Introduction:
Hematological cancers are traditionally treated primarily with chemotherapy, radiation, and hematopoietic stem cell transplantation (HSCT). In recent times, CAR-T cell therapy has transformed the treatment of blood cancers and obtained outstanding responses, particularly in B-cell acute lymphocytic leukemia (B-ALL) that has relapsed or is refractory (R/R), non-Hodgkin lymphoma (NHL), and multiple myeloma (MM). Currently, the most often used targets in CAR-T cell therapy are CD19 and BCMA. However, many other new therapeutic targets are being investigated.
What Is Chimeric Antigen Receptor T (CAR-T) Cell Therapy?
Chimeric antigen receptor (CAR) T cell therapy is a technique that uses genetic engineering to modify T cells, a subset of white blood cells, to enable them to recognize and eliminate cancerous cells. Because CAR-T cell therapy modifies T cells' genes to enable them to fight cancer, it is occasionally referred to as a form of cell-based gene therapy. Even in cases where other forms of cancer treatment are no longer effective, this kind of treatment can be quite beneficial.
What Is the Process Involved in Making CAR-T Cells?
1. Gathering T Cells:
First, a process known as leukapheresis is used to extract white blood cells, including T cells, from the individual's blood. Individuals typically lie in bed or recline in a reclining chair for this operation. White blood cells are extracted from the blood through one IV (intravenous) line, and the blood is reinfused into the body with the other, necessitating the use of two IV lines. Occasionally, a central venous catheter—a unique kind of IV line with both IV lines integrated right into it is employed. Throughout the operation, the patient will have to remain seated or in a prone position for two to three hours.
2. Creating CAR-T Lymphocytes:
Once the white cells are extracted, the T cells are isolated, transferred to a laboratory, and manipulated by introducing the gene corresponding to the particular chimeric antigen receptor (CAR). They are, therefore, CAR-T cells. Then, in the laboratory, these cells are expanded and multiplied. The production of the vast quantity of CAR-T cells required for this treatment can take many weeks.
3. Getting the Injection of CAR-T Cells:
The patient will receive their CAR-T cells back after an adequate number has been produced. The patient may get chemotherapy a few days before the CAR-T cell infusion in order to assist in reducing the quantity of other immune cells. This increases the likelihood that the CAR-T cells will become activated to combat the malignancy. Because CAR-T cells function best while there are still some cancer cells to assault, this chemotherapy is typically not very effective. The CAR-T cells proliferate and have the ability to aid in the destruction of other cancer cells once they attach to cancer cells.
What Are the Most Promising Targets for CAR-T Cell Treatment in Hematological Cancers?
At present, the most popular targets for CAR-T cell therapy are CD19 and BCMA. Relapse following CAR-T cell therapy is a common occurrence despite the remarkable results of anti-CD19 and anti-BCMA CAR-T cell therapy in B cell malignancies. Furthermore, other possible targets are presently being studied because of the antigenic diversity of acute myeloid leukemia (AML) and the absence of CD19 in Hodgkin lymphoma (HL) and T-cell cancers.
What Are the Currently Approved CAR-T Cell Treatments?
Currently, the US Food and Drug Administration (FDA) has granted authorization for six CAR-T cell products to treat R/R B cell malignancies: Tisagenlecleucel, Axicabtagene ciloleucel, Brexucabtagene autoleucel, Lisocabtagene maraleucel, Idecabtagene vicleucel, and Ciltacabtagene autoleucel. These products target the most common target antigens, CD19 (cluster of differentiation 19) and B cell maturation antigen (BCMA).
What Are the Effective Targets for CAR-T Cell Treatments?
1. B Cell Lymphoblastic Leukemia or Lymphoma:
One of the most significant target antigens for B cell malignancies, such as NHL and B-ALL, is CD19. Anti-CD19 CAR-T cell treatment has significantly changed the curative picture of B cell malignancies in recent years, demonstrating quick and long-lasting responses among individuals with R/R B-ALL and NHL. More than 90 percent of B cell lymphomas express CD20, making it a desirable target for CD20-positive B cell lymphomas. Rituximab, an anti-CD20 monoclonal antibody, has demonstrated outstanding effectiveness against NHL in recent years.
2. T Cell Lymphoblastic Leukemia or Lymphoma:
It is desirable to target CD7 for the treatment of T-ALL (T-cell acute lymphoblastic leukemia), as it is abundantly expressed in 95 percent of T-ALL patients. Around 85 percent of T-cell malignancies, including peripheral T-cell lymphoma (PTCL) and T-cell lymphoblastic lymphoma (T-LBL), express CD5. A new study has shown that anti-CD5 CAR-T cells can successfully eradicate cancerous T cells.
3. Hodgkin Lymphoma (HL):
In classical HL, CD30 expression is common. Currently, several research studies are being conducted to assess the effectiveness of anti-CD30 CAR-T cell treatment in patients with R/R HL.
4. Acute Myeloid Leukemia:
CAR-T cell treatment for AML (acute myeloid leukemia) has not been as successful as ALL (acute lymphocytic leukemia) due to antigenic diversity. More than 80 percent of AML patients have leukemic stem cells with high expressions of CD123 and CD33; however, these proteins also occur in hematopoietic stem cells. Thus, focusing on them may raise the possibility of chronic myelosuppression. In recurrent AML following allogeneic hematopoietic stem cell transplantation, anti-CD38 CAR-T cell therapy is efficacious, as the majority of AML blast cells express CD38.
5. Multiple Myeloma:
Since BCMA is one of the most promising treatment targets for multiple myeloma. The Food and Drug Administration (FDA) has approved Idecabtagene vicleucel and Ciltacabtagene autoleucel, two anti-BCMA CAR-T cell products, for the treatment of R/R MM. Currently, anti-BCMA CAR-T cell therapy has been shown to be successful in R/R MM and has produced exceptional results.
What Are the Adverse Effects of CAR-T Cell Treatment?
Even though CAR-T cell treatment has shown considerable promise in treating hematological cancers, side effects such as cytokine release syndrome (CRS, a disorder that appears when the body creates an excessive amount of cytokines), CAR-T cell-related encephalopathy syndrome (CRES, a second most frequent adverse effect that can happen either before or after CRS), B cell aplasia, cytopenia (a disorder characterized by decreased production of platelets, red blood cells (RBC), and white blood cells (WBC)), and CRS-related coagulopathy continue to pose a significant obstacle. These issues could potentially be fatal if proactive measures are not taken.
Conclusion
Several individuals have benefited from the use of chimeric antigen receptor (CAR) T-cell therapy, which has emerged as a potent therapeutic option for hematological malignancies. The FDA has approved six CAR T-cell products at present, while numerous others are being researched and are undergoing clinical trial research.
