CAR-T cell immunotherapy for acute myeloid leukemia
Quotation
acute myeloid leukemia (AML) is a malignant tumor caused by the proliferation and differentiation of bone marrow hematopoietic stem cells. It is most common in adult acute leukemia and has the highest fatality rate. With high heterogeneity, it clones malignant hyperplasia in bone marrow and other hematopoietic tissues, inhibits normal hematopoietic, and infiltrates other tissues and organs, leading to a series of blood disorders such as anemia, bleeding, infection, and is prone to complications such as infection, lung inflammation, renal failure, arrhythmia and other symptoms due to the damage of the immune system. Even with standard combination chemotherapy, the 5-year survival rate for patients younger than 60 years is 40% to 55%, while the 5-year survival rate for patients older than 60 years is only 10% to 15%.
Hematopoietic stem cell transplantation (HSCT) is another important treatment for AML, suitable for younger patients and high-risk patients. It mainly includes autologous transplantation and allotransplantation. Autologous hematopoietic stem cell transplantation (auto-HSCT) is the collection and storage of the patient's own stem cells, and 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) is when stem cells are obtained from a donor matching the patient's type, treated, and transplanted into the patient. However, both methods have their own problems, such as low survival rates and rejection reactions. Other effective treatment options for AML need to be explored.
CAR T cell therapy is an emerging tumor targeting therapy technology that modifies a patient's own T cells so that they can recognize and attack tumor cells. CAR T cells targeting CD19 have made remarkable achievements in the treatment of B lymphocyte malignancies, and CAR T cell therapy for AML is also being studied and tested. Modified CARs give T cells the ability to specifically recognize tumor antigens, so it is required that the targets recognized by CAR T cells should be highly expressed on the surface of tumor cells, and not expressed or low expressed in normal tissues, so as to avoid the toxic side effects caused by off-target CAR T cells when killing tumor cells. Therefore, the selection of appropriate tumor cell surface receptors is of Paramount importance. However, most of the surface markers of tumor cells in AML patients exist on normal hematopoietic stem cells and mature blood cells, and the difficulty in screening 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 crosslinking or binding with ligands, mediates inhibitory signals, and regulates intracellular calcium mobilization, cell adhesion, leukemia cell apoptosis, myeloid cell maturation, and cytokine production. CD33 is expressed in approximately 90% of AML cells, but is also expressed at low levels in normal hematopoietic cells, and is also found in leukemia progenitor cells. Therefore, CD33 is a promising therapeutic target for AML. The constructed CD33 CAR T cells showed good killing effect both in vivo and in vitro, and the survival of AML mice was prolonged. However, the mice injected with CAR-T showed blood toxicity, resulting in the reduction of peripheral blood myeloid cells, monocytes, hematopoietic stem cells, etc. The Chinese People's Liberation Army General Hospital reported a case of CD33 CAR T cell therapy in the treatment of relapsed and refractory AML patients. After infusion of 1.12×109 CD33 CAR T cells, the patient achieved partial response (PR) at week 2, but the disease progressed rapidly at week 9, and the patient died at week 13. Clinical data show that CD33 CAR-T still has problems such as cytotoxicity and short duration, and further studies are needed to overcome these problems.
02 CD123 CAR-T
CD123 is the α subunit of IL-3 receptor. After binding with IL-3, CD123 collects IL-3Rβ chain to form complex, activates downstream JAK2, mediates cell proliferation activity. CD123 is usually expressed on hematopoietic stem cells, but overexpressed on tumor cells such as acute myeloid leukemia and acute lymphoblastic leukemia, which promotes excessive proliferation of tumor cells. Therefore, CD123 is a potential target for the treatment of AML. In vitro and in vivo experiments have proved that CD123 CAR T cells can effectively kill primary AML cells and have significant myeloablative effect, with little damage to normal myeloid cells. In a Phase I clinical trial for AML, four patients were treated with CD123 CAR T cells and had varying degrees of remission. In another study, a patient achieved a complete response 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 promising potential in the treatment of AML, but significant cytotoxicity remains a major challenge.
03 CLL-1 CAR-T
C-type lectin like molecule-1 (CLL-1) is a type II transmembrane glycoprotein that exists as an inhibitory receptor in myeloid cells of peripheral blood and bone marrow, as well as 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 (LSC), CLL-1 CAR-T is more likely to be used as a patient-specific treatment strategy. In the current study, CLL-1 CAR-T showed better therapeutic effects in animal models, but could not avoid tumor recurrence. In another clinical study, seven out of 10 patients received a partial response, but all had pancytopenia and two died from the infection. The related research of CLL-1 CAR-T is still in its infancy, and there are some problems such as insufficient efficacy and blood toxicity. In the future, multi-target CAR-T may be used as a possible research direction.
General junction
CAR T cell therapy has achieved good efficacy in the treatment of B-cell malignancies and also shows potential for the treatment of AML. At present, CD33, CD123 and CLL-1 are the main therapeutic targets, and although some preliminary clinical results have been achieved, there are still some limiting factors for their application, such as post-treatment side effects, limited CAR T cell survival, and CAR T cell production. 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.
