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Chimeric Antigen Receptor T (CAR-T) Cellular Immunotherapy is a new type of precision targeted therapy for the treatment of tumors.
Currently, it is effective in the treatment of B-cell acute lymphoblastic leukemia (B-ALL) and B-cell lymphoma.
But CAR-T treatment of acute T-lymphocytic leukemia/lymphoblastic lymphoma (T-ALL/LBL) has just started
.
The team of Professor Zhang Mingzhi from the Department of Oncology of the First Affiliated Hospital of Zhengzhou University used CD7 CAR-T cells to treat T-ALL/LBL, and his two CD7 CAR-T cells to treat T-ALL/LBL related studies were selected for this year's ASH poster presentation
.
Yimaitong sincerely invites Professor Zhang Mingzhi to accept an interview to discuss the difficulties in diagnosis and treatment of T-ALL/LBL, and the latest research progress of CD7 CAR-T in the treatment of T-ALL/LBL
.
Diagnosis and treatment status of T-ALL/LBL and treatment difficulties T-ALL/LBL is a highly malignant tumor.
70% of patients develop a mass at the onset of the disease, accompanied by leukemia symptoms such as bone marrow invasion
.
The clinical manifestations of T-ALL/LBL are also biased.
Some patients only present with mediastinal masses, and some patients only present with large numbers of leukemia cells in peripheral blood and bone marrow
.
T-ALL/LBL tends to occur in adolescents.
The reasons for visits are mostly chest tightness and chest discomfort.
Physical examination reveals mediastinal mass, pericardial effusion or pleural effusion
.
Bone marrow aspiration can find tumor cells
.
T-ALL / LBL rapid progression, invasive strong, high strength applications requiring chemotherapy, commonly used in clinical treatment for type BF 90 embodiment, Hyper-CVAD programs
.
Due to the existence of primary and secondary drug resistance, some patients have relapsed after first-line treatment, and the white blood cells and platelets in the blood continue to be low after multi-line treatment
.
Chemotherapy cannot be continued .
Acute early precursor T lymphocytic leukemia/lymphoblastic lymphoma (ETP-ALL/LBL) cells often have stem lines (such as CD34, HLA-DR positive expression) or myeloid differentiation (CD13, CD33, CD117 positive expression), this Patients with T-ALL/LBL are more malignant, prone to primary or secondary drug resistance, and the 5-year survival rate is less than 30%
.
For relapsed and refractory T-ALL/LBL, ETP, certain gene mutations or complex karyotypes, how to improve the therapeutic effect is a difficult problem in clinical treatment
.
CAR-T treatment of T-ALL/LBL challenges , These patients may be cured for a long time
.
However, in T-cell lymphoma, the application of CAR-T has been blank
.
Professor Zhang Mingzhi introduced that CAR-T treatment for patients with B-cell lymphoma is to use the patient’s normal T cell culture to make CAR-T cells to attack and kill B cells.
The effect is significant, and it is applied to T-ALL/LBL patients.
In the treatment of, there are many challenges in the clinic
.
First, "cannibalism" between CAR-T cells
.
As one of the important targets, the expression rate of CD7 in T lymphocytes is about 95%, and the expression rate is high and stable during the initial diagnosis, chemotherapy, and recurrence of patients
.
Therefore, after the infusion of CAR-T cells, CAR-T cells not only attack tumor cells, but also cause CAR-T cells to attack each other
.
The current response strategy is to apply endoplasmic reticulum technology to inhibit the expression of CD7 on the surface of T lymphocyte membranes to prevent CAR-T cells from killing each other
.
Second, in the process of collecting T cells, the tumor cells were collected by mistake and made into CAR-T
.
The consequence of this is that the cultured CAR-T cells are tumor-like and cannot be used in treatment
.
