AABB News: Regenerative Medicine’s Long Journey From Bench to Bedside

October 13, 2021

Note: This article originally appeared in the October 2021 issue of AABB News, a member benefit of AABB.

The field of regenerative medicine is devoted to healing diseased or damaged tissues or organs either using a patient’s own cells or donor cells, or with engineered tissues or organs.

The field is generally divided into three areas or disciplines — tissue engineering and biomaterials, cell therapy, and immunomodulation therapy, explained Anthony Atala, MD, the G. Link Professor and Director of the Wake Forest Institute for Regenerative Medicine, and founder of the Regenerative Medicine Foundation.

Beyond just the development of these technologies, though, is a massive effort to effectively adapt them to the clinic.

“I am a surgeon and started doing this more than 30 years ago,” Atala said. “As a surgeon, I was motivated by the need of patients. Surgeons are putting things into patients — metal or plastic — that we know are not the best option, but right now are the only options.”

Indeed, many of the approaches under development in the field of regenerative medicine are attempts to help people with few or no other options. These include people whose tissue or organs have been damaged by disease, trauma or inherited conditions. According to AABB, estimates indicate that about one in three Americans might benefit from regenerative medicine.1

“We can do better for these patients,” Atala said. “We can create tissue that belongs.”

Lab-Grown Organs

Atala has been leading several efforts to do better for patients by — among other things — developing laboratory grown organs. In 2014, he led a research team in the successful development of vaginal organs for four teenage girls with a rare genetic condition called Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome. MRKH includes a range of abnormalities involving vaginal and uterine abnormalities; dilation, progressive traction and surgery are among the main treatment options.

“In this approach we used the patient’s own cells,” Atala said. “We start out by taking a very small sample of tissue from the organ of interest and then we expand those cells outside the body.”

The cells are seeded onto biodegradable scaffolds or 3D printed and put into an incubator with similar conditions to the human body where they are allowed to mature. Once mature, they are put back into the patient, he said.

In the case of the vaginal organs, the materials were hand-sewn into a vagina-like shape and tailor-made to fit each patient. A canal was created in each patient’s pelvis and the scaffold sutured into place. Follow-up showed that the scaffold had developed into a tri-layered vaginal structure, and, at the time of a pilot study, the engineered organs had remained functional up to 8 years after surgery.2

“The work to get to this clinical application started with basic research back in the 1990s,” Atala said. “It took us years to get it to the patient.”

In fact, the first use of this type of approach occurred in 1998 when Atala and colleagues engineered replacement bladders.

The strategy for all of these is similar, Atala said, with variations based on complexity. Every structure is complex, but flat structures such as the skin are the least complex. Tubular structures, like the urethra or blood vessels, are a second level of complexity. Hollow structures like the stomach or the uterus are a third level of complexity, and solid organs like a kidney or a heart are the most complex.

“The cell biology is also important to make sure you get the right cells and expand cells to the right quantities,” Atala said. “You have to have the right ‘soup’ — like growth factors — to nourish cells and make sure they grow appropriately.”

Harnessing the Immune System

Another area of regenerative medicine receiving a lot of attention in recent years is chimeric antigen receptor (CAR) T-cell therapy, a type of immunotherapy that uses a patient’s own T cells to attack cancer cells.

“First we collect blood from the patients and isolate their T cells. Then, we engineer the T cells to express CARs , which are synthetic receptors that guide T cells to find cancer cells efficiently,” said Reona Sakemura, MD, PhD, a member of the T Cell Engineering Lab at Mayo Clinic, Rochester, Minn. “Once we successfully generate and expand the CAR T cells, the patient will receive low-dose chemotherapy to kill their own immune cells and then they will receive the CAR T cells through a process similar to blood transfusion.”

CAR T-cell therapy is the first FDA-approved therapy to use genetically engineered T cells in patients with cancer. To date, there are CAR T-cell therapies approved for adult patients with relapsed or refractory multiple myeloma, adult patients with relapsed or refractory large B-cell lymphoma, patients with relapsed or refractory mantle cell lymphoma, young adult patients with relapsed or refractory acute lymphoblastic leukemia, adults with primary mediastinal B-cell lymphoma, high-grade B-cell lymphoma and follicular lymphoma.

Clinical trials of CAR T-cell therapy for these hematologic malignancies have all shown remarkable outcomes, Sakemura said.

In theory, CAR T-cell therapy could be applied to any cancer, but the target antigen — the cell surface protein the CAR recognizes — should be specific to cancer cells. All FDA-approved CAR T-cell products have targeted the CD19 antigen, with the exception of the multiple myeloma therapy (idecabtagene, bluebird bio and Cellgene Corp.), which targets B-cell maturation antigen (BCMA).

“If the target antigen is expressed on the surface of healthy cells, CAR T-cells may target those healthy tissues or organs, resulting in serious toxicity,” Sakemura said.

