Cell therapy
Cell therapy is a therapy in which viable cells are injected, grafted or implanted into a patient in order to effectuate a medicinal effect, for example, by transplanting T-cells capable of fighting cancer cells via cell-mediated immunity in the course of immunotherapy, or grafting stem cells to regenerate diseased tissues.
Cell therapy originated in the nineteenth century when scientists experimented by injecting animal material in an attempt to prevent and treat illness. Although such attempts produced no positive benefit, further research found in the mid twentieth century that human cells could be used to help prevent the human body rejecting transplanted organs, leading in time to successful bone marrow transplantation as has become common practice in treatment for patients that have compromised bone marrow after disease, infection, radiation or chemotherapy. In recent decades, however, stem cell and cell transplantation has gained significant interest by researchers as a potential new therapeutic strategy for a wide range of diseases, in particular for degenerative and immunogenic pathologies.
Background
Cell therapy can be defined as therapy in which cellular material is injected or otherwise transplanted into a patient. The origins of cell therapy can perhaps be traced to the nineteenth century, when Charles-Édouard Brown-Séquard injected animal testicle extracts in an attempt to stop the effects of aging. In 1931 Paul Niehans – who has been called the inventor of cell therapy – attempted to cure a patient by injecting material from calf embryos. Niehans claimed to have treated many people for cancer using this technique, though his claims have never been validated by research.In 1953 researchers found that laboratory animals could be helped not to reject organ transplants by pre-inoculating them with cells from donor animals; in 1968, in Minnesota, the first successful human bone marrow transplantation took place. In more recent work, cell encapsulation is pursued as a means to shield therapeutic cells from the host immune response. Recent work includes micro-encapsulating cells in a gel core surrounded by a solid, but permeable, shell.
Bone marrow transplants are the most common and well established cell transplantation therapies. The first recording of a successful bone marrow transplant, dates back to 1956 by dr. E Donnall Thomas, who treated a leukemia patient with their twin-siblings bone marrow. In general, for patients presenting damaged or destroyed bone marrow, for example after chemotherapy and/or radiation for acute myeloid leukemia, bone marrow derived cells can be infused into the patients blood stream. Here the injected cells are able to home into the affected bone marrow, integrate, proliferate and recover or re-establish its biological function e.g. the haematopoiesis. Annually an estimated 18,000 patients require potentially life-saving bone marrow transplants in the US.
For a long time, bone marrow transplantation was the only clinically applicable method of cell transplantation, however, since the 1990s, cell therapy has been investigated for a wide scale of pathologies and disorders. Cell therapy provided a novel approach to effectuate therapeutic efficacy. Previously, medical agents could only be effective by directing and inducing the patients own cells. However, in many diseases and disorders, cell are compromised by e.g. senescence, limited blood supply, inflammation, or simply a reduction in the number of cells. Cell therapy offers a new strategy that supports the introduction of new and active cells to restore previously compromised or deteriorated tissue- and organ structures. As such, in recent times, cell therapy has been recognized as an important field in the treatment of human disease, and investigations are ongoing in articular cartilage, brain tissue, spine, heart, cancers, etc. As a consequence cell therapy as a strategy has been attracting significant investments by commercial entities which suggest strong prospects for future growth.
In 2021 Atara biotherapeutics became the first ever allogeneic T cell therapy company to be reviewed by any regulatory agency in the world
Mechanisms of action
Cell therapy is targeted at many clinical indications in multiple organs and by several modes of cell delivery. Accordingly, the specific mechanisms of action involved in the therapies are wide-ranging. However, there are two main principles by which cells facilitate therapeutic action:- Stem, progenitor, or mature cell engraftment, differentiation, and long-term replacement of damaged tissue. In this paradigm multipotent or unipotent cells differentiate into a specific cell type in the lab or after reaching the site of injury. These cells then integrate into the site of injury, replacing damaged tissue, and thus facilitate improved function of the organ or tissue. An example of this is the use of cells to replace cardiomyocytes after myocardial infarction, to facilitate angiogenesis in ischemic limb disease, or the production of cartilage matrix in intervertebral disc degeneration.
