(Selected Tables and Figures referenced, but not present in this blog
can be found in their corresponding Science Version blogs)
A rapidly increasing area of immunotherapy are new methods using immunogenetic and immunogenomic (you may want to do a quick refresher on those sciences in Blog #10) methods. They include:
“editing” cells and genes;
replacing cells and genes;
transplantation of cells and genes including direct cell transplants and using specialized cells called stem cells in a process called “regenerative medicine:;
gene replacement procedures including something called CAR-T or CAAR-T cell therapies which we’ll be explaining in some depth in Blog #25; and
gene editing procedures including CRISPR-Cas9 (and 13) therapies, again to be explained in Blog #26.
All of these immunotherapies are targeted, organ-specific treatments, as in stem cell therapies, as well as disseminated therapies treating the patient’s whole genome, as in CAR-T, CAAR-T and CRISPR therapies. Some of these treatment techniques have similar applications but with different treatment goals as in autoimmune diseases, genetic disorders, cancers, and numerous other congenital, acquired, and chronic conditions. These innovative and “disruptive” biomedical and cellular therapies enjoy piggybacking off the successes of other genetic and cancer treatments and vice versa. The impact of these procedures and, granted their complexities, are of such consequence to immunotherapy that each deserves its own blog. So let’s start with stem cell therapies and then address each subsequent procedure in detail in separate blogs.
Blog #22: Immunotherapeutic procedures (PART 1: Stem cell transplantation therapy)
Stem cells are cells within the body originate during embryologic development and are called embryonic stem (ES) cells). During early life and growth these cells are non-specific or “undifferentiated” and have the potential to develop into many, and any different types of future adult stem cells found in organs and tissues in the body. They also differentiate into red blood cells and white blood cells (WBCs) which you will remember include lymphocytes or immune cells (Figure 5.2). Adult stem cells serve as a repair system for the body. In some organs, such as the gut and bone marrow, they regularly divide to repair and replace worn-out or damaged tissues. When these cells, particularly the more undifferentiated types, are used in cell-based therapies to treat disease, the process is referred to as regenerative or reparative medicine. The clinical value of the ES cells lies in their ability to form any kind of cell, a process called “differentiation.” This means they can start as embryonic, or their more scientific name, pluripotent stem cells (PSCs) and differentiate into specific adult stem cells and essentially repair, replace and regenerate normal healthy tissue. In a more sinister role, they can also differentiate into disease-oriented progenitor cells. But, perhaps the most important potential application of human stem cells is their generation of cells and tissues that could be used for cell-based therapies like “stem-cell transplantation.” Stem cells, directed to differentiate into specific cell types, offer the possibility of a renewable source of replacement cells and tissues to treat diseases including macular degeneration, spinal cord injury, stroke, burns, heart disease, diabetes, osteoarthritis, and rheumatoid arthritis (RA). Stem cells can be readily harvested from bone marrow (called bone marrow transplant); adipose (fat) tissue, a bountiful source of stem cells; and other bodily tissues. They are then bioengineered or “induced” into undifferentiated pluripotent cells (iPSCs) suitable for transplantation into diseased and degenerated organs and body structures (e.g., diabetes, osteoarthritis, etc.). These iPSC cells then regenerate and begin to replace the abnormal cells with new, normal cells and even potentially functioning organs, a process called organ morphogenesis (Figure 5.2). Currently, muscle and bone tissue are particularly amenable to cell and tissue regeneration. Stem cell transplantation procedures include a number of methods to deliver targeted therapeutic genes into the body through direct delivery and/or cell delivery (Fig. 5.3). Direct delivery packages the gene into an engineered vehicle, like an attenuated (neutralized) virus that is injected into the patient, whereupon it penetrates the genome and the therapeutic gene is thus delivered to the targeted organ system. The weakness of this method of delivery includes the random integration of the gene into every chromosome in the patient’s body with unknown potential adverse effects. Conversely, the cell delivery method removes embryonic stem (ES) cells from the patient and introduce the “packaged gene” directly into those removed ES cells and then return back into the patient. The use of undifferentiated ES cells as the vehicle for gene retransplant to the patient offers additional specificity to the process where the ES cells can replicate only in the target organ. The objective of stem cell transplantation therapy in immunology is to destroy the mature, long-lived, weakened immune cells and generate a new, properly functioning immune system. This process has enormous potential in autoimmune diseases, cancers, and other hereditary and acquired genetic mutations resulting in immune system compromise. The patient’s stem cells are used in a procedure known as autologous (from “one’s self”) stem cell transplantation. First, patients receive injections of a growth factor, that coaxes large numbers of undifferentiated stem cells to be released from the bone marrow into the bloodstream. These cells are then harvested from the blood, purified away from the body's mature immune cells, and stored. After sufficient quantities of these undifferentiated cells are obtained, the patient undergoes a regimen of cytotoxic, cell-killing drugs and/or radiation therapy that eliminates the body's abnormal mature immune cells. Then, the undifferentiated stem cells are returned to the patient via a blood transfusion into the circulation where they migrate to the bone marrow and begin to differentiate to become mature immune cells. Through this procedure the body’s immune system is then restored.
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