Gurus of Advanced Medicine

How is the advanced medicine field currently shaping up?

David Williams: One of the key developments is simply the recognition that these science-led – but incredibly challenging – medical therapies can deliver, from a clinical point of view. In recent years, there has been a resurgence of gene therapies and the use of induced pluripotency stem cells – and successes are finally being seen. More companies are now engaging with these therapies and investing to reach patients at scale. Increasing clarity in the regulatory environment is also helping to create successes in the field, and there is growing national strategic support from a number of countries worldwide to help the medical profession and industry move cell therapies and other regenerative medicines forward.

Timothy Allsopp: The dominant therapeutic concept being tested clinically was once mesenchymal stromal cell therapy (MSC), but this approach lacked efficacy in many diseases (although undoubtedly success exists in bone and cartilage repair). Concomitantly, the field has experienced an evolution, with new paradigms emerging, such as genemodified immunotherapies and previously identified concepts, such as embryonic stem cell and induced pluripotent stem cells (collectively hPSCs), and complex tissue engineered products, finally reaching clinical-stage testing. There has also been notable progress in first market approvals for gene therapy, ex vivo stem cell gene therapy, a number of pivotal clinical studies, and unprecedented levels of investment for biotech companies.

Thomas Heathman: The cell therapy industry, as a whole, is finally moving from the discovery stage, where the challenges are mainly biological, to a stage where cell therapy developers and manufacturers are facing engineering challenges in terms of truly industrializing and commercializing therapies. This leap forward has been buoyed by the efficacy demonstrated by chimeric antigen receptor T (CAR-T) cells, and recent announcements of filings with the FDA from Kite Pharma and a positive recommendation for Novartis’ CTL019 from an FDA advisory panel. Generally speaking, the increasing body of positive clinical data has led to increased investment in the field, and placed higher priority on tackling manufacturing and scalability issues, which currently contribute to the high cost of goods for advanced therapy products. Changes in regulations to specifically cover advanced therapies have also been significant. For example, in November 2014, Japan passed a new regenerative medicine law which enables therapeutic development sponsors to receive conditional marketing approval and generate revenue from regenerative products while clinical trials are being conducted, after safety and an early indication of efficacy have been established.

What have been the field’s biggest success stories so far?

TA: By far the most impressive early progress concepts involve using a patient’s own ex vivo CAR-T cells to target blood cancers. Near complete molecular remission from disease was reported for a few patients and significant improvements in disease status for many others. European Medicines Agency approval for Glybera, a gene therapy to restore lipoprotein lipase deficiency, and the first ex vivo stem cell gene therapy, Stremvelis, are also major landmarks. Stremvelis, in particular, represents a success for the technology sector for a number of reasons. It stems from a successful public-private partnership between GlaxoSmithKline and the San Rafaelle Institute in Milan, highlighting the key role that collaboration can play in the sector. Stremvelis also exemplifies how a novel paradigm – using a patient’s own bespoke cells – can be pursued by big pharma, querying the assumption that pharma prefers a business model based on the historical practice of providing mass produced, “off-the-shelf” medicines.

Stéphane Boissel: Regenerative medicine has been a dream of scientists for more than 30 years. It is now a clinical reality with a new generation of CAR-T products yielding incredibly promising data in some hematological disorders. In 2017, CAR-T therapies will likely become a commercial reality, with the impending launch of the world’s first two products. Both Novartis and Kite Pharma have filed Biologics License Applications for their separate CAR-T products with the FDA, and both received Breakthrough Therapy designation. Considering that Kite was founded eight years ago, it’s amazing that KTE-C19, their lead product, could reach FDA licensure in B-cell lymphoma after less than five years of clinical development. The company has built the appropriate manufacturing, logistic and commercial infrastructure, and from a timeline viewpoint, I’m not sure there is any equal precedent in the biopharma industry.

Catherine Bollard: I’m with Stéphane and Timothy, and am really excited by advances in cellular immunotherapy, such as those for hematologic cancers. Successes seen so far include using tumor-directed T-cell therapies, such as CD19-CAR-T cells for CD19+ B-cell leukemias and lymphomas, and virus-specific T-cells for virus-associated cancers. There is a lot of science emerging in the T cell therapy field and I think we will see numerous breakthroughs for patients with unmet medical needs.

What are the biggest misconceptions about cell therapies?

DW: Many in the industry believe that the manufacture of advanced medicines and cell therapies is very special compared with other products. For the last decade or so, my team has been working hard to understand where we can transfer techniques from other areas that involve making things at scale with demanding precision; for example, my personal background is in the manufacturing of drug delivery devices within the pharmaceutical supply chain and in consumer micro-electronics for computing and telecomms – and many of the problems are the same. We’ve also been looking at the significant differences, so that we can decide on what the field really needs to focus on to flourish.