In order to avoid this risk, it is stipulated that all T-ALL/LBL patients with peripheral blood or bone marrow invasion, tumor cell expression must be CD7+, CD4-, CD8-, in the process of collecting cells, collecting CD4+, CD8+ normal Cells, which can effectively avoid the collection of tumor cells
.
If it is a mass type T-ALL/LBL patient, there is no tumor cell invasion in the peripheral blood and bone marrow, generally there will be no collection of tumor cells
.
Third, the patient's immunity is greatly reduced after CAR-T treatment
.
During CAR-T treatment, CAR-T cells attack CD7+ normal T lymphocytes, and the patient's immune system will also suffer certain damage, leading to infection
.
Studies have shown that CD7-T lymphocytes and CD7+ T lymphocytes have little difference in immune function
.
Therefore, the CD7+ CAR-T is produced while cultivating and expanding the patient’s CD7- T lymphocytes.
After the patient’s CD7+ T lymphocytes are severely attacked, the patient’s CD7+ T lymphocytes are reinfused to prevent serious infections caused by the patient’s low cellular immunity
.
At present, after more than a dozen cases of practice, it is found that the overall effective rate of T-ALL/LBL patients with mass type is >70% and the CR rate is 50% due to the influence of tumor microenvironment.
For leukemia patients, CAR-T is used.
The treatment can reach a higher remission rate, and the CR rate is almost 100%
.
The treatment effect of relapsed T-ALL/LBL patients is affected by multiple factors.
T-ALL/LBL patients treated with CAR-T also have recurrence
.
In previous studies, some patients were positive for CD7 expression before treatment, and then tested negative for CD7 expression again after recurrence, that is, off-target effects occurred
.
One reason may be that the body has undergone antigen modulation and no longer secretes CD7; the other reason is the heterogeneity of the tumor, that is, the tumor cells themselves contain CD7-negative (CD7-) T lymphoma cells, which have undergone CAR-T Treatment, CD7+ T lymphoma cells are killed, leading to the dominant growth of CD7- T lymphoma cells, and the proportion increases
.
These are problems that need to be resolved in the future
.
Professor Zhang said that among the dozen or so patients who have been treated, most of the patients participated in the CD7-CAR-T clinical trial after the failure of allogeneic hematopoietic stem cell transplantation and multi-line chemotherapy
.
These patients are late in disease and usually have poor physique; some patients have poor quality T cells, resulting in low quality CAR-T cells; previous multi-line and multi-course chemotherapy and hematopoietic stem cell transplantation have failed, which will affect the efficacy of CAR-T
.
It is recommended that hematopoietic stem cell transplantation followed by CAR-T treatment.
Professor Zhang mentioned that a question that will be mentioned in every discussion is hematopoietic stem cell transplantation followed by CAR-T treatment, or CAR-T treatment followed by hematopoietic stem cell transplantation? Professor Zhang believes that CAR-T treatment after hematopoietic stem cell transplantation is a more reasonable option
.
The smaller the tumor burden and the fewer tumor cells, the better the CAR-T treatment effect
.
First, hematopoietic stem cell transplantation is used to reduce tumor burden, and then CAR-T treatment is used to remove small residual lesions
.
If CAR-T treatment is performed first, and then hematopoietic stem cell transplantation, the immune attack and defense capabilities established by the patient after CAR-T treatment may be destroyed by the pretreatment program of hematopoietic stem cell transplantation
.
If the patient still has CAR-T cells or has been cured, hematopoietic stem cell transplantation is not necessary
.
Professor Zhang suggested that if you are concerned about recurrence, use CAR-T treatment first and then hematopoietic stem cell transplantation.
Patients should be selected for patients with high risk of recurrence, and it is best to take three months apart, when CAR-T cells basically lose their effectiveness.
; Or check that the patient has no CAR-T in his body and there are high-risk recurrence factors, consider bridging hematopoietic stem cell transplantation
.
