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Chimeric Antigen Receptor T Cell (CAR-T) therapy has always been the focus of attention in the field of hematological malignancies.
On April 16, 2021, Professor Xu Kailin, Director of the Institute of Hematology, Xuzhou Medical University, gave the first national visit to the Chinese Medical Association.
At the Lymphocytic Disease Academic Conference and the 2021 International Lymphoma Update Symposium, the research progress of CAR-T treatment of relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) and the disease after CAR-T treatment were shared For the mechanism of recurrence and its coping strategies under development, Yimaitong organizes the main content of the report as follows.
The current status of CAR-T research on ALL.
Currently, the popular targets of CAR-T therapy for B-cell ALL (B-ALL) treatment are mainly CD19, followed by CD22 and CD20.
Two CAR-T therapies for the treatment of R/R B-ALL that have been marketed internationally all target CD19, namely Tisagenlecleucel (Tisa-cel) and Axicabtagene Ciloeucel (Axi-cel), and their costimulatory molecules are respectively It is 4-1BB and CD28.
Judging from the research results of CD19 CAR-T treatment of R/RB-ALL at home and abroad (the following table), the complete remission (CR) rate of domestic research is about 80%-96%, which is higher than the data of foreign research.
Professor Kailin Xu said that the CAR structure has been continuously optimized, and the conditions for entry into different clinical trials are not exactly the same.
Moreover, with the deepening of clinical trials, researchers have become more experienced in handling CAR-T adverse events.
Therefore, they cannot be arbitrary.
It is believed that domestic CAR-T research is better than foreign countries.
In fact, there is still a big gap between domestic and foreign countries in terms of original research.Table 1 Representative results of foreign CD19 CAR-T treatment of R/R B-ALL Table 2 Representative results of domestic CD19 CAR-T treatment of R/R B-ALL The long-term follow-up data of the ELIANA study showed that at 6 months The event-free survival (EFS) rate and overall survival (OS) rate were 73% and 90%, respectively; the EFS rate and OS rate at 12 months were 50% and 76%, respectively.
It can be seen that the CD19 CAR-T treatment R/ The long-term efficacy of RB-ALL is not ideal.
The results of the study of CD22CAR-T in the treatment of B-ALL (Nat Med 2018 Jan; 24(1):20-28) showed that 5 patients with CD19dim or CD19-relapsed B-ALL after previous CD19 CAR-T treatment received CD22 CAR- T is still valid.
Professor Kailin Xu pointed out that CD22 CAR-T is very meaningful as a supplement to CD19 CAR-T.
Professor Kailin Xu said that with the optimization of CAR structure and adverse event management strategies, the incidence of adverse events in CAR-T treatment will gradually decrease, and the maintenance of long-term efficacy in the future will become an urgent problem to be solved.
Previous studies on the possible mechanism of disease recurrence after CAR-T treatment (Nirali N et al.
Nature ReviewsClinical Oncology.
2019) have shown that up to 50% of precursor B-ALL patients are receiving CD19 CAR-T or CD22 CAR-T treatment 12 The disease recurs within months.
Early relapses are mostly antigen-positive recurrences, and late recurrences are mostly antigen-negative recurrences.
Possible mechanisms of antigen-positive recurrence: 1) Inherent T cell quality is poor: Inherent T cell quality is one of the determinants of CAR-T cell persistence, and previous multi-line chemotherapy or radiotherapy has a certain impact on it.
2) CAR-T cell subgroups (the ratio of CD4+ to CD8+ T cells is 1:1): It is not clear which subgroups of CAR-T cells have the most critical anti-tumor effects.
3) The impact of costimulatory molecules in the CAR structure: The median duration of CAR-T cells based on 4-1BB is longer, and the peak expansion of CAR-T cells based on CD28 appears earlier after infusion.
Which of the persistence and rapid expansion of CAR-T cells has the more critical effect on the efficacy remains to be further studied and explored.
4) CAR-T cells lack central memory or stem cell-like memory T cells 5) Increased expression of PD-1 during CAR-T treatment will shorten the lifespan of CAR-T cells, and PD-1/PD-L1 blockade can improve Persistence of CAR-T 6) Humans have natural immune rejection to the variable region of murine CAR single-chain antibody, which is also one of the mechanisms of relapse after murine CAR-T treatment.
At present, there are more and more researches on humanized CAR-T.