TA: There is an unrealistic expectation that donor MSCs can treat everything. MSC therapies will continue to be tested, and have demonstrated some effect for symptom modification in early stage trials for anti-inflammatory and musculoskeletal repair mechanisms. In the last decade, however, only two MSC-based products have received approval, Procyhmal and TemCell for Crohn’s and GvHD, respectively, which is the very thin edge of a large wedge of basic and non-clinical research effort with this technology. Frequently, assumptions have been made that nonclinical evidence of efficacy will successfully translate into major symptom modification, via a predominant class of therapeutic action for the majority of patients diagnosed. Large-scale clinical studies are demonstrating that this is not the case. Another major misconception is that advanced medicines should only be tested in patients for whom approved medicines are failing – this is often not the best scenario for demonstrating efficacy, and the risk–benefit analysis needs to be re-evaluated.

TH: I would add that another misconception is that patient-specific (typically autologous) cell therapies are too expensive to commercialize, and that the future of cell therapy has to lie in off-the-shelf cell therapies (always allogeneic cell therapies, where the manufacture of doses for multiple patients is possible from a single donor). We must keep in mind that rigorous industrialization efforts have not yet been applied to patientspecific cell therapies. I believe that there will be a commercial future for both autologous and allogeneic therapies – as long as the clinical and economic value proposition can be developed, on a case-by-case basis.

SB: There are still some who are skeptical about whether cell therapies will ever take off because of manufacturing and pricing issues. Developing cell therapies and other advanced medicines is certainly challenging – and we don’t yet know how pricing will play out – but, in my view, cell therapies will be a success. And we won’t have to wait for long to see who has been right or wrong about the field’s potential!

CB: One of the biggest misconceptions we encounter at the International Society for Cellular Therapy (ISCT) is the belief that all successful T-cell therapies are CAR-T cells. It is better to publicize the fact that there is a wealth of highly successful clinical data being seen in the T-cell therapy field: antigen specific T-cells (for example, targeting viruses) and other genetically modified T-cell strategies, such as abTCR-transduced T-cells, suicide gene modified T-cells, and/or T-cells engineered to resist the immune-suppressive microenvironment.

Timothy Allsopp is the founder and Managing Director of consulting and strategy firm, Consilium, UK. Until recently, he was the Head of Stem Cell & Cell Therapy Lead at Neusentis, a Pfizer research unit.

Stéphane Boissel has experience in investment banking and the biotech immunotherapy space. Today, he is CEO of TxCell, France, which focuses on personalized T-cell immunotherapies.

Catherine Bollard is President of the International Society for Cellular Therapy. She also leads a research laboratory focusing on the development of novel cell therapeutics as Director of the Program for Cell Enhancement and Technologies for Immunotherapy within the Children’s Research Institute of Children’s National Health System and George Washington University School of Medicine & Health Sciences, USA.

Thomas Heathman has a PhD in regenerative medicine from Loughborough University, UK, and today is Business Leader in the Technology Development, Manufacturing Development & GTP Services, at PCT, a Hitachi Group Company, USA, a global contract development and manufacturing organization for the cell therapy industry.

David Williams is Professor of Healthcare Engineering at Loughborough University, UK, and was founding Director of the Loughborough-led Engineering and Physical Sciences Research Council Centre for Innovative Manufacturing in Regenerative Medicine. He was awarded an OBE for services to science and engineering in the Queen’s Birthday Honours List in 2014.

Why has progress with allogeneic cell therapies been slow?

DW: Early approaches to allogeneic therapies may have been conditioned by a big pharma/blockbuster vision of what our field should or could be. Blockbuster opportunities tend to be occupied by incumbents who have become very good at what they do, and it can be tough for an unproven, high-cost disrupter to make their case. We disrupters need to emphasize the continued requirement to address unmet medical needs and must be exact about the medical needs we aim to meet, understand how our approach will meet these needs, and be able to communicate all of this in a way that is convincing to busy clinicians.

TA: I believe there will be a future for allogeneic-based therapies, and exciting concepts based on restoring cell function using hPSC are currently being clinically tested. Using orthotopic transplantation of hPSC-derived products to regenerate replacement healthy, functioning tissues may be a more reasonable mechanism to test next, as the paradigm of systemic transplantation of cells to modulate local inflammatory or tissue repair processes (as with MSC) has not proven to be a success on the whole. Time will tell whether an allogeneic approach proves to be more or less efficient than other types of therapies in delivering novel, disease-modifying treatment options to patients and their healthcare providers.

SB: Allogeneic technologies will be an important component of the field in the future. The only question to me is: “when?”

What are the main challenges involved in moving cell therapies into commercial manufacture?

