CAR-T cell immunotherapy for the treatment of acute myeloid leukemia
Quotation
Acute myeloid leukemia (AML) is a malignant tumor caused by clonal proliferation and differentiation disorders of bone marrow hematopoietic stem cells. It is the most common acute leukemia in adults and has the highest fatality rate. It has high heterogeneity, and its clones proliferate malignantly in bone marrow and other hematopoietic tissues, inhibit normal hematopoiesis, and infiltrate other tissues and organs, leading to a series of blood diseases such as anemia, bleeding, and infection. Due to damage to the immune system, It is prone to complications such as infection, lung inflammation, renal failure, arrhythmia and other symptoms. Traditional treatment options are mainly chemotherapy. Even after receiving standard combination chemotherapy, the 5-year survival rate of patients aged <60 years old is 40% to 55%, while the five-year survival rate of patients aged ≥60 years old is only 10% to 15%.
Hematopoietic stem cell transplantation (HSCT) is another important treatment for AML, suitable for younger patients and high-risk patients. Mainly include autologous transplantation and allogeneic transplantation. Autologous hematopoietic stem cell transplantation (auto-HSCT) collects and stores the patient's own stem cells. After chemotherapy or radiotherapy, the stem cells are transplanted back into the patient's body to re-establish normal hematopoietic function. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) refers to obtaining stem cells from a donor that matches the patient's type, processing them, and transplanting them into the patient's body. However, both methods have their own problems, such as low survival rate and rejection. Other effective treatments for AML need to be explored.
CAR-T cell therapy is an emerging tumor-targeted treatment technology that modifies the patient's own T cells so that they can recognize and attack tumor cells. CAR-T cells targeting CD19 have achieved remarkable results in the treatment of B lymphocyte malignancies, and CAR-T cell therapy for AML is also being studied and tested. The modified CARs endow T cells with the ability to specifically recognize tumor antigens. Therefore, it is required that the targets recognized by CAR-T cells should be highly expressed on the surface of tumor cells and have no or low expression in normal tissues to avoid CAR-T cells from detecting tumor antigens. When killing tumor cells, it causes toxic side effects due to off-target effects. Therefore, selecting appropriate tumor cell surface receptors is a top priority. However, most surface markers of tumor cells in AML patients are present on normal hematopoietic stem cells and mature blood cells. The difficulty in selecting targets limits the application of CAR-T cell therapy in the treatment of AML. Currently, the commonly used targets mainly include CD33 , CD123, CLL-1, etc.
01 CD33 CAR-T
CD33 is a glycosylated transmembrane protein expressed in myeloid cells. It is activated after cross-linking or binding to ligands, mediates inhibitory signals, and regulates intracellular calcium mobilization, cell adhesion, leukemia cell apoptosis, and myeloid cells. Maturation and cytokine production, etc. CD33 is expressed on approximately 90% of AML cells, but is also expressed at low levels on normal hematopoietic cells, and its expression is also found on leukemic progenitor cells. Therefore, CD33 is a very potential therapeutic target for AML. The constructed CD33 CAR-T cells showed good killing effects in vivo and in vitro, and the survival period of AML mice was prolonged. However, mice injected with CAR-T developed hematological toxicity, resulting in a decrease in peripheral blood myeloid cells, monocytes, and hematopoietic stem cells. The General Hospital of the People's Liberation Army of China reported a case of CD33 CAR-T cell therapy in the treatment of relapsed and refractory AML patients. After the patient was infused with a total of 1.12×109 CD33 CAR-T cells, the patient achieved partial remission (PR) at the 2nd week. , but the condition progressed rapidly in the 9th week, and the patient died in the 13th week of reinfusion. Clinical data shows that CD33 CAR-T still has problems such as cytotoxicity and short duration, and further research is needed to overcome the problems.
02 CD123 CAR-T
CD123 is the α subunit of the IL-3 receptor. After binding to IL-3, it recruits the IL-3Rβ chain to form a complex, activates downstream JAK2, and mediates cell proliferation activity. CD123 is usually expressed on hematopoietic stem cells and is overexpressed on tumor cells such as acute myeloid leukemia and acute lymphoblastic leukemia, promoting excessive proliferation of tumor cells. Therefore, CD123 is a potential target for the treatment of AML. In vivo and in vitro experiments have proven that CD123 CAR-T cells can effectively kill primary AML cells, have significant myeloablative effects, and cause less damage to normal myeloid cells. In a phase I clinical trial for AML, four patients all experienced varying degrees of remission after receiving CD123 CAR-T cell therapy. In another study, a patient achieved complete remission after receiving CD123 CAR-T infusion, but died on day 56 due to acute graft-versus-host disease and organ failure. CD123 CAR-T cells have shown good potential in the treatment of AML, but cytotoxicity that cannot be ignored is still a huge challenge.