Since these patients are mostly patients who have failed multi-line chemotherapy, hematopoietic stem cell transplantation should give priority to allogeneic hematopoietic stem cell transplantation, and use donor hematopoietic cells to recast the patient's internal environment and anti-tumor immune defense
.
Summary·As a highly malignant tumor, T-ALL/LBL is highly aggressive, and its large number of clinical treatment and research needs have not been met
.
CAR-T, as a treatment method with significant curative effect in diseases such as B-cell lymphoma and acute lymphoblastic leukemia, is currently less studied in T-ALL/LBL and faces many challenges
.
Professor Zhang Mingzhi’s team has made bold attempts to this end, constantly exploring solutions in research, and provided a large amount of research foundation and guidance for the clinical application of CAR-T treatment of T-ALL/LBL
.
Professor Zhang Mingzhi, PhD supervisor, Director of Cancer Center, The First Affiliated Hospital of Zhengzhou University, Member of the Standing Committee of the Chinese Medical Association Oncology Branch, Member of the Standing Committee of the Chinese Medical Association Oncology Branch, Standing Committee Member of the Chinese Medical Association Oncology Branch, Translational Medicine Group Leader, Chinese Society of Clinical Oncology (CSCO) China Vice Chairman of the Expert Committee of the Anti-Lymphoma Alliance Deputy Director of the Lymphoma Subcommittee of the Hematological Oncology Committee of the Chinese Society of Geriatrics Deputy Director of the Lymphoma Subcommittee of the China Precision Medicine and Hematology Professional Committee Vice Chairman of the Oncology Branch of the Henan Medical Association Deputy Director of the Oncology Branch of the Henan Medical Association Henan Province Director of the Lymphoma Professional Committee of the Anti-Cancer Association Henan Provincial Department of Science and Technology Outstanding Talents Undertake 4 National Natural Science Foundation, 19 provincial and departmental scientific research projects, published 315 academic papers (159 SCI articles), and won 6 provincial science and technology awards References: [1]ASH 2021,abstract#3829.
[2]ASH 2021,abstract#3830.
Stamp "read the original text" and we will make progress together
Currently, it is effective in the treatment of B-cell acute lymphoblastic leukemia (B-ALL) and B-cell lymphoma.
But CAR-T treatment of acute T-lymphocytic leukemia/lymphoblastic lymphoma (T-ALL/LBL) has just started
.
The team of Professor Zhang Mingzhi from the Department of Oncology of the First Affiliated Hospital of Zhengzhou University used CD7 CAR-T cells to treat T-ALL/LBL, and his two CD7 CAR-T cells to treat T-ALL/LBL related studies were selected for this year's ASH poster presentation
.
Yimaitong sincerely invites Professor Zhang Mingzhi to accept an interview to discuss the difficulties in diagnosis and treatment of T-ALL/LBL, and the latest research progress of CD7 CAR-T in the treatment of T-ALL/LBL
.
Diagnosis and treatment status of T-ALL/LBL and treatment difficulties T-ALL/LBL is a highly malignant tumor.
70% of patients develop a mass at the onset of the disease, accompanied by leukemia symptoms such as bone marrow invasion
.
The clinical manifestations of T-ALL/LBL are also biased.
Some patients only present with mediastinal masses, and some patients only present with large numbers of leukemia cells in peripheral blood and bone marrow
.
T-ALL/LBL tends to occur in adolescents.
The reasons for visits are mostly chest tightness and chest discomfort.
Physical examination reveals mediastinal mass, pericardial effusion or pleural effusion
.
Bone marrow aspiration can find tumor cells
.
T-ALL / LBL rapid progression, invasive strong, high strength applications requiring chemotherapy, commonly used in clinical treatment for type BF 90 embodiment, Hyper-CVAD programs
.
Due to the existence of primary and secondary drug resistance, some patients have relapsed after first-line treatment, and the white blood cells and platelets in the blood continue to be low after multi-line treatment
.
Chemotherapy cannot be continued .