DW: The manufacture of these therapies involves two principal challenges: making the same thing more than once, and making the same thing in more than one place. There is a lot of understanding and experience in manufacturing already gained from high-volume production, but personalized, autologous cell therapies are driving the industry to better understand the latter point, as they need to be made close to clinical settings.

TA: There are three main challenges when it comes to developing cell and tissue therapies. First is the challenge of developing suitable analytical assays to define and monitor the consistency of a therapy’s functional attributes for product release after manufacture. Appropriate analytics are especially needed for autologous therapies to assess potency and to be used for comparability across batches for a single patient, or across multiple patients. It is essential that these analytical techniques be non-destructive, or at least do not use up too much of the product.

The second challenge relates to sample processing and the need for scalable, affordable production platforms. There are currently no “one-automated-platform-suits-all” approaches for commercial-scale development, and manufacturers are instead dependent on manual, skilled specialists working in accredited cleanroom facilities – which inevitably makes manufacture prone to human error and processing variability. A number of pioneering, approved autologous therapies have found overcoming the barrier of major inflexion problematic in terms of scaling between clinical production and commercial manufacture, but most suspect that the hard lessons learned so far will benefit the future of the whole sector. The third challenge is the overall cost of production and reimbursement. At this time, there are no clear or consistent global-scale examples that exemplify how therapies should be reimbursed.

TH: Today’s cell therapies, including autologous and allogeneic therapies, are manufactured using highly manual and often open processes, which pose significant commercialization challenges in terms of maintaining consistent quality, supply chain sustainability and minimizing costs. Furthermore, because patient-specific therapies cannot be scaled up but instead must be scaled out, there are specific challenges when it comes to achieving economies of scale. Solutions, however, may include:

• rigorous understanding of the desired product quality profile
• minimizing the number of unit operations in themanufacturing process
• avoiding peak capacity by evenly distributing labor requirementsacross the process
• driving development to minimize variation and maximizeproduct yield
• closing and automating process steps
• sharing infrastructure across multiple product manufacturing processes (in-house or externally)
• demonstrating product comparability following process modifications.

Cell therapy developers need to look closely at the drivers for commercially viable manufacturing of their product, with an eye to establishing processes, as early as possible, that deliver high quality and robust products that can scale to meet demand over the commercial life of the product. And, importantly, they need to do so with a reimbursable cost of goods.

CB: I believe that the Holy Grail for the industry is the development of “off-the-shelf”, universal products. In time, I think we will see advances in this area, but patient-specific cells are the way forward for now and these need to be manufactured on demand in a viable timeframe. For gene-modified T-cells, there have been challenges regarding scale up. Looking at the cell therapy field as a whole, I believe that a key question is whether to move to centralized manufacturing facilities versus individual centers for product manufacture on a larger scale.

What improvements in manufacturing technologies are needed?

DW: All unit processes need to be made more robust and repeatable. There is also the question of how we grow the supply chain for the key enablers, including process automation and mechanization, and robust characterization – especially given that instruments developed for research laboratories do not always work well in settings that are determining manufacturing quality. New advanced technologies are emerging, but we also have to generate business models that permit viable machine supply businesses, without pushing up prices for media and consumables that result in unacceptable cost of goods.

TA: The scale out of more than minimally manipulated autologous therapies poses a major challenge for developers. There is a regulatory requirement to demonstrate comparability of measurements for the therapy across many decentralized production sites or from a single, near-to-patient production site. For therapies with a potentially short shelf life, generating data on safety, sterility, purity, identity and potency before release of a patient-specific dose is challenging. As many of these measurements currently depend on the use of assays that are destructive, it can also be a hindrance if material is limited (though less of a problem if patient bio-samples can be banked for later use). Sensitive assay technologies that provide reliable results for sterility and potency in turn-around times that meet clinical demand are needed.

TH: Firstly, online monitoring and control systems need to be integrated into cell therapy manufacturing. Secondly, we need harmonization to allow more seamless integration of technologies within a single process. I would also like to see the introduction of devices which, rather than being designed as “magic boxes” customized to one specific product’s manufacturing process, are designed to handle a range of unit operations, providing a true manufacturing platform, common to an entire category of cell therapies. There is a defined market need for flexible, automated and closed-system solutions like this, for which the cost should be much more economical for each developer than an entirely customized device.

CB: Members of ISCT also believe that the industry needs to move to closed, automated manufacturing systems. We also need more attention on “GMP-in-a-box” concepts so that centers can manufacture therapies without needing a physical “GMP space” – such a move would help to broaden the applicability of cell therapeutics beyond boutique centers.