03 CLL-1 CAR-T
C-type lectin-like molecule-1 (CLL-1) is a type II transmembrane glycoprotein that serves as an inhibitory receptor in myeloid cells in peripheral blood and bone marrow and in most AML cells, and is not expressed in normal hematopoietic stem cells and other tissues. Since CLL-1 is not a universal target on leukemic stem cells (LSCs), CLL-1 CAR-T is more likely to serve as a patient-specific treatment strategy. In the current study, CLL-1 CAR-T showed good therapeutic effects in animal models, but it could not avoid tumor recurrence. In another clinical study, 7 of 10 patients achieved partial remission after receiving treatment, but all patients developed symptoms of pancytopenia, and two patients died of infection. Research related to CLL-1 CAR-T is still in its infancy, and there are problems such as insufficient efficacy and blood toxicity. Multi-target CAR-T may be a possible research direction in the future.
Summarize
CAR-T cell therapy has achieved good results in the treatment of B-cell malignancies and has also shown potential for the treatment of AML. Currently, CD33, CD123 and CLL-1 are the main therapeutic targets. Although some preliminary clinical results have been achieved, there are still some limiting factors in their application, such as side effects after treatment, limited survival of CAR-T cells, CAR -Production of T cells, etc. Therefore, further research and optimization are still needed to improve its efficacy and safety, such as optimizing the CAR structure, finding new specific targets, dual-target CAR-T, and inserting suicide genes into the CAR. In the future, with the continuous development and improvement of CAR-T cell therapy-related technologies, it will play a more important role in the treatment of AML.
Shenzhen Cell Valley is currently optimizing CAR-T targeting CD33, CD123 and CLL-1, including dual-target CAR-T R&D projects combined with other targets. It is expected that these problems can be overcome through optimization. Limitations of targets in AML treatment.
Acute myeloid leukemia (AML) is a malignant tumor caused by clonal proliferation and differentiation disorders of bone marrow hematopoietic stem cells. It is the most common acute leukemia in adults and has the highest fatality rate. It has high heterogeneity, and its clones proliferate malignantly in bone marrow and other hematopoietic tissues, inhibit normal hematopoiesis, and infiltrate other tissues and organs, leading to a series of blood diseases such as anemia, bleeding, and infection. Due to damage to the immune system, It is prone to complications such as infection, lung inflammation, renal failure, arrhythmia and other symptoms. Traditional treatment options are mainly chemotherapy. Even after receiving standard combination chemotherapy, the 5-year survival rate of patients aged <60 years old is 40% to 55%, while the five-year survival rate of patients aged ≥60 years old is only 10% to 15%.
Hematopoietic stem cell transplantation (HSCT) is another important treatment for AML, suitable for younger patients and high-risk patients. Mainly include autologous transplantation and allogeneic transplantation. Autologous hematopoietic stem cell transplantation (auto-HSCT) collects and stores the patient's own stem cells. After chemotherapy or radiotherapy, the stem cells are transplanted back into the patient's body to re-establish normal hematopoietic function. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) refers to obtaining stem cells from a donor that matches the patient's type, processing them, and transplanting them into the patient's body. However, both methods have their own problems, such as low survival rate and rejection. Other effective treatments for AML need to be explored.
CAR-T cell therapy is an emerging tumor-targeted treatment technology that modifies the patient's own T cells so that they can recognize and attack tumor cells. CAR-T cells targeting CD19 have achieved remarkable results in the treatment of B lymphocyte malignancies, and CAR-T cell therapy for AML is also being studied and tested. The modified CARs endow T cells with the ability to specifically recognize tumor antigens. Therefore, it is required that the targets recognized by CAR-T cells should be highly expressed on the surface of tumor cells and have no or low expression in normal tissues to avoid CAR-T cells from detecting tumor antigens. When killing tumor cells, it causes toxic side effects due to off-target effects. Therefore, selecting appropriate tumor cell surface receptors is a top priority. However, most surface markers of tumor cells in AML patients are present on normal hematopoietic stem cells and mature blood cells. The difficulty in selecting targets limits the application of CAR-T cell therapy in the treatment of AML. Currently, the commonly used targets mainly include CD33 , CD123, CLL-1, etc.
