Several cell therapies are now approved for treating human disease and many more are being developed. In this article, we review the latest research in cell therapy development, including advances made in the lab that show promise for translation to the clinic, to improvements in developing, testing and manufacturing.

Cell therapy is the transfer of cells into a patient, either cells from the patient themselves (autologous) or from a donor (allogeneic), for therapeutic purposes. Researchers have been attempting to use cells as treatments for hundreds of years, but for several decades, the only successful application was the use of bone marrow transplantation for leukemia.1 Today, key advances in understanding and genetic engineering of stem- and non-stem (somatic) cells have led to a series of cell therapy approvals. The first stem cell therapy was approved in 2014 for a rare condition called severe limbal stem cell deficiency (LSCD) caused by burns to the eye,2 and in 2017, the first chimeric antigen receptor (CAR) T-cell treatment, Kymriah (tisagenlecleucel), was approved for children and young adults with B-cell leukemia.3

Following these authorizations, the global market for cell-based therapies was valued at USD 21.6 billion in 2022 and is expected to expand to USD 62.4 billion in 2030.4 Although the largest market share is oncology, cell therapies are being explored for a wide range of other indications including central nervous system (CNS) and neurodegenerative diseases, autoimmune disease, cardiovascular disease and rare, orphan diseases.1

Cell therapies are either based on stem or somatic cells. In this article, we explore some examples highlighting both approaches, and the challenges of translating their promise in the clinic.

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One of the fastest-moving areas of cell therapy is the development of CAR T cells in oncology. In this approach, T cells collected from patients or donors are engineered to express a chimeric antigen receptor that recognizes unique tumor antigens, grown in large numbers, and then administered back to patients. Despite the excitement in the field since the first approvals, there remain considerable challenges. These include the difficulty of reproducing the success seen in hematological cancers to solid tumors, and optimizing patient response in terms of the amount and duration of anti-tumor immunity. 1

For a long time, a major challenge for many of these therapies was manufacturing the cells, says David Zhang, a member of the Mooney lab at the Wyss Institute for Biologically Inspired Engineering, Harvard University. Then people figured out better ways of making lots of CAR T cells from a process perspective, with different bioreactor systems and other technological advancements. However, although it became possible to make large numbers of T cells from patient samples, there was still huge variation in individual patient responses to treatment. This led to retrospective analyses of attributes of the cells and factors during the manufacturing process that influence patient response. But the one thing that no one seemed to be looking at was how to optimize the way the T cells were getting activated in the first place, says Zhang. We knew that how we activated the cells was really important to the response we got, so we developed a system to fine tune activation parameters, and see how this affected their function.

The system is designed to mimic the function of the T-cell zone in human lymph nodes, by comprising biodegradable mesoporous silica rods that can be loaded with immune-stimulatory molecules called cytokines. The rods are coated with a lipid bilayer, to which you can attach different activating antibodies. T cells require three signals to be able to proliferate and differentiate: a T-cell receptor stimulation signal, costimulatory signals and a mitogenic growth signal, says Zhang. Our system allows T cells to naturally rearrange the artificial membranes to form an immunological synapse while supporting paracrine signaling, mimicking two important parts of physiological T-cell activation.

Zhang used this system to fine tune all the different parameters that could influence the ultimate T-cell product. But the one thing that really influenced the resulting cell phenotype and function was changing the amount or dose of T-cell stimulation the cells received.

We found that theres a quantitative relationship between your starting cell population, the amount of stimulation you provide, and the phenotype and function of the CAR T cells, says Zhang. We were able to fine-tune the levels of T-cell stimulation to match different phenotypes of the T cells obtained from patients with leukemia, which allowed us to produce CAR T cells with significantly enhanced tumor-clearing activity in a patient-specific manner.

The team used a simple machine learning model to find a pattern between these parameters, which Zhang says can easily be adapted to any starting cell population and any desired CAR T product characteristics, such as enhanced tumor memory, rapid proliferation or a durable response.5 This means that it becomes possible to fine-tune the product based on the patients original T-cell sample.

Given that T-cell samples are always phenotyped, and sometimes genotyped, at the start of manufacturing, similar strategies could be used to personalize the therapy using our approach, says Zhang. It means you can start with one donor sample, and potentially generate, for example, three different CAR T products that are better for different use cases or even different stages of the disease.