Finding a unique target antigen is difficult in general and one of the most challenging aspects of applying this technology to solid tumors.

“Clinical trials of CAR T-cell therapy in patients with solid tumors have not been successful,” Sakemura said. “This is thought to be due in part to the cancer microenvironment and supporting cells, which inhibit infused CAR T cells.”

Other barriers to further clinical translation of this therapeutic strategy include associated serious side-effects like cytokine release syndrome and neurotoxicity, inhibition of CAR T-cells by the  tumor and patients’ own immune system, and the complexity and expenses involved in the process.

For example, the lag time for establishing CAR T-cell products has an average time from drawing the patient’s blood to infusion of the CAR T-cells of about 3 to 4 weeks, Sakemura said.

“Patients with aggressive cancer may not be able to wait for such an amount of time before treatment,” he said.

The cost of CAR T-cell therapy is also prohibitive. According to the American Society of Clinical Oncology, the average cost of CAR T-cell therapy, including the hospital care, is in excess of $400,000.3

“Many researchers, including our group, are working on how to address the obstacles of CAR T-cell therapy,” Sakemura said.

Mesenchymal Stromal Cells

Other areas of regenerative medicine involve exploring the potential of mesenchymal stromal cells (MSCs) and induced pluripotent stem cells (iPSCs).

When people first began using MSCs, it was thought that specific biological properties that they showed in the laboratory after being isolated from a donor's body, i.e. differentiation into various cell types, like bone cells or cartilage cells, could directly replace diseased cells in the patient's body, but that was not the case, according to Richard Schäfer, MD, FRSB, assistant professor and medical director of transfusion medicine at the Institute for Transfusion Medicine and Gene Therapy, Freiburg, Germany.

Now there is a more updated hypothesis of how MSCs work based on their capability to produce trophic factors that stimulate neighboring cells to start repairing damaged tissue, Schäfer explained. Another intriguing feature is that MSCs affect the immune system of the host, he added. This has been shown in preclinical and clinical studies.

“It doesn’t sound very intuitive but in many degenerative diseases we have inflammation as part of the pathology or process of the disease,” Schäfer said. “If you have a cell type that is able to fight inflammation, it might be beneficial.”

Depending on the type and stage of the disease, one or the other of these mechanisms, or a combination of both, may exert beneficial effects.

Most clinical trials use MSCs derived from bone marrow or adipose tissue, but they can also be derived from a variety of sources including umbilical cord, Schäfer said, which are easily accessible.

In the field of MSCs, there are many ongoing clinical trials, with mostly heterogenous outcomes, Schäfer said. One study estimated more than 1,050 clinical trials registered at FDA.gov exploring the use of MSCs.4

MSCs have been tested in the treatment of myocardial infarction, skeletal disease, rheumatoid arthritis, stroke, kidney injury and even to treat acute respiratory distress syndrome in patients with COVID-19.5

One phase-3 trial of MSCs studied their use in complex perianal fistulas in Crohn’s disease and showed patients treated with MSCs had a significantly higher rate of remission compared with placebo.6 Based on these results, the treatment (Alofisel, Takeda) was granted central marketing authorization by the European Medicines Agency.

Among the other successful areas of study for MSCs is immune modulation of graft-versus-host disease, according to Schäfer. In all, there are 10 globally approved MSC therapies for indications including graft-versus-host disease, Crohn’s disease, knee cartilage defects, connective tissue disorders, spinal cord injury, critical limb ischemia, amyotrophic lateral sclerosis and acute MI.7

Induced Pluripotent Cells

iPSC cells were born from the controversy surrounding the use of embryonic stem cells, Schäfer said. Embryonic stem cells have the biological properties or blueprint to make any cell type found in the human body (pluripotency). These cells were attractive for research but faced many ethics hurdles. In 2012, Shinya Yamanaka was awarded the Nobel Prize in Physiology or Medicine for his discovery that mature cells could be reprogrammed to become pluripotent.

In 2017, researchers at the Riken Institute, Japan, announced that they would begin a trial testing iPS cell transplant from donors to patients with wet-type age-related macular degeneration.8 More recently this technique was tested in a patient with pigmentary retinal degeneration.9

In 2020, this technique was used to carry out the world’s first transplant of cardiac muscle cells by researchers in Japan. Researchers used thin sheets of tissue made from iPS cells and grafted them into a patient with a diseased heart. The hope is that the implanted sheets will grow and secrete a protein to regenerate blood vessels, improving cardiac function. As of December 2020, three patients had received transplantation.10

“iPSCs are very elegant and applicable technology,” said Schäfer, who is involved in projects aiming to translate iPSC technology into patient care.

Yet, despite almost a decade since their discovery, there are currently no FDA-approved iPS cell-based therapies. However, there are four phase-1/2 clinical trials testing these products for age-related macular degeneration, advanced solid tumors, relapsed/refractory acute myeloid leukemia and chronic heart failure.11

The Future

Right now, the field of regenerative medicine is only in its infancy, and the researchers and clinicians exploring these techniques have high hopes for the future while acknowledging some of the barriers to development.