01 CD33 CAR-T
CD33 is a glycosylated transmembrane protein expressed in myeloid cells. It is activated after cross-linking or binding to ligands, mediates inhibitory signals, and regulates intracellular calcium mobilization, cell adhesion, leukemia cell apoptosis, and myeloid cells. Maturation and cytokine production, etc. CD33 is expressed on approximately 90% of AML cells, but is also expressed at low levels on normal hematopoietic cells, and its expression is also found on leukemic progenitor cells. Therefore, CD33 is a very potential therapeutic target for AML. The constructed CD33 CAR-T cells showed good killing effects in vivo and in vitro, and the survival period of AML mice was prolonged. However, mice injected with CAR-T developed hematological toxicity, resulting in a decrease in peripheral blood myeloid cells, monocytes, and hematopoietic stem cells. The General Hospital of the People's Liberation Army of China reported a case of CD33 CAR-T cell therapy in the treatment of relapsed and refractory AML patients. After the patient was infused with a total of 1.12×109 CD33 CAR-T cells, the patient achieved partial remission (PR) at the 2nd week. , but the condition progressed rapidly in the 9th week, and the patient died in the 13th week of reinfusion. Clinical data shows that CD33 CAR-T still has problems such as cytotoxicity and short duration, and further research is needed to overcome the problems.
02 CD123 CAR-T
CD123 is the α subunit of the IL-3 receptor. After binding to IL-3, it recruits the IL-3Rβ chain to form a complex, activates downstream JAK2, and mediates cell proliferation activity. CD123 is usually expressed on hematopoietic stem cells and is overexpressed on tumor cells such as acute myeloid leukemia and acute lymphoblastic leukemia, promoting excessive proliferation of tumor cells. Therefore, CD123 is a potential target for the treatment of AML. In vivo and in vitro experiments have proven that CD123 CAR-T cells can effectively kill primary AML cells, have significant myeloablative effects, and cause less damage to normal myeloid cells. In a phase I clinical trial for AML, four patients all experienced varying degrees of remission after receiving CD123 CAR-T cell therapy. In another study, a patient achieved complete remission after receiving CD123 CAR-T infusion, but died on day 56 due to acute graft-versus-host disease and organ failure. CD123 CAR-T cells have shown good potential in the treatment of AML, but cytotoxicity that cannot be ignored is still a huge challenge.
03 CLL-1 CAR-T
C-type lectin-like molecule-1 (CLL-1) is a type II transmembrane glycoprotein that serves as an inhibitory receptor in myeloid cells in peripheral blood and bone marrow and in most AML cells, and is not expressed in normal hematopoietic stem cells and other tissues. Since CLL-1 is not a universal target on leukemic stem cells (LSCs), CLL-1 CAR-T is more likely to serve as a patient-specific treatment strategy. In the current study, CLL-1 CAR-T showed good therapeutic effects in animal models, but it could not avoid tumor recurrence. In another clinical study, 7 of 10 patients achieved partial remission after receiving treatment, but all patients developed symptoms of pancytopenia, and two patients died of infection. Research related to CLL-1 CAR-T is still in its infancy, and there are problems such as insufficient efficacy and blood toxicity. Multi-target CAR-T may be a possible research direction in the future.
Summarize
CAR-T cell therapy has achieved good results in the treatment of B-cell malignancies and has also shown potential for the treatment of AML. Currently, CD33, CD123 and CLL-1 are the main therapeutic targets. Although some preliminary clinical results have been achieved, there are still some limiting factors in their application, such as side effects after treatment, limited survival of CAR-T cells, CAR -Production of T cells, etc. Therefore, further research and optimization are still needed to improve its efficacy and safety, such as optimizing the CAR structure, finding new specific targets, dual-target CAR-T, and inserting suicide genes into the CAR. In the future, with the continuous development and improvement of CAR-T cell therapy-related technologies, it will play a more important role in the treatment of AML.
Shenzhen Cell Valley is currently optimizing CAR-T targeting CD33, CD123 and CLL-1, including dual-target CAR-T R&D projects combined with other targets. It is expected that these problems can be overcome through optimization. Limitations of targets in AML treatment.
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