One of the most promising new technologies to emerge from the biotechnology era is cell therapy. The purpose of cell therapy is to introduce cells into the body to treat a disease or condition. Contrary to popular belief, cell therapy of the type being developed by leading companies and research institutions under the auspices of the FDA and other regulatory agencies does not involve injecting undifferentiated cells such as embryonic stem cells into the body. Rather, the cells are already differentiated (e.g., muscle cells, gland cells, retinal pigment epithelial cells) prior to use in clinical trial patients.

One of cell therapy’s most enthusiastic proponents is Alameda-based BioTime (BTX) CEO Brian Culley. He and his colleagues are concentrating their cell therapy research in regenerative medicine, which utilizes advances in stem cell biology, biomaterials, lab-generated cells and tissues, and biologics to engineer and provide healthy cells, tissues, and organs to patients with chronic degenerative diseases. This revolution in medical science changes the focus from treating the symptoms of chronic and degenerative diseases to providing actual cures.

Culley – who joined BioTime as CEO in September 2018 – has more than 25 years of business and scientific experience in the life sciences industry. Prior to joining BioTime, he served as interim CEO at Artemis Therapeutics, Inc. He was previously CEO of Mast Therapeutics, Inc. (“Mast”), until Mast’s merger with Savara, Inc. He holds a B.S. in biology from Boston College, masters in biochemistry and molecular biology from the University of California, Santa Barbara, and an M.B.A. from Cornell University.

As part of a new cell therapy industry series, WuXi AppTec Communications spoke with Culley about how this new technology can be developed to bring new therapies to patients and specifically BioTime’s efforts to use cell therapy in regenerative medicine.

WuXi: What kinds of cell therapies are on the market and under development?

Brian Culley: Cell therapy is a term which includes many different approaches to treating illness or other human conditions. For example, the use of whole cells to restore activity to areas of the body which have lost function due to age or trauma, holds great promise as a way to treat or prevent degenerative diseases. There are large and growing research efforts behind these approaches. However, harnessing the power of whole cells is incalculably more complex than treating a patient with a single molecule, so at this time there aren’t many approved cell therapies. Their complexity, though, is part of their appeal, because we can accomplish things with whole cells that are impossible with discrete molecules. As one example, bone marrow transplantation is a type of cell therapy which has been a standard and life-saving procedure for decades. So, we are very confident that cell therapy approvals are coming, it’s just that small molecules have a significant head-start.

WuXi: What kinds of diseases can be treated with cell therapies?

Brian Culley: Cell therapies likely will address a great number of ailments, but the main targets to date have been areas where single molecules are absent, have failed, or simply aren’t practical. For example, it’s difficult to envision someone developing a small molecule that can repair a person’s spinal cord, but it’s completely plausible that whole cells could help restore some function in that setting.

Other indications that may be treated by small molecules, can also be targets for cell therapies, such as cancer or systemic inflammatory diseases such as graft-versus-host-disease, rheumatoid arthritis, or Crohn’s disease. And cellular replacement indications certainly could include orthopedic unmet needs such as bone and soft tissue repair, chronic wounds, and other age-related diseases.

WuXi: What are the limitations of cell therapies?

Brian Culley: Current limitations typically include high development costs, an evolving regulatory framework due to their novelty and lack of precedent, and the logistics of transporting and storing cellular products. As with any therapy, though, there are increasingly viable solutions to these limitations and the magnitude of these barriers is offset by their clinical benefit.

WuXi: What kinds of technologies are required to make cell therapy-based medicines?

Brian Culley: Technologies required for successful development of cell therapy-based medicines include cell and tissue culture capabilities, a GMP manufacturing facility, delivery technology, which may involve a medical device, new approaches to assay development and analytical chemistry, and development of new surgical techniques and medical devices.

WuXi: How will cell therapies evolve over the next 10 years?

Brian Culley: Most experts anticipate a wave of progress in the field over the next decade. We expect to see a noticeable improvement in manufacturing capabilities, including integration of “fill-finish” processes to decrease costs, and a better understanding of how critical process parameters are related to clinical outcomes. Additionally, finding ways to achieve enhanced immunological control for stable engraftment of allogenic products will be important for broad, cost-effective adoption of those treatments.

WuXi: What are some of the major challenges in bringing cell therapies to patients? Is manufacturing the most difficult hurdle?

Brian Culley: Diverse clinical evidence strongly supports the view that cell therapy is a promising modality, so manufacturing and logistics are probably the biggest common hurdle at this time. This would include everything from growing the cells in a consistent manner, to how they are handled at the point of care. This is a big reason why BioTime brought its GMP manufacturing in-house. Additionally, depending on the route of delivery and target anatomical destination, procedural development, maintenance, and viability are all also important considerations.

WuXi:  Is gene editing the key technology in cell therapies?

Brian Culley: Gene editing may prove to be highly effective in certain settings, for example with autologous therapy aimed at a specific genetic defect such as sickle cell disease, but it’s probably not going to be important in every situation.

WuXi: Is there a role for small molecule drugs with cell therapies?

Brian Culley: Yes. As soon as you have two therapies available, someone will try a combination of them, but the regulatory complexities of a clinical program with more than one active ingredient may preclude that approach in all but the rarest of cases.  Generally speaking though, it is anticipated that combination therapies could provide beneficial outcomes in these complex diseases.

WuXi:  How would you compare cell therapies to gene therapies?

Brian Culley: Cell therapies and gene therapies are similar in many ways, such as from a manufacturing process perspective, but they’re different in how the product is handled in the supply chain and the ways in which they are administered. Clearly, though, both approaches will ultimately enjoy broad commercial success in a variety of applications.

WuXi: What cell therapies is your company developing and what diseases do they target?

Brian Culley: Our lead cell therapy program, OpRegen®, is being developed to treat the dry form of age-related macular degeneration, or Dry AMD. OpRegen is currently in a Phase I/IIa clinical trial. OpRegen cells are embryonic stem cell-derived retinal pigment epithelial (RPE) cells which replace the lost RPE cells associated with the disease.

We presented data from our OpRegen clinical trial at the Association for Research in Vision and Ophthalmology (ARVO) meeting in Hawaii earlier this year, and we  recently presented additional data at the American Association of Ophthalmology (AAO) meeting in Chicago.

WuXi: How does your approach differ from other cell therapy companies?

Brian Culley: Unlike most other cell therapy companies, BioTime’s cell therapy platform uses normal pluripotent cells which have not been genetically modified, and which retain the capacity to form any of the hundreds of human cell types, thereby giving us access to the widest range of potential applications. Additionally, our cells have a theoretically limitless proliferative capacity, meaning their divisions could produce enough material to treat patients in even the largest indications.

WuXi: What regulatory challenges do you face?

Brian Culley: All cell therapy programs face challenges from a lack of regulatory precedent. Sometimes the regulatory frameworks are imprecise or not well adapted for this class of therapeutic, but the regulatory agencies are fully aware of this and have shown an ability to adapt as new frontiers emerge.

For example, the US FDA has adopted a largely favorable regulatory framework, designed to facilitate early conditional approval based on a strong safety profile and preliminary efficacy, which can accelerate promising therapies, especially for patients who have few or no therapeutic alternatives.

Challenges aside, we consider cell therapy to be the most exciting area in all of biotechnology. The field is in the midst of an amazing transition from one which holds great promise to one which delivers compelling clinical evidence. The next few years promise to be an exciting time.