Working in the field of oncology, one of the greatest revolutions that has taken place has been CAR T-cell therapy, giving hope to hundreds of patients suffering from a virulent form of cancer. It is an innovative treatment that basically provokes an individual's immune system to fight against cancer by using genetically engineered T cells that target and kill malignant cells. CAR T-cell therapy has heralded new opportunities in cancer treatment for those cases where all other hopes were lost. The details will be covered in this review: the basics of CAR T-cell therapy, its details of the procedure with relation to tumor targeting and interplay with bone marrow-associated treatments, and also the complications that arise and the management of side effects to give a better understanding of this new modality of therapy.
What is CAR T-Cell Therapy?
Chimeric antigen receptor T-cell therapy, commonly called CAR T-cell therapy, is a kind of immunotherapy that involves modifying the patient's T cells to enable them to recognize the cancer cells and attack them better. T cells are part of the key building blocks of an immune system which identifies and clears any pathogen or abnormal cell from the body. Scientists have found a way of genetically modifying these T cells to target only cancer cells.
It starts with the extraction of T cells from the patient's blood. The cells are then engineered in a laboratory to express chimeric antigen receptors. CARs are synthetically developed molecules that are designed to bind to certain antigens on the surface of the cancer cells. This genetic modification essentially transforms T cells into strong cancer killers.
T-cell therapy is sometimes referred to as cell-based gene transfer due to the genetic alteration of the T cells. This allows them to identify and bind with antigens on cancerous cells, consequently killing them. It is a novel treatment that has turned out to be quite successful for some blood cancers, such as leukemia and lymphoma.
How CAR T-Cell Therapy Works
Understanding CAR T-cell therapy requires understanding the basics regarding how the immune system works and how CAR T-cells enhance that process to fight cancer.
Immune System Basics
The immune system contains a very intricate network of interlinked cells and proteins at its command to fight an infection or disease. T cells are at the core of the system, hunting down the abnormal cells—that is, identifying and then destroying them. On their surfaces, some receptors bind with antigens specific molecules that are on the surface of the pathogens or cancerous cells.
One can consider the relationship of T cell receptors and antigens to be like a lock-and-key system. The antigen is the lock, while the T cell receptor is the key that fits into it. Thus, upon encounter with an antigen for which it has a receptor, the T cell is activated to respond against the threat. This natural process is harnessed and honed in CAR T-cell therapy.
CARs and Genetic Modification
Chimeric antigen receptors are designed to recognize certain antigens on tumor cells. Several manipulations need to be done to generate CAR T-cell therapy:
T Cell Collection: T cells belonging to the patient are harvested through a process called leukapheresis. During leukapheresis, the apheresis machine extracts T cells from other blood components. This is typically done via an infusion or using a catheter introduced into one of the large veins, usually at the collarbone area.
Genetic modification: After collection, the T cells are sent for laboratory genetic modification to express CARs. This involves introducing genes encoding CAR into T cells using viral vectors. The CARs are designed to interact with specific antigens appearing on cancer cells, such as CD19 in some leukemias and lymphomas.
Expansion: The genetically modified T cells are expanded in the laboratory and increase in number up to the amount required for treatment. This step of expansion ensures that a large number of CAR T cells are available for infusion back into the patient.
Infusion: After expansion, the CAR T cells are infused into the patient's bloodstream. Prior to infusion, patients can undergo conditioning treatments such as low-dose chemotherapy to enhance the engraftment and proliferation of CAR T cells.
FDA-Approved CAR T-Cell Therapies
The FDA has approved several CAR T-cell therapies against certain blood cancers. These therapies include:
Tisagenlecleucel: FDA approved for ALL and large B-cell lymphoma. Axicabtagene ciloleucel: Approved for large B-cell lymphoma and some follicular lymphomas. Brexucabtagene autoleucel: Approved for mantle cell lymphoma. Lisocabtagene maraleucel: Approved for large B-cell lymphoma. Idecabtagene vicleucel: Approved for multiple myeloma. Ciltac: Granted approval for the treatment of multiple myeloma and other blood cancers.