In 2018, the National Academy of Sciences, Engineering, and Medicine had a public workshop to discuss some of the sources of variability involved in the clinical translation of regenerative engineering products. A published summary of this workshop discusses these challenges.12 One source of variability stems from patients, including such phenomena as tissue-specific immune responses to implant, dosing, cellular engraftment, variation in inflammatory response and more. In cases involving donor tissue, similar variations can occur. Variability in the manufacturing process is also a challenge.

Specifically, manufacturing and its associated costs remain an obstacle to more widespread use of CAR T-cell therapy.

“One of the manufacturing steps that makes it expensive is using a virus to engineer the CAR T-cells,” Sakemura said. “We are working on cheaper, non-viral methods to established CAR T cells to make a more affordable treatment.”

Researchers are also trying to reduce the lag times of initiating CAR T-cell therapy, which they hope will increase its efficacy by allowing receipt of the product when patients’ tumor burden is lower.

Despite these challenges, many additional CAR T-cell therapies are being tested in clinical trials, with more than 600 trials underway globally.13

Despite some success for MSCs and iPSCs, generally, preclinical studies have not translated into clinical advances. To address some of the variability that may exist, Schäfer has committed himself to what he calls looking at “what’s in the bag.” In other words, when there are products being derived from these cell types, how uniform or not uniform are the cells within these products?

“We see heterogeneity within MSCs, but also iPSC derivatives and stem cell therapies in general,” Schäfer said. “Does this heterogeneity have any relevance for the potency of these therapeutics?”

For Atala, the future goals of regenerative medicine are twofold.

“First, the goal is to expand the number of different types of tissues that we can put into patients,” Atala said. “Second, is to expand the number of patients that can benefit from these technologies.”

1. AABB. Regenerative Medicine. https://www.aabb.org/newsresources/resources/cellular-therapies/facts-about-cellulartherapies/regenerative-medicine. Accessed September 26, 2021.

2. Raya-Rivera A, Esquiliano D, Fierro-Pastrana, et al. Tissue-engineered autologous vaginal organs in patients: a pilot cohort study. Lancet. 2014;384:329-336.

3. ASCO. CAR-T Therapy. Policy Brief. September 2019. https://www.asco.org/sites/new-www.asco.org/files/content-files/advocacyand-policy/documents/CARTPolicyBrief.pdf. Accessed September 26, 2021.

4. Levy O, Kuai R, Siren EMJ, et al. Shattering barriers toward clinically meaningful MSC therapies. Sci Adv. 2020;6(30):eaba6884.

5. Canham MA, Campbell JDM, Mountford JC. The use of mesenchymal stromal cells in the treatment of coronavirus disease 2019. Journal of Translation Medicine. 2020;18:359.

6. Panes PJ, Garcia-Olmo D, Van Assche G, et al. Expanded allogeneic adipose-derived mesenchymal stem cells (Cx601) for complex perianal fistulas in Crohn’s disease: a phase 3 randomised, double-blind controlled trial. Lancet. 2016;388:1281-1290.

7. Alliance for Regenerative Medicine. Available Products. https://alliancerm.org/available-products/. Accessed September 27, 2021.

8. Graduate School of Medicine. Faculty of Medicine, Osaka University. Clinical trial on cardiomyocyte sheets made from iPS cells to treat heart failure – latest status of clinical trials. https://www.med.osaka-u.ac.jp/eng/archives/6393. Accessed September 27, 2021.

9. Riken Center for Development Biology. Clinical safety study using autologous iPSC-derived retinal cell sheet for AMD. April 4, 2017. http://www.cdb.riken.jp/en/news/2017/researches/0404_10328.html. Accessed September 27, 2021.

10. Kyodo News. 1st-ever iPS visual cell transplant performed without complications. October 16, 2020. https://english.kyodonews.net/news/2020/10/7c9e75ff0f1c-1st-ever-ips-visual-cell-transplantperformed-without-complications.html. Accessed September 27, 2021.

11. Jha BS, Farnoodian M, Bharti K. Regulatory considerations for developing a phase 1 investigational new drug application for autologous induced pluripotent stem cells-based therapy product. STEM CELLS Translational Medicine. 2020;10(2):198-208.

12. Beachy SH, Nair L, Laurencin C, et al. Sources of variability in clinical translation of regenerative engineering products: insights from the National Academies Forum on Regenerative

Medicine. Regenerative Engineering and Translational Medicine. 2020;doi:10.1007/s40883-020-00151-5.

13. May B. Barriers and solutions to expanding access to CAR T-cell therapy. ASCO Daily News. August 9, 2020. https://dailynews.ascopubs.org/do/10.1200/ADN.20.200294/full/. Accessed September 27, 2021.