At present, Shenzhen Cell Valley is optimizing CAR-T for CD33, CD123 and CLL-1 targets, including its joint dual-target CAR-T research and development project with other targets, which is expected to overcome the limitations of these targets in the treatment of AML after optimization.
acute myeloid leukemia (AML) is a malignant tumor caused by the proliferation and differentiation of bone marrow hematopoietic stem cells. It is most common in adult acute leukemia and has the highest fatality rate. With high heterogeneity, it clones malignant hyperplasia in bone marrow and other hematopoietic tissues, inhibits normal hematopoietic, and infiltrates other tissues and organs, leading to a series of blood disorders such as anemia, bleeding, infection, and is prone to complications such as infection, lung inflammation, renal failure, arrhythmia and other symptoms due to the damage of the immune system. Even with standard combination chemotherapy, the 5-year survival rate for patients younger than 60 years is 40% to 55%, while the 5-year survival rate for patients older than 60 years is only 10% to 15%.
Hematopoietic stem cell transplantation (HSCT) is another important treatment for AML, suitable for younger patients and high-risk patients. It mainly includes autologous transplantation and allotransplantation. Autologous hematopoietic stem cell transplantation (auto-HSCT) is the collection and storage of the patient's own stem cells, and 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) is when stem cells are obtained from a donor matching the patient's type, treated, and transplanted into the patient. However, both methods have their own problems, such as low survival rates and rejection reactions. Other effective treatment options for AML need to be explored.
CAR T cell therapy is an emerging tumor targeting therapy technology that modifies a patient's own T cells so that they can recognize and attack tumor cells. CAR T cells targeting CD19 have made remarkable achievements in the treatment of B lymphocyte malignancies, and CAR T cell therapy for AML is also being studied and tested. Modified CARs give T cells the ability to specifically recognize tumor antigens, so it is required that the targets recognized by CAR T cells should be highly expressed on the surface of tumor cells, and not expressed or low expressed in normal tissues, so as to avoid the toxic side effects caused by off-target CAR T cells when killing tumor cells. Therefore, the selection of appropriate tumor cell surface receptors is of Paramount importance. However, most of the surface markers of tumor cells in AML patients exist on normal hematopoietic stem cells and mature blood cells, and the difficulty in screening 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 crosslinking or binding with ligands, mediates inhibitory signals, and regulates intracellular calcium mobilization, cell adhesion, leukemia cell apoptosis, myeloid cell maturation, and cytokine production. CD33 is expressed in approximately 90% of AML cells, but is also expressed at low levels in normal hematopoietic cells, and is also found in leukemia progenitor cells. Therefore, CD33 is a promising therapeutic target for AML. The constructed CD33 CAR T cells showed good killing effect both in vivo and in vitro, and the survival of AML mice was prolonged. However, the mice injected with CAR-T showed blood toxicity, resulting in the reduction of peripheral blood myeloid cells, monocytes, hematopoietic stem cells, etc. The Chinese People's Liberation Army General Hospital reported a case of CD33 CAR T cell therapy in the treatment of relapsed and refractory AML patients. After infusion of 1.12×109 CD33 CAR T cells, the patient achieved partial response (PR) at week 2, but the disease progressed rapidly at week 9, and the patient died at week 13. Clinical data show that CD33 CAR-T still has problems such as cytotoxicity and short duration, and further studies are needed to overcome these problems.
02 CD123 CAR-T
CD123 is the α subunit of IL-3 receptor. After binding with IL-3, CD123 collects IL-3Rβ chain to form complex, activates downstream JAK2, mediates cell proliferation activity. CD123 is usually expressed on hematopoietic stem cells, but overexpressed on tumor cells such as acute myeloid leukemia and acute lymphoblastic leukemia, which promotes excessive proliferation of tumor cells. Therefore, CD123 is a potential target for the treatment of AML. In vitro and in vivo experiments have proved that CD123 CAR T cells can effectively kill primary AML cells and have significant myeloablative effect, with little damage to normal myeloid cells. In a Phase I clinical trial for AML, four patients were treated with CD123 CAR T cells and had varying degrees of remission. In another study, a patient achieved a complete response 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 promising potential in the treatment of AML, but significant cytotoxicity remains a major challenge.
03 CLL-1 CAR-T
C-type lectin like molecule-1 (CLL-1) is a type II transmembrane glycoprotein that exists as an inhibitory receptor in myeloid cells of peripheral blood and bone marrow, as well as 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 (LSC), CLL-1 CAR-T is more likely to be used as a patient-specific treatment strategy. In the current study, CLL-1 CAR-T showed better therapeutic effects in animal models, but could not avoid tumor recurrence. In another clinical study, seven out of 10 patients received a partial response, but all had pancytopenia and two died from the infection. The related research of CLL-1 CAR-T is still in its infancy, and there are some problems such as insufficient efficacy and blood toxicity. In the future, multi-target CAR-T may be used as a possible research direction.
General junction
CAR T cell therapy has achieved good efficacy in the treatment of B-cell malignancies and also shows potential for the treatment of AML. At present, CD33, CD123 and CLL-1 are the main therapeutic targets, and although some preliminary clinical results have been achieved, there are still some limiting factors for their application, such as post-treatment side effects, limited CAR T cell survival, and CAR T cell production. 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.
At present, Shenzhen Cell Valley is optimizing CAR-T for CD33, CD123 and CLL-1 targets, including its joint dual-target CAR-T research and development project with other targets, which is expected to overcome the limitations of these targets in the treatment of AML after optimization.
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