The Applications of Cell Therapy

Cell therapy: a recap

Cell therapy refers to the transplantation of human cells to either replace or repair damaged tissues and/or cells. A variety of different cell types, including stem cells and immune cells, are used as cell therapies. With an evolving understanding of our cells and the immune system, scientists are finding new ways to use our cells as therapeutic agents.

The uses of cell therapy

Below, we expand upon the applications of cell therapy, including its utility in cancer, regenerative medicine and autoimmunity.

CAR T-cell cancer therapy

Chimeric antigen receptor (CAR) T cell therapy is a cancer immunotherapy in which T cells are derived from a patient's blood and then genetically engineered in vitro to express an artificial receptor. This lets the T cells target specific tumor antigens.

The steps of CAR T-cell therapy. Credit: Technology Networks

The steps involved for CAR T-cell therapy include:

Leukapheresis: Blood is drawn from the vein of the patient's arm; the blood moves through an apheresis machine in which the leukocytes are removed by continuous centrifugation, and the rest of the blood is returned to the patient.

T-Cell engineering and expansion: T cells are isolated from apheresis product and other cell types are removed that may inhibit T-cell expansion. The cells are then transduced with the CAR construct DNA using a viral vector, such as a lentivirus. The cells are checked to ensure they express the new receptor and then expanded until they reach an appropriate concentration (therapeutic dose). 

CAR T-cell infusion: Before CAR T-cell infusion, the patient undergoes lymphodepletion (chemotherapy to remove lymphocytes), which allows a favorable immune environment for CAR T-cell expansion, persistence and therapeutic activity in vivo, once administered.¹ Patients are then monitored over several weeks.

The engineered receptor is typically a mouse-derived monoclonal antibody presenting as a continuous peptide single-chain variable fragment (scFV) connected through an extracellular spacer domain to provide flexibility to the receptor.² The scFVs recognize the target antigen on the tumor surface, which confers activation through its intracellular signaling domains. The T cell then elicits the effector function, causing tumor cell apoptosis.³

1. A viral vector transfers CAR-coding DNA into an immune cell. The antigen-binding region of the CAR is taken from a monoclonal antibody. 2. When this region recognizes an antigen on a tumor cell, the signal is amplified back to the nucleus. 3. Here, antitumor transcription begins. 4. This transcription produces cytokines that destroy the tumor cell.  Credit: Technology Networks. Adapted from Chan et al. https://www.mdpi.com/2227-9059/10/4/804

CAR T-cell therapy has shown promise over the past decade, with 6 current FDA-approved products.⁴ These CAR T-cell therapies treat B-cell relapsed or refractory leukemia, lymphoma, (CD19 as the target antigen), and multiple myeloma (B-cell maturation protein as the target antigen). Some of these therapeutics have been around long enough to obtain survival data; for example, a 2021 study looked at the long-term follow-up of patients (children and young adults) with B-cell acute lymphoblastic leukemia and found over 60% of patients were still alive without their cancer coming back.⁵ Other studies also show high remission rates after CAR T-cell therapy.⁶

Regenerative medicine

Regenerative medicine has emerged as a new and promising therapeutic avenue for patients with limited or no other options for treatment. The main concept for regenerative medicine is tissue regeneration and replacing damaged cells. The use of stem cells has become an effective approach for treatment through the inhibition of inflammation and apoptosis. For example, stem cells can sense pro-inflammatory factors and reduce inflammation by releasing cytokines, such as TGFβ and IL-10, to inhibit dendritic cell migration, maturation, and antigen presentation. These factors can also suppress T-cell response.⁷

Stem cells can also stimulate cell recruitment and angiogenesis and have the capability for differentiation.⁸ Different cell types, including human pluripotent stem cells (hPSCs), multipotent stem cells, progenitor cells and terminally differentiated cells are being investigated for their regenerative properties.

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The most popular cell types for regenerative medicine are hPSCs and mesenchymal/stromal stem cells. hPSCs are used for vision repair by differentiating into retinal pigment epithelium cells in the context of macular dystrophy.^9,10 Their utility in cardiac muscle re-muscularization by differentiation into cardiomyocytes in the context of cardiac disease.¹¹ And in spinal cord injury using human embryonic stem cell-derived oligodendrocyte progenitor cells.¹² 

MSCs have been found and derived from different sources, including:

• Adipose tissue (AT)
• Bone marrow (BM)
• Umbilical cord (UC)
• Placenta
• Amniotic fluid
• Dental pulp

The most popular MSCs used as therapeutics currently under clinical trial are derived from BM, UC and AT, with some already being FDA-approved. MSCs have been proven effective in treating multiple diseases, including those of the nervous system, pulmonary disease, cardiovascular conditions and wound healing. ¹³

These cells can be administered in many ways. Engineered materials are often used for administration; examples include cells encapsulated or coated with polymers or nanoparticles, scaffolds or films embedded with cells. ¹⁴ Scaffold materials can be seeded with cells to be delivered to a target site for tissue repair. For example, cardiomyocytes (heart muscle cells) are fabricated into conductive patches to improve cardiac function. ¹⁵ Or hydrogel surfaces encapsulated with human adipose-derived stem cells and limbal epithelial stem cells for corneal repair.¹⁶

Autoimmunity

Autoimmunity refers to the human body mounting an attack against itself, producing a response against its cells, tissues, or other constituents, leading to chronic inflammation and injury. Typically, autoimmune diseases are related to an imbalance in the immune homeostasis. Examples of such conditions include rheumatoid arthritis (RA), type 1 diabetes, multiple sclerosis, lupus, and irritable bowel disease (IBD). Stem cells can be used to slow or stop the progression of autoimmune disease. 

MSCs have been showed to be beneficial for autoimmune disease based on their immunosuppressive properties.¹⁷ In the context of RA, the antirheumatic drug methotrexate (a drug that has been shown to cause side effects such as liver and gastrointestinal injuries) remains the best candidate for therapy. However, MSCs have been shown to decrease the production of pro-inflammatory cytokines, suppress pro-inflammatory Th17 cells, and upregulate regulatory T cells (white blood cells).¹⁸

In inflammatory bowel disease, which includes diseases such as ulcerative colitis (UC) and Crohn's disease, the administration of MSCs showed therapeutic potential by restoring epithelial barrier integrity.¹⁹

In the context of type 1 diabetes mellitus (T1DM), MSCs have been shown to play a role in lowering fasting blood sugar levels, hemoglobin A1c and C-peptide. Although multiple clinical trials are underway, the mechanism of action is still unknown.²⁰

Conclusion

Cell therapies showcase immense potential in revolutionizing medical treatments across various domains: The success of CAR T-cell therapy in treating certain cancers, regenerative medicine for tissue repair and treating autoimmune diseases.

CAR T and hematopoietic stem cell transplantation are the only FDA-approved cell therapies. However, almost 700 current stem cell-based clinical trials are taking place (almost 500 of these are based in the United States), according to the National Center for Biotechnology Information (NCBI), suggesting a bright future for the field.²¹