Immune system performs a very important function in our body to protect us from the diseases or any foreign materials that try to invade our body and harm us, but it has some limitations. Many foreign particles are not detected by our immune system. What if someone engineers it and converts our lymphatic cells into supercells!
What is Immune System?
Human beings are vertebrate organisms and have the Adaptive Immune System along with the Innate Immune System which is present in all plants and animals. This Adaptive Immune System provides us with immunological memory, which helps us to fight the pathogens or viruses which our body has encountered earlier.
The major components of this system are Lymphocytes which majorly consist of B-cells and T-cells. Let’s look into the major function of these cells and then go into the details of what this immune engineering does.
B-cells, also known as B-lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system by secreting antibodies. Humoral immunity is associated with the macromolecules found in extracellular fluids like blood and lymphatic system.
B-cells can release antibodies which stick on the surface of the pathogen or a virus.These antibodies can identify almost any harmful material but are not enough to kill some harmful elements like cancer cells. The ability to kill is only associated with T-cells.
A T-cell, or T-lymphocyte, is a type of lymphocyte that plays a central role in cell-mediated immunity. T-cells can be distinguished from other lymphocytes, such as B-cells and natural killer cells, by the presence of a T-cell receptor on the cell surface.
T-cells have a lot of types of effector cells, which respond to stimuli and helps in activation of other types of T-cells. Other types include helper cells, which help to activate cytotoxic T-cells (killer cells) and memory T-cells, which remain antigen-specific for a long time even after the infection is gone.
Summarising the action of these 2 types of cells, we can see that B-cells can help in recognising almost any type of harmful pathogen or even cancer cells but lack the ability to kill, whereas T-cells have the ability to kill these infected cells. If a cell can perform both of these functions, we could possibly kill cancer.
The fundamental idea behind engineered T-cells is the creation of a hybrid molecule, stuck to the T-cells’ surface, combining the cancer-homing power of antibodies with the deadly killing abilities of an army of T-cell clones.
These immune super soldiers are made using healthy T-cells taken from a patient’s blood. They are given the genetic instructions to make cancer-seeking antibodies in addition to their normal T cell receptor and are forced to replicate to form an entire upgraded army. They are then injected back into the body to seek out cancer cells.
Science behind Super T-Cells
Both B-cells and T-cells have receptors on the cell body which helps to identify different pathogens in the body. But T-cells have the killer ability but not the identification power of the antibodies released by the B-cells.
So, for these super T-cells to work, they need to have a genetically engineered receptor which has a part T-cell receptor which helps to activate the killing power of the T-cell body, and a part of B-cell antibody which can detect even the cancer cells.
For this, the experimentation on Chimeric Antigen Receptor (CAR) began for the treatment of Leukaemia (Blood Cancer).CAR is a type of receptor which combines the power of both antibody of a B-cell and the receptor of T-cell to activate cytotoxic cells. The concept of CARs was first described 25 years ago as a means of introducing tumour specificity into adoptive cell therapy. Research has been going on it since then for creating a perfect CAR which can actually detect tumour cells and activate the cell as well to destroy them. The previous generations of CAR had very limited responses. These receptors were not able to trigger the T-cells to function. Every generation of CAR had different functions and limitations:
- The first generation of CAR, when engaged, activated and induced proliferation of T-cells but could lead to anergy (natural immune responsiveness is destroyed)
- The second generation of CARs had improved the replicative capacity and persistence of modified T-cells.
- The third generation of CAR is being developed which is increases cell proliferation and persistence even further.
The properties of these genetically engineered cells also depend on the conditions in which these cells were cultured. The in vitro culture (Test tube experiments on the micro-organisms) of the T-cell expansion plays an important role to increase the composition of effector, naive, and memory T-cells in the manufactured product. As we know that effector cells are directly responsible for the cytotoxicity of the immune system (effector cells activates cytotoxic cells), they have the least replicative capacity (cell division) among all its brothers. This calls for an effective cell culture so that replicative ability of the effector cells can be increased so as to increase the overall effectiveness of engineered immune system.
How would a T-cell express a CAR?
Gene transfer technologies are used to engineer T-cells to express CARs instead of its normal receptor. Viral Vector* methods like retroviral or lentiviral are used for long-term gene expression.
Viral Vectors are tools used by molecular biologists to deliver genetic material into cells. This process can be done both, inside a living organism or in a cell culture. Viruses have evolved specialised molecular mechanisms to efficiently transport their genomes inside the cells they infect. Biologists use this ability of the viruses to infect the target cell. They can target the exact specific set of cells they want and infect only those. The essential proteins are also removed from the virus so as to stop the virus from multiplying and destroying the cell. This contains the necessary genes for modification of a normal T-cell and in the cell cultures, these viruses make the required changes in the genes of the T-cell.
These viral vector methods are useful for a long-term gene expression and hence, a long-term disease control from a single infusion of the engineered T-cells. This long-term expression also has a theoretical risk of transformation if gene transfer results in dysregulation of an oncogene (gene responsible for conversion a normal cell into tumour cell). For this reason, Short term expression is generally chosen. A short-term expression may also be desirable for CARs directed against antigens expressed on normal cells when sustained on-target toxicity is a concern.
This research also had some other problems associated:
- Changing the receptor on the cell means changing its interaction with other cells. This triggers the natural immune response of the body, in turn killing these modified cells.
- Sometimes, these cells could turn against the healthy cells and result in a lot of collateral damage.
Limitations and future scope
This research has currently been focused on blood cancer arising from B-cells. Because these cancers all arise from B-cells, they have one important thing in common: they all make a molecule called CD19.
Currently, the CAR T-cells developed can recognise CD19 and attacks any cell that makes it. CAR T-cells might be capable of chasing down cancer cells in the blood, solid tumours have extra layers of defence against immune attack, and breaching this barrier will be difficult.
The latest generations of CAR T-cells are now also being engineered to resist the inactivating influence of solid tumours, and some are even being trained to target the cells that shield the cancer cells from immune attack.
We need to know that we can keep these super soldiers under control before we unleash their full potential in the clinic. But if we can get it right, the immune system could become a powerful weapon in the fight against cancer.