- Cells that have the capacity to release soluble factors such as cytokines, chemokines, and growth factors which act in a paracrine or endocrine manner. These factors facilitate self-healing of the organ or region by inducing local cells or attracting cells to migrate towards the transplantation site. Early cell passages have been shown to be more efficient paracrine activity than later passages. The delivered cells remain viable for a relatively short period and then die. This includes cells that naturally secrete the relevant therapeutic factors, or which undergo epigenetic changes or genetic engineering that causes the cells to release large quantities of a specific molecule. Examples of this include cells that secrete factors which facilitate angiogenesis, anti-inflammation, and anti-apoptosis. This mode of action is proposed by companies such as Pluristem and Pervasis that use adherent stromal cells or mature endothelial cells to treat peripheral artery disease and arteriovenous access complications.
Cell therapy strategies
Allogeneic
In allogeneic cell therapy the donor is a different person to the recipient of the cells. In pharmaceutical manufacturing, the allogenic methodology is promising because unmatched allogenic therapies can form the basis of "off the shelf" products. There is research interest in attempting to develop such products to treat conditions including Crohn's disease and a variety of vascular conditions.Autologous
In autologous cell therapy, cells are transplanted that are derived from the patients own tissues. Multiple clinical studies are ongoing that obtain stromal cells from bone-marrow, adipose tissue, or peripheral blood to be transplanted at sites of injury or stress; which is being actively explored for e.g. cartilage and muscle repair. It could also involve the isolation of matured cells from diseased tissues, to be later re-implanted at the same or neighboring tissues; a strategy being assessed in clinical trials for e.g. the spine in preventing disc reherniation or adjacent disc disease. The benefit of an autologous strategy is that there is limited concern for immunogenic responses or transplant rejection. Nevertheless, an autologous strategy is often costly due to patient-by-patient processing, thus preventing the option to create large quality-controlled batches. Moreover, autologous strategies generally do not allow for product quality and effectiveness testing prior to transplantation, as it is highly donor dependent. This is a particular concern as often the patient functioning as donor is diseased, and this can impact cell potency and quality.Xenogeneic
In xenogeneic cell therapies, the recipient will receive cells from another species. For example, the transplantation of pig derived cells to humans. Currently, xenogeneic cell therapies primarily involve human cell transplantation into experimental animal models for assessment of efficacy and safety, however future advances could potentially enable xenogeneic strategies to humans as well.Types of cells
Human embryonic stem cells
Research into human embryonic stem cells is controversial, and regulation varies from country to country, with some countries banning it outright. Nevertheless, these cells are being investigated as the basis for a number of therapeutic applications, including possible treatments for diabetes and Parkinson's disease.Neural stem cell therapy
Neural stem cells are the subject of ongoing research for possible therapeutic applications, for example for treating a number of neurological disorders such as Parkinson's disease and Huntington's disease.Mesenchymal stem cell therapy
MSCs are immunomodulatory, multipotent and fast proliferating and these unique capabilities mean they can be used for a wide range of treatments including immune-modulatory therapy, bone and cartilage regeneration, myocardium regeneration and the treatment of Hurler syndrome, a skeletal and neurological disorder.Researchers have demonstrated the use of MSCs for the treatment of osteogenesis imperfecta. Horwitz et al. transplanted bone marrow cells from human leukocyte antigen -identical siblings to patients with OI. Results show that MSCs can develop into normal osteoblasts, leading to fast bone development and reduced fracture frequencies. A more recent clinical trial showed that allogeneic fetal MSCs transplanted in utero in patients with severe OI can engraft and differentiate into bone in a human fetus.
Besides bone and cartilage regeneration, cardiomyocyte regeneration with autologous BM MSCs has also been reported recently. Introduction of BM MSCs following myocardial infarction resulted in significant reduction of damaged regions and improvement in heart function. Clinical trials for treatment of acute MI with Prochymal by Osiris Therapeutics are underway. Also, a clinical trial revealed huge improvements in nerve conduction velocities in Hurler's Syndrome patients infused with BM MSCs from HLA-identical siblings.