Acute early precursor T lymphocytic leukemia/lymphoblastic lymphoma (ETP-ALL/LBL) cells often have stem lines (such as CD34, HLA-DR positive expression) or myeloid differentiation (CD13, CD33, CD117 positive expression), this Patients with T-ALL/LBL are more malignant, prone to primary or secondary drug resistance, and the 5-year survival rate is less than 30%
.
For relapsed and refractory T-ALL/LBL, ETP, certain gene mutations or complex karyotypes, how to improve the therapeutic effect is a difficult problem in clinical treatment
.
CAR-T treatment of T-ALL/LBL challenges , These patients may be cured for a long time
.
However, in T-cell lymphoma, the application of CAR-T has been blank
.
Professor Zhang Mingzhi introduced that CAR-T treatment for patients with B-cell lymphoma is to use the patient’s normal T cell culture to make CAR-T cells to attack and kill B cells.
The effect is significant, and it is applied to T-ALL/LBL patients.
In the treatment of, there are many challenges in the clinic
.
First, "cannibalism" between CAR-T cells
.
As one of the important targets, the expression rate of CD7 in T lymphocytes is about 95%, and the expression rate is high and stable during the initial diagnosis, chemotherapy, and recurrence of patients
.
Therefore, after the infusion of CAR-T cells, CAR-T cells not only attack tumor cells, but also cause CAR-T cells to attack each other
.
The current response strategy is to apply endoplasmic reticulum technology to inhibit the expression of CD7 on the surface of T lymphocyte membranes to prevent CAR-T cells from killing each other
.
Second, in the process of collecting T cells, the tumor cells were collected by mistake and made into CAR-T
.
The consequence of this is that the cultured CAR-T cells are tumor-like and cannot be used in treatment
.
In order to avoid this risk, it is stipulated that all T-ALL/LBL patients with peripheral blood or bone marrow invasion, tumor cell expression must be CD7+, CD4-, CD8-, in the process of collecting cells, collecting CD4+, CD8+ normal Cells, which can effectively avoid the collection of tumor cells
.
If it is a mass type T-ALL/LBL patient, there is no tumor cell invasion in the peripheral blood and bone marrow, generally there will be no collection of tumor cells
.
Third, the patient's immunity is greatly reduced after CAR-T treatment
.
During CAR-T treatment, CAR-T cells attack CD7+ normal T lymphocytes, and the patient's immune system will also suffer certain damage, leading to infection
.
Studies have shown that CD7-T lymphocytes and CD7+ T lymphocytes have little difference in immune function
.
Therefore, the CD7+ CAR-T is produced while cultivating and expanding the patient’s CD7- T lymphocytes.
After the patient’s CD7+ T lymphocytes are severely attacked, the patient’s CD7+ T lymphocytes are reinfused to prevent serious infections caused by the patient’s low cellular immunity
.
At present, after more than a dozen cases of practice, it is found that the overall effective rate of T-ALL/LBL patients with mass type is >70% and the CR rate is 50% due to the influence of tumor microenvironment.
For leukemia patients, CAR-T is used.
The treatment can reach a higher remission rate, and the CR rate is almost 100%
.
The treatment effect of relapsed T-ALL/LBL patients is affected by multiple factors.
T-ALL/LBL patients treated with CAR-T also have recurrence
.
In previous studies, some patients were positive for CD7 expression before treatment, and then tested negative for CD7 expression again after recurrence, that is, off-target effects occurred
.
One reason may be that the body has undergone antigen modulation and no longer secretes CD7; the other reason is the heterogeneity of the tumor, that is, the tumor cells themselves contain CD7-negative (CD7-) T lymphoma cells, which have undergone CAR-T Treatment, CD7+ T lymphoma cells are killed, leading to the dominant growth of CD7- T lymphoma cells, and the proportion increases
.
These are problems that need to be resolved in the future
.