The possible mechanisms of antigen-negative recurrence or low antigen expression recurrence: 1) Loss of CD19 antigen: including the formation of CD19 isoforms, the reduction of CD19 expression, and the reduction of CD19 transported to the cell surface.
2) The modulation of CD19 (the mechanism of immune escape), loss: CAR-T kills the target cells at the same time, the target cells transfer the target antigen to CAR-T, causing CAR-T to kill each other.
3) The phenotype of malignant tumor cells is heterogeneous, and there are CD19- subclones (for example: ph+ ALL).
4) ALL usually appears in the form of mixed leukemia.
In addition to the above mechanisms, the presence of cancer stem cells is also one of the mechanisms leading to recurrence.
Whether the early cancer stem cells are CD19+ or CD19- is still controversial.
The coping strategies for recurrence after CAR-T treatment are based on the above recurrence mechanism, and the researchers have also adopted corresponding coping strategies.
Humanized CAR-T can greatly reduce the human body’s immune response to heterologous sequences, but the remaining small amount of murine sequences can still make the human body produce a certain immune response.
Therefore, the development of fully humanized CAR-T has become a CAR -T is one of the development trends of clinical application.
At present, fully human CAR-T such as CD19 and CD22 have been used in clinical research. In addition, in order to kill tumor stem cells, researchers have tried CAR-T bridging allogeneic hematopoietic stem cell transplantation.
The results of the study show that CAR-T treatment of adult ALL patients reaches minimal residual disease negative (MRD-) CR and then bridging allogeneic hematopoietic stem cells Transplantation can significantly improve the survival of patients.
In addition, in order to better simulate the activation process of natural T cells, the researchers tried to express 12 different costimulatory factors in parallel on the structure of CD20 CAR.
Preclinical studies have confirmed that CD20 CAR-T cells expressing OX40 in parallel have more Good proliferation and expansion ability, and reduced apoptosis after antigen stimulation, can effectively eliminate CD20+ B cells, and significantly extend the survival time of tumor-bearing mice.
The clinical trial results of the CAR-T cells for the treatment of R/R diffuse large B-cell lymphoma (DLBCL) patients showed that all 5 patients in the group achieved remission, 2 patients received CR, and 3 patients received partial remission (PR ), no severe cytokine release syndrome (CRS) occurred, and no neurotoxicity.
Professor Kailin Xu said that he looks forward to the results of the study of CD20 CAR-T cells expressing OX40 in parallel for the treatment of ALL.
The results of most studies have shown that patients who relapse after remission of CD19 CAR-T treatment have poor curative effect after re-infusion of the original CAR-T cell therapy, and the CR rate is less than 30%.
Professor Kailin Xu said that after CD19 CAR-T treatment relapses, you can consider changing the treatment target, dual-target CAR-T treatment, changing humanized or fully humanized CAR-T therapy, or replacing CAR-T with other costimulatory molecules.
Treatment etc.
In addition to the exploration in the CAR-T field, the researchers also combined CD19CAR-T with other monoclonal antibodies and small molecule drugs, including PD1/PD-L1 inhibitors, lenalidomide, demethylation drugs, and ritual Ciximab, 4-1BB agonist, PI3K inhibitor, BTK inhibitor, etc.
Professor Kailin Xu said that the combination of CD19 CAR-T and other drugs is a direction that is very worth exploring.
There are many related clinical trials and good research results have been achieved.
But at present, whether the combination of CD19 CAR-T and other drugs can help ALL patients There is a lack of head-to-head research to verify the benefits. Professor Kailin Xu Director of the Institute of Hematology, Xuzhou Medical University Director of the Hematopoietic Stem Cell Transplantation Center of Xuzhou Medical University The chairman of the Jiangsu Provincial Hematology Branch National Natural Science Foundation, the first review and final review expert, the Ministry of Health, and the young and middle-aged experts with outstanding contributions from Jiangsu Province stamp "read the original text", and we will make progress together
On April 16, 2021, Professor Xu Kailin, Director of the Institute of Hematology, Xuzhou Medical University, gave the first national visit to the Chinese Medical Association.
At the Lymphocytic Disease Academic Conference and the 2021 International Lymphoma Update Symposium, the research progress of CAR-T treatment of relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) and the disease after CAR-T treatment were shared For the mechanism of recurrence and its coping strategies under development, Yimaitong organizes the main content of the report as follows.
The current status of CAR-T research on ALL.