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An alternative to harvesting mature cells like T cells is to differentiate or engineer immature stem cells into your desired cell therapeutic product. One of the most active areas of research using this approach is in restoring or protecting the function of nerve cells. In Justin Ichidas lab at the University of Southern California, they are growing stem cells into different types of nerve cells to be used as treatments and for screening drugs. One of their projects, in collaboration with Jon-Paul Pepper, a specialist in facial reconstructive surgery, aimed to help people who sustained facial nerve injuries after an accident.6 These injuries often affect motor neurons in the face muscles, and although the nerve can regenerate it does so very slowly, by the time the muscle has already atrophied, explains Ichida. Because we can grow motor neurons from stem cells, we thought perhaps these cultivated cells could babysit the muscle, until the real nerve regenerates. To test this, they cut the sciatic nerve in mice and introduced motor neurons grown from induced pluripotent stem cells. The home-grown stem cells successfully extended their axons and innervated the muscle. After a couple of months, you could see there was a huge difference in preserved muscle mass, whereas the leg muscles in mice that did not receive the motor neuron therapy, completely atrophied away, says Ichida. What was really interesting, is that the nerve cells didnt require any additional stimulation to innervate the muscle in the way that a natural nerve would do.

Now, Ichida is turning his attention to another type of cell that can be derived from pluripotent stem cells, called microglia. There is growing evidence that microglia, which are the primary immune cells in the brain, play a critical role in the duration and progression of neurodegenerative diseases such as motor neuron disease (also known as amyotrophic lateral sclerosis; ALS).7 We studied stem cells derived from patients with C9orf72 ALS, the most common form, and found a neuroprotective population of microglia, says Ichida.

Although many of the microglial cells that we derived from patients are actually neurotoxic, we found that when they were grown in close proximity to a C9orf72 motor neuron, they switch into a protective state. These protective microglia do exist in the brains of ALS patients, but they are in the minority. Having made this discovery, Ichidas team transplanted the protective microglia into mice harboring a mutation that causes ALS and identified the signaling pathway that switches the microglia from a neurotoxic to a neuroprotective state. Now, they plan to engineer the cells to lock them into a neuroprotective state so they can be transplanted into patients. One hurdle is to see whether stem cells can be transplanted into the human brain, says Ichida. Its been recently shown in rodents that you can transplant microglia and that the grafts extend broadly throughout the brain, so we have some proof of concept already there.

Further proof of concept comes from another study where engineered stem cells were transplanted into the CNS and showed early clinical promise. In the first clinical trial of its kind, a team of investigators from Cedars-Sinai Medical Center demonstrated that it was possible to deliver a combined stem cell and gene therapy into the spinal cord of patients with ALS.8 The stem cells produce a protein called glial cell line-derived neurotrophic factor (GDNF) which can promote the survival of motor neurons. The trial has proved the short-term safety of the approach, and now larger numbers of patients are needed to test its efficacy.

The key in ALS, and its very similar in Parkinsons disease and Alzheimers disease, is that these are very genetically diverse diseases, and so for most patients we dont have a full understanding of the genetic causes behind each persons condition, says Ichida. What we can do is take these patients stem cells and remake their neurons in a dish. Then, because these neurons in the lab mimic the same disease process in the patient, we can reprogram them, or we can use them to test new drugs that will work. In this way, were going to find treatments that are more likely to work across the whole breadth of the ALS population.

References (Click to expand)

1.Bashor CJ, Hilton IB, Bandukwala H, Smith DM, Veiseh O. Engineering the next generation of cell-based therapeutics.Nat Rev Drug Discov. 2022;21(9):655-675. doi: 10.1038/s41573-022-00476-6

2.First stem-cell therapy recommended for approval in EU. European Medicines Agency. https://www.ema.europa.eu/en/news/first-stem-cell-therapy-recommended-approval-eu. Published September 17, 2018. Accessed March 9, 2023.

3.FDA approval brings first gene therapy to the United States. FDA. https://www.fda.gov/news-events/press-announcements/fda-approval-brings-first-gene-therapy-united-states. Published March 24, 2020. Accessed March 9, 2023.

4.Cell therapy market size & trends analysis report, 2030. Grand View Research. https://www.grandviewresearch.com/industry-analysis/cell-therapy-market. Accessed March 9, 2023.

5.Zhang DKY, Adu-Berchie K, Iyer S, et al. Enhancing CAR-T cell functionality in a patient-specific manner.Nat Commun. 2023;14(1):506. doi: 10.1038/s41467-023-36126-7

6.Pepper JP, Wang TV, Hennes V, Sun SY, Ichida JK. Human induced pluripotent stem cell-derived motor neuron transplant for neuromuscular atrophy in a mouse model of sciatic nerve injury. JAMA Facial Plast Surg. 2017;19(3):197-205. doi: 10.1001/jamafacial.2016.1544

7.Clarke BE, Patani R. The microglial component of amyotrophic lateral sclerosis. Brain. 2020;143(12):3526-3539. doi: 10.1093/brain/awaa309

8. Baloh RH, Johnson JP, Avalos P, et al. Transplantation of human neural progenitor cells secreting GDNF into the spinal cord of patients with ALS: a phase 1/2a trial. Nat Med. 2022;28(9):1813-1822. doi: 10.1038/s41591-022-01956-3

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