Professor Zhang said that among the dozen or so patients who have been treated, most of the patients participated in the CD7-CAR-T clinical trial after the failure of allogeneic hematopoietic stem cell transplantation and multi-line chemotherapy
.
These patients are late in disease and usually have poor physique; some patients have poor quality T cells, resulting in low quality CAR-T cells; previous multi-line and multi-course chemotherapy and hematopoietic stem cell transplantation have failed, which will affect the efficacy of CAR-T
.
It is recommended that hematopoietic stem cell transplantation followed by CAR-T treatment.
Professor Zhang mentioned that a question that will be mentioned in every discussion is hematopoietic stem cell transplantation followed by CAR-T treatment, or CAR-T treatment followed by hematopoietic stem cell transplantation? Professor Zhang believes that CAR-T treatment after hematopoietic stem cell transplantation is a more reasonable option
.
The smaller the tumor burden and the fewer tumor cells, the better the CAR-T treatment effect
.
First, hematopoietic stem cell transplantation is used to reduce tumor burden, and then CAR-T treatment is used to remove small residual lesions
.
If CAR-T treatment is performed first, and then hematopoietic stem cell transplantation, the immune attack and defense capabilities established by the patient after CAR-T treatment may be destroyed by the pretreatment program of hematopoietic stem cell transplantation
.
If the patient still has CAR-T cells or has been cured, hematopoietic stem cell transplantation is not necessary
.
Professor Zhang suggested that if you are concerned about recurrence, use CAR-T treatment first and then hematopoietic stem cell transplantation.
Patients should be selected for patients with high risk of recurrence, and it is best to take three months apart, when CAR-T cells basically lose their effectiveness.
; Or check that the patient has no CAR-T in his body and there are high-risk recurrence factors, consider bridging hematopoietic stem cell transplantation
.
Since these patients are mostly patients who have failed multi-line chemotherapy, hematopoietic stem cell transplantation should give priority to allogeneic hematopoietic stem cell transplantation, and use donor hematopoietic cells to recast the patient's internal environment and anti-tumor immune defense
.
Summary·As a highly malignant tumor, T-ALL/LBL is highly aggressive, and its large number of clinical treatment and research needs have not been met
.
CAR-T, as a treatment method with significant curative effect in diseases such as B-cell lymphoma and acute lymphoblastic leukemia, is currently less studied in T-ALL/LBL and faces many challenges
.
Professor Zhang Mingzhi’s team has made bold attempts to this end, constantly exploring solutions in research, and provided a large amount of research foundation and guidance for the clinical application of CAR-T treatment of T-ALL/LBL
.
Professor Zhang Mingzhi, PhD supervisor, Director of Cancer Center, The First Affiliated Hospital of Zhengzhou University, Member of the Standing Committee of the Chinese Medical Association Oncology Branch, Member of the Standing Committee of the Chinese Medical Association Oncology Branch, Standing Committee Member of the Chinese Medical Association Oncology Branch, Translational Medicine Group Leader, Chinese Society of Clinical Oncology (CSCO) China Vice Chairman of the Expert Committee of the Anti-Lymphoma Alliance Deputy Director of the Lymphoma Subcommittee of the Hematological Oncology Committee of the Chinese Society of Geriatrics Deputy Director of the Lymphoma Subcommittee of the China Precision Medicine and Hematology Professional Committee Vice Chairman of the Oncology Branch of the Henan Medical Association Deputy Director of the Oncology Branch of the Henan Medical Association Henan Province Director of the Lymphoma Professional Committee of the Anti-Cancer Association Henan Provincial Department of Science and Technology Outstanding Talents Undertake 4 National Natural Science Foundation, 19 provincial and departmental scientific research projects, published 315 academic papers (159 SCI articles), and won 6 provincial science and technology awards References: [1]ASH 2021,abstract#3829.
[2]ASH 2021,abstract#3830.
Stamp "read the original text" and we will make progress together