SB: I agree that many companies developing cell therapies or other advanced medicines need more automated and closed systems – and I would add that there has been a lot of investment pouring into cell therapy manufacture over the last five years from sponsors, contract manufacturing organizations and equipment makers. Already, manufacturing lead-time and failure rates have decreased significantly. I’m cautiously optimistic that processes will continue to improve so that we can routinely manufacture cell products at a commercial scale, and claim that they are close to being off-the-shelf products.

What should the field be prioritizing?

DW: A key area for the field to focus on is the interaction between regulation, standards and manufacturing strategy. Underlying this is the need for the community to address its approach to comparability. There is increased level of informed discussion here, including the recognition by regulatory agencies that the practicalities of de-centralized manufacture should be explored. The development of standards is also a significant area for international collaboration.

TA: The design of advanced therapies needs to be more tightly aligned with improved understanding of disease development and individual patient profiles. We must also consider prevention rather than symptom modification as a goal. A fresh look at companion diagnostics would be beneficial to more closely tailor a patient’s advanced therapy. We should also consider the fact that advanced therapies are being approved, but not adopted and reimbursed in healthcare systems. There are several reasons linked to this, but a principal one is affordability. All stakeholders involved in developing advanced therapies are responsible for finding an appropriate solution – and perhaps a radical rethink is needed rather than attempting to evaluate cost-effectiveness in the traditional way.

TH: The industry needs to set standards that will speed up development efforts across the field, and accelerate the process of innovation to resolve key manufacturing constraints to commercial viability. For example, with common standards for for T-cell characterization – agreed upon by the FDA – each developer stands to benefit by reducing the cost of development. Efforts are under way to look at setting these standards, through the Alliance for Regenerative Medicine and other groups.

CB: Collaboration is crucial. ISCT is working with organizations to help establish standards that ensure quality in the clinic, as well as in the laboratory. Such priorities will be critical to improve the safety for patients receiving cell-based therapies. To that end, ISCT is one of the co-parent societies for The Foundation for the Accreditation for Cellular Therapy (FACT), a voluntary organization that sets practice standards for cellular therapy, including transplant and regenerative medicine.

SB: We first need to prove that these therapies can be safe and efficacious in a range of indications. At the moment, successes with CAR-T cells, for example, are being seen in LAL and B-cell lymphomas. If we can get results in a wider range of diseases, it will create more awareness about the potential of advanced therapies with broader scientific, physician and patient communities. We then need to continuously invest in improving logistics and manufacturing, and finally work with payers to find the most acceptable reimbursement system that fulfills the needs of all stakeholders: patients, payers and drug development companies – who need a good return on investment to continue to invest and innovate in this challenging field.

What are your predictions for the field?

DW: I have always believed that cell therapies will be like other similar fields in medical technology; we can expect a few big products, as well as a variety of smaller ones. We can use the autologous route to establish a track record and trust in the clinic, as well as ways forward for reimbursement. I don’t expect to see many big wins in the field, but the big products that do emerge will make a significant difference.

TA: In the near future, there will be several gene-modified, patient specific immunotherapies on the market. Promising clinical data from early stage studies using allogeneic immunotherapy platforms will also have been generated. There will also be a surge of new gene therapies in development, categorized as defective protein replacement strategies, as improvements in vector design and a better understanding of how to deliver these more precisely arise from optimizing approaches to cell tropism.

I think the long-term horizon is tremendously exciting. If the science translates successfully and safely, future prospects include approaches for stimulating local tissue regeneration, in trauma and degenerative disease, and using precision genome editing to repurpose the function of somatic cells in vivo.

TH: Most cell therapies today are manufactured in cleanrooms, but in the future closed and automated systems will dominate. These systems mitigate the risks of cross-contamination and therefore allow concurrent processing of multiple batches, in lower grade clean rooms, which results in enormous savings in terms of facility operation and efficiency, as well as reduced labor costs. Remember – every hour of labor saved in a patient-specific process is one hour saved on every single dose you manufacture (as each batch is made for one patient).

Automation and integration will also play a role in the future of cellular therapies. Just think about the personal computer industry. Computers used to be massive because all the different functions were in separate modules, but the functions have been progressively integrated into smaller, unitary pieces of equipment. The same thing will happen in cell therapy manufacture; all the different steps involved in cell therapy will one day be integrated so that a single, closed unit can execute multiple operations.

CB: I’m really confident about cell-based immunotherapies and I can’t wait to see them advance even further. As accessibility and toxicity management improve, it’s possible to foresee a future where chemotherapy and radiotherapy are no longer the mainstays of cancer treatment, replaced instead by new therapies that focus on enhancing anti-tumor immunity. It would make a tremendous difference to patients.

SB: Ours is an industry in the making and we’ve already come so far. A few years from now, we will be talking about cellular therapy as we now talk about other biotherapies, such as monoclonal antibodies. Cell therapies will just be one part of the medical arsenal used daily to efficiently treat serious disease.