Introduction
Hematological malignancies are primary cancers of the blood and blood-forming organs (bone marrow and lymphoid tissues). Traditionally, the treatment of hematological malignancies is administered by chemotherapy, radiotherapy, and stem cell transplantation. Immune-targeted therapy has become a new possibility for the treatment of hematological malignancies. This means that a new understanding in the interaction between the immune system and cancer cells holds promise for immunotherapy development.
Introducing T-Cells: key players in the immune system. T-Cells (also known as T lymphocyte) aid in protecting one’s body from infection by determining the specificity of antigens (forgien bodies) and once activated, helper T-cells will secrete cytokines. These cytokines will stimulate antibody producing cells and this whole process should protect the immune system. But the question remains of how this system could be applied to cancer?
Enter the chimeric antigen receptor (CAR). This is a laboratory made receptor that is designed to bind to certain proteins on cancer cells. Chimeric antigen receptors have been added to T-Cells in the lab with the hopes that once CAR binds to the cancer cell, it may stimulate the T-Cells natural immune response. Therapies using this tournament are individualized to each type of cancer due to a focus on the unique proteins that CAR must bind to. For example, in certain kinds of leukemia or lymphoma, the cancer cells have an antigen called CD19. The CAR T-cell therapies to treat these cancers are made to attach to the CD19 antigen and the treatment will not work for a cancer that does not have the CD19 antigen.
This therapy may seem like a solution to all of the hematological malignancies, but this seemingly exceptional solution may be a gamble with the risk of death.
DownFalls and Disadvantages
On-Target / Off-Tumor Toxicity
This is a direct attack on normal, healthy tissue that has the shared expression of the targeted antigen. Biomolecular causes of hematological malignancies can be expressed in normal tissues and lymphoid tissues which is why the CAR-T cells will view the wrong tissue as their target. In other words, this is when the cells attack the normal / non-malignant tissue. Researchers have found a handful of solutions for this. Firstly, there is a treatment with the combined control system of switchable dual receptor CAR-T cells and immune checkpoints (this is done to ensure that the CAR-T cells are in the correct location, targeting the correct antigens). This is typically a system requiring two antigens to activate the CAR-T cells. Also, there is inhibitory CAR (iCAR) therapy that could recognize antigens expressed in tissue that is healthy. This will ensure the antitumor activity of CAR-T cells and also prevent the off-target toxicity. These solutions have been proven to work in a handful of case studies, but need more trial in order to prove true effectiveness and minimal damage to one’s body.
Cytokine Release Syndrome
Often referred to as CRS, Cytokine Release Syndrome is a systemic immune stress inflation. It is caused by rapid rates of proliferation and the release of cytokines after CAR-T cells are introduced to the body. Within thai therapy, Car-T cells produce an immense number of cytokines which often leads to CRS. Symptoms of this will include: a fever (the most common anung patients), neurological changes, low blood pressure (for extended periods of time), and hypoxia (where oxygen cannot reach the tissue level of one’s body). As this is the most common downfall of the therapy, researchers have searched for solutions. One of which consists of a new CAR-T cell therapy designed based on CRS in which the CAR-T cells will stimulate a limited amount of cytokines, but just enough to keep the immune response active. Additionally, researchers have considered using the C-reactive protein to evaluate the severity of the reaction so that a manageable approach to future CAR-T cell therapy can be made.
Neurotoxicity
In general, this is damage to the nervous system and often related to CRS (and can occur with CRS after CAR-T cell therapy). The mechanism of this and how CAR-T cells cause this is unknown due to how recent the therapy was used in clinical trials. Symptoms of this will include a language disorder, hallucinations, seizures and severe encephalopathy (brain function changes). Furthermore, encephalopathy will lead to death in most cases. The damage to the brain is typically correlated with high levels of cytokines and endothelial activation in cerebrospinal fluid. While looking for solutions to CRS in retrospect the CAR-T cell therapy, researchers have found a somewhat stable way to treat this before serious progression. This was done with the usage of IL-6 targeted therapy and corticosteroids, but this is a reactionary measure and not a previontary one. The correlation between CAR-T cells and neutralizing factors shows promise in the future, but as of now, there is a need of trial
Relapse
As with many cancer treatments, relapse is possible. There are two known types of relapses for CAR-T cell therapy. Target-negative relapse:this is caused by the loss of antigen after CAR-T cell therapy is done. In this replacement, all antitumor antigens will be diminished within the body, hence leaving room for tumor buildup. Secondly, there is antigen-positive relapse which is directly caused by a change in the cell’s micorenviormney. This occurs when CAR-T cells diminish to a miniscule amount during treatment so there is nothing to fight the malignant growth. A common solution to this is the usage of Allo-HSCT (allogeneic hematopoietic stem cell transplant). This is a procedure in which healthy stem cells are inserted into the patient in hopes of a non-fatal result. As there is a valuable solution to these types of relapse, the ultimate goal is to have a minimal relapse rate, so more testing is needed.
Conclusion
Overall, CAR-T cells have a promising future in treating hematological malignancies. This therapy is done to screen the targets on the surface of the tumor cells and then create CAR-T cells to be inserted into the patient. Additionally, clinical trials applied CAR-T cells in treatment and CAR-T cells have aided in the further studies of hematological malignancies. There still are disadvantages to CAR-T cells which makes them potentially dangerous with side effects such as CRS, neurotoxicity, off-tumor toxicity and of course relapse. CAR-T cell therapy will continue to develop and further studies will be made to focus of the areas in which the treatment is lacking.
– Katia Krishtopa ‘24
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