in ensuring integrity of the product is maintained by the time the cell therapy product reaches the end user facility (usually the hospital). Cryopreservation strategies must not only ensure the product is fully potent by the time of administration (usually stored in the frozen state), but the time from thawing to administration must also be accounted for (during which the product is stored at temperatures far above freezing).
All of this must be done while ensuring cGMP compliance, which is related to the maintenance of tightly controlled production, process and personnel flow documentation.
We have previously discussed efforts aimed at improving standardization for cell therapy product development across various markets, and the gaps that currently exist in harmonizing various guidelines, including the key organizations operating in that space.
If you have particular comments/thoughts in relation to what you consider the most important considerations to be with regards to cell therapy product development, we would love to hear them. This is part of a concerted effort to understand the developer and market sentiments that align with bringing more clarity to issues that will ultimately help cell therapy products find more favorable paths to market.
Feel free to share them in the comments or email us at firstname.lastname@example.org.
A recent article in the Sun Sentinel highlighted the fast pace of growth that the cell therapy field in South Florida is currently enjoying: over 40% of the 5,500 biotech companies operating in the State are located in South Florida, the article states—and they have contributed to a staggering 75% growth of the biotech industry in the pasty six years.
This fast pace of growth is not expected to slow down soon. Companies such as Akron Biotech—which was recently profiled in a separate Sun Sentinel article—are heavily investing in new technologies, new laboratory space, new personnel and new partnerships to seize this momentum and maximize the potential of new research and medical needs.
Academic institutions such as Palm Beach State College, The Scripps Research Institute and Florida Atlantic University have been critical in providing educated and trained workforce professionals to fill the growing needs of the biotechnology and cell therapy industry employers in the area.
Akron has been a strong supporter of the local biotech community’s efforts since our inception, by partnering with academic institutions and other companies.
Palm Beach State College’s Biotechnology program has been a long-term partner of Akron Biotech, collaborating on not only professional development, but technology transfer and various strategic partnerships as well.
This year, Akron Biotech will participate in PBSC’s 4th Annual Biotech Networking Event and Career Panel which brings together professionals that cover a variety of roles in the local biotech community, including academic leaders (Dr. Ken Dawson-Scully of FAU and Dr. Joseph Kissil of Scripps Florida), management professionals (Dr. Liton Roy, Manager of Laboratory Operations at Sancilio & Company and Mrs. Julie Wilkinson, COO at ImmunoSite) as well as industry professionals (which includes Mrs. Shannon Pasley, laboratory technician at Akron Biotech) to discuss careers in manufacturing, academic research and corporate biotechnology.
The event takes place on April 14th at PBSC’s Palm Beach Gardens campus, from 5:30 – 7:30 PM. For more details, go here.
For those not in the vicinity, Akron Biotech is gearing up to participate at the International Society of Cellular Therapy‘s annual meeting in Las Vegas, Nevada, which takes place from May 27-30 at Caesars Palace.
The meeting will highlight Akron’s products, research and development and exciting news, and we will be showcase a number of research presentations. Mark your calendards in advance, and we will be sharing more details closer to the event. Contact us if you would like to set up individual meetings.
Akron will also participate at a number of other meetings throughout the year, which will include the 4th Annual Tissue Engineering and Regenerative Medicine World Congress, which takes place from September 8-11 in Boston, MA and Stem Cell Meeting on the Mesa, from October 7-9 in La Jolla, CA.
We will be posting more details about these meetings as the time comes.
Release criteria for cell therapy products typically tend to vary among manufacturers. When the products are cell-based, moreover, establishing a set of analytical data to characterize said product is frequently an arbitrary decision driven by convenience, assay availability, experience and convention. These rules, however, do not imply a legally-bound responsibility on the part of the supplier, they merely offer that particular cell therapy product’s quality information.
It has been widely documented that one of the major obstacles to any commercial impact of cell therapy products has been the lack of a single reliable set of standards against which such products are characterized.
Measurement of biological activity of a growth factor, for instance, often relying on cellular behavior in a dose-response assay, assumes an inherent variability which is dependent on the specific treatment conditions and the analytical environment during the biological assay. Variability, as we previously discussed, may be introduced due to factors independent of cellular behavior, and this would include raw material source or protocol modifications. Traceability becomes important in ensuring that such variables are not contributors to the final product quality, but, again, no standards currently exist to force suppliers to abide by them.
It is at this point important to mention that the cell therapy industry has attempted to bring clarity to these issues by forming various standardization agencies. These are, broadly:
- Manufacturing standards (ISO)
- International accreditation agencies (FACT, AABB)
- Pharmacopeias (USP, EP, JP)
All of the above organizations work within their own remits to address certain aspects of the cell therapy development process, to ultimately generate more compliant products and processes. These agencies do not only represent cell therapy products – they broadly address various consumer and medical products and materials. However, while there are many agencies, there is still a strong need for further harmonization efforts to bring about consensus among the different agencies and avoid uncertainties when developing a specific cell therapy product.
One such harmonization alliance is AHCTA (Alliance for Harmonization of Cell Therapy Accreditation), whose objective is to “[create] a single set of quality, safety and professional requirements for cellular therapy including haematopoietic stem cell (HSC) transplantation.”
Achieving standards, however, ultimately requires complying with guidelines for the measurement of the quality of cell therapy products – from biological assays to parameters that are part of the product’s release testing specifications.