Currently, the popular targets of CAR-T therapy for B-cell ALL (B-ALL) treatment are mainly CD19, followed by CD22 and CD20.
Two CAR-T therapies for the treatment of R/R B-ALL that have been marketed internationally all target CD19, namely Tisagenlecleucel (Tisa-cel) and Axicabtagene Ciloeucel (Axi-cel), and their costimulatory molecules are respectively It is 4-1BB and CD28.
Judging from the research results of CD19 CAR-T treatment of R/RB-ALL at home and abroad (the following table), the complete remission (CR) rate of domestic research is about 80%-96%, which is higher than the data of foreign research.
Professor Kailin Xu said that the CAR structure has been continuously optimized, and the conditions for entry into different clinical trials are not exactly the same.
Moreover, with the deepening of clinical trials, researchers have become more experienced in handling CAR-T adverse events.
Therefore, they cannot be arbitrary.
It is believed that domestic CAR-T research is better than foreign countries.
In fact, there is still a big gap between domestic and foreign countries in terms of original research.Table 1 Representative results of foreign CD19 CAR-T treatment of R/R B-ALL Table 2 Representative results of domestic CD19 CAR-T treatment of R/R B-ALL The long-term follow-up data of the ELIANA study showed that at 6 months The event-free survival (EFS) rate and overall survival (OS) rate were 73% and 90%, respectively; the EFS rate and OS rate at 12 months were 50% and 76%, respectively.
It can be seen that the CD19 CAR-T treatment R/ The long-term efficacy of RB-ALL is not ideal.
The results of the study of CD22CAR-T in the treatment of B-ALL (Nat Med 2018 Jan; 24(1):20-28) showed that 5 patients with CD19dim or CD19-relapsed B-ALL after previous CD19 CAR-T treatment received CD22 CAR- T is still valid.
Professor Kailin Xu pointed out that CD22 CAR-T is very meaningful as a supplement to CD19 CAR-T.
Professor Kailin Xu said that with the optimization of CAR structure and adverse event management strategies, the incidence of adverse events in CAR-T treatment will gradually decrease, and the maintenance of long-term efficacy in the future will become an urgent problem to be solved.
Previous studies on the possible mechanism of disease recurrence after CAR-T treatment (Nirali N et al.
Nature ReviewsClinical Oncology.
2019) have shown that up to 50% of precursor B-ALL patients are receiving CD19 CAR-T or CD22 CAR-T treatment 12 The disease recurs within months.
Early relapses are mostly antigen-positive recurrences, and late recurrences are mostly antigen-negative recurrences.
Possible mechanisms of antigen-positive recurrence: 1) Inherent T cell quality is poor: Inherent T cell quality is one of the determinants of CAR-T cell persistence, and previous multi-line chemotherapy or radiotherapy has a certain impact on it.
2) CAR-T cell subgroups (the ratio of CD4+ to CD8+ T cells is 1:1): It is not clear which subgroups of CAR-T cells have the most critical anti-tumor effects.
3) The impact of costimulatory molecules in the CAR structure: The median duration of CAR-T cells based on 4-1BB is longer, and the peak expansion of CAR-T cells based on CD28 appears earlier after infusion.
Which of the persistence and rapid expansion of CAR-T cells has the more critical effect on the efficacy remains to be further studied and explored.
4) CAR-T cells lack central memory or stem cell-like memory T cells 5) Increased expression of PD-1 during CAR-T treatment will shorten the lifespan of CAR-T cells, and PD-1/PD-L1 blockade can improve Persistence of CAR-T 6) Humans have natural immune rejection to the variable region of murine CAR single-chain antibody, which is also one of the mechanisms of relapse after murine CAR-T treatment.
At present, there are more and more researches on humanized CAR-T.
The possible mechanisms of antigen-negative recurrence or low antigen expression recurrence: 1) Loss of CD19 antigen: including the formation of CD19 isoforms, the reduction of CD19 expression, and the reduction of CD19 transported to the cell surface.
2) The modulation of CD19 (the mechanism of immune escape), loss: CAR-T kills the target cells at the same time, the target cells transfer the target antigen to CAR-T, causing CAR-T to kill each other.
3) The phenotype of malignant tumor cells is heterogeneous, and there are CD19- subclones (for example: ph+ ALL).
4) ALL usually appears in the form of mixed leukemia.
In addition to the above mechanisms, the presence of cancer stem cells is also one of the mechanisms leading to recurrence.
Whether the early cancer stem cells are CD19+ or