These approvals represent the huge step forward in CAR T-cell therapy that is developing a sound platform for effectively treating a variety of hematological malignancies.
Bone Marrow and CAR T-Cell Therapy
It is also involved in the production of blood cells: red blood cells, white blood cells, and platelets. Bone marrow cells are collected for use in therapy, especially in bone marrow transplantation, to reconstitute the normal production of blood cells in patients whose bone marrow has been damaged.
Bone marrow harvesting refers to the collection of stem cells from the bone marrow or blood for use in transplantation. These stem cells move out of the bone marrow into general circulation, whereupon they recolonize — reconstitute — blood cell populations of the patient. Sometimes, this method is used in association with CAR T-cell therapy, most often among patients who have been exposed to treatments significantly affecting the bone marrow.
Tumor Targeting and CAR T-Cell Therapy
CAR T-cell therapy depends on precise targeting of tumoral cells. The key characteristics of this therapy include the activation of tumoral-targeting ligands at the surface of CAR T-cells. These designed ligands are able to recognize specific antigens existing on the cancerous cell surface and, by that, enable CAR T-cells to recognize and destroy malignant cells.
The mechanisms by which CAR T cells target tumors are still being optimized. Investigations focus on:
Activating Tumor-Targeting Ligands: Several reports describe the development of CARs with increased tumor-associated antigen specificity and affinity. All of these efforts focus on making the targeting of cancer cells more effective by CAR T cells.
Elimination of Tumor-Infiltrating CDX T cells: In all, tumor-infiltrating CDX T cells are major contributors to immune escape and resistance to therapy; hence, strategies for their depletion are underway in order to ensure the effectiveness of CAR T cell therapy.
Attention to Tumor Stages: CAR T-cell therapy needs to be addressed to tumors at different development stages. This early treatment prevents them from progressing through all tumor stages, thereby going through better treatment results.
Side-Effects of CAR T-Cell Therapy
Besides the various advantages, it is not free of risks. The identification and management of side effects are essential in ensuring safety and treatment success. Some common and severe adverse side effects include:
CRS is another common and serious side effect that occurs in relation to CAR T-cell therapy. It takes the form of a systemic response that arises when CAR T cells release large amounts of cytokines within the blood, thereby causing the immune system to get over-activated. Common symptoms of this condition include:
• High fever and chills
• Difficulty breathing
• Severe nausea and vomiting
• Diarrhea
• Dizziness or light-headedness
• Headaches
• Fast heartbeat
• Fatigue
• Aches in the muscles and joints
The CRS can range from mild to severe and may necessitate emergent medical intervention. Treatment primarily includes general supportive care, such as hydration, fever management, and medications like tocilizumab or corticosteroids aimed at dampening the immune response.
Neurologic Effects
CAR T-cell therapy can also influence the nervous system, which gives rise to a diversity of neurological symptoms, such as the following:
- Headaches
- Changes in level of consciousness
- Confusion or agitation
- Seizures
- Tremors
- Difficulty with speech or comprehension
- Loss of balance
Neurologic effects range from mild to severe and require special management in the more severe instances. Patients may need to stop driving and operating heavy machinery until they recover from their symptoms.
Other Severe Side Effects
Other serious side effects include:
- Infusion reactions
- Abnormal levels of blood minerals
- Increased infections from low white blood cell count
- Low blood counts
- These side effects need to be monitored well for timely management so that the patient does not face danger or discrepancy in treatment efficacy.
Bone Marrow and Tumor Research
Bone marrow is another area of research related to the treatment and monitoring of tumors. In this context, the role of bone marrow in the production of red blood cells needs to be understood to be able to make sense of the different treatments for cancer, especially CAR T-cell therapy.
Bone Marrow Harvesting for Transplantation: It is a process of collecting stem cells from the bone marrow or blood to reconstitute damaged or diseased bone marrow. The harvested cells are capable of migrating from the bone marrow into the bloodstream and re-establishing normal blood cell production.