The National Institute of Standards and Technology (NIST) is hosting a two-day workshop on strategies to improve measurement accuracy for cell therapy products. This includes measurements such as cell viability, functionality, cell counts and includes both talks as well as hands-on tasks.
The workshop takes place on May 11 and May 12, 2015 at NIST in Gaithersburg, MD. More information as well as registration options can be access by clicking here.
T cell therapy is in the spotlight once again. This week, Science Translational Medicine dedicated an entire special issue to immunotherapy. Among the articles and perspective, the journal published a review, by Ton Schumacher at Netherlands Cancer Institute and Carl June at the University of Pennsylvania, on the regulatory and manufacturing hurdles currently facing T cell therapy as it fights its way to market. The review, accessible via this link, highlights hurdles such as lack of standardization and scale up when laying down the path for T cell therapy to wider market acceptance. Scale-up manufacturing is a significant concern for therapies that, by the time regulatory filings are underway, have only been manufactured in smaller clinical batches. These manufacturing runs have to be scaled up in ways that will not compromise the efficacy criteria that have been established for the cellular product ahead of the manufacturing campaigns, and thus avoiding to jeopardize any regulatory claims. Moreover, personalization of T cell therapies introduces a new set of criteria which further convolutes simple paradigms for immunotherapy that had been established before.
At the recent 13th International Congress on Targeted Anticancer Therapies, Prof Antoni Ribas at the UCLA Jonsson Comprehensive Cancer Center, Los Angeles discussed the current commercial climate around T cell therapy and claimed that we are now at the cusp of a shift in tide wherein there is enough evidence to know that such therapies work, and, as consequence, we should expect more commercial investment in the further commercialization of such approaches.
You can watch the interview here.
Akron Biotech is part of this shift moving forward: we have been involved in the entire process of cell therapy development – from planning through to raw material qualification and supply and manufacturing and process validation for more rapid regulatory approval – and are innovating in those areas. We are always happy to answer any questions about your process – contact us here.
In related news, Akron Biotech has this week been featured in the Sun Sentinel in an editorial feature. CEO Claudia Zylberberg discussed recent developments at the company, including our recent expansion to a larger facility and much more. Read the feature here.
Cell Therapy Highlights: Stem cell-based HIV Trials, Progenitor Cell Transplantation and Germline editing controversy
This week, we highlight some of the more interesting headline-making news and research findings that have appeared over the past week.
FDA Approves Sangamo’s Stem Cell-based HIV Cure Trials
The Food and Drug Administration (FDA) last week approved clinical trials to test a functional cure to treat HIV based on gene editing of blood stem cells. The technique, developed by Sangamo BioSciences, is based on blood-producing stem cells derived from HIV-infected patients whose genes are edited to to create a mutation in the protein CCR5. This mutation eventually prevents HIV from attaching to the body’s blood cells. While HIV remains in the affected patient’s body, it has no ability of infecting T cells.
The trials will be conducted at the City of Hope Medical Center in California by Sangamo BioSciences and researchers from the Keck School of Medicine at the University of Southern California.
Promising pancreatic progenitor cell transplantation findings for Type 2 diabetes published in Stem Cell Journal
The lab of Timothy Kieffer, of the University of British Columbia in Canada, published promising results of an animal study on the use of stem cell transplantation for the treatment of Type 2 diabetes in the journal Stem Cell Reports last week. The authors treated mice with induced type 2 diabetes with encapsulated pancreatic progenitor cells derived from human embryonic stem cells alongside anti-diabetic drugs. After transplantation and alongside treatment with anti-diabetic drugs, the authors found that the cells developed into fully-functional beta cells, and caused improvement in body weight and hyperglycemia in treated patients.
Germline modification approach draws controversy
A lot was written in the past few weeks by various media outlets about germline cell modification. The gene splicing technology that has enabled such modifications to the germline genome and which has received the most attention – and controversy – recently is called CRISPR-Cas9, which stands for clustered regularly interspaced short palindromic repeats and which we wrote about in a previous blog. Jennifer Doudna, a co-inventor of the technology alongside Craig Mello and David Biltmore and five other scientists, co-wrote an opinion piece in Science magazine this week urging caution in using CRISPR and calling for discussion to support further developments and application of the technology. Others have been less subtle. The ISSCR and ARM both issued statements calling for moratoriums on germline editing calling it potentially unsafe, while proponents say it is a way to “cleanse” the genome from deleterious genes and avoid passing on genetic diseases.
The Whitepaper brings together leading experts in the field of cell therapy. Titled “Critical Elements in the Development of Cell Therapy Potency Assays for Ischemic Conditions,” the Whitepaper discusses key issues of importance in the development of a potency assay for treatment of ischemic disorders treated with cell therapy products. These include issues of function, biological activity and nature of the products, such as cell source and culture method, and in doing so the Whitepaper offers an opinion on the current use of cell therapy products toward more efficient process development.
To read the entire paper, click here.
This paper is part of Akron’s ongoing engagement with leading industry associations and workgroups, and speaks of our high committment to disseminating knowledge for more effective cell therapies, which we have been striving for since our inception.
Akron has years of experience in designing and developing processes and offering tools that facilitate the discovery and development of new cell therapies, as well as assisting industry and academic institutions in their development efforts. This includes potency assay design, implementation and validation, as well as whole-process optimization and process control.
If you have specific needs, please get in touch with us for a survey and see how we can help at email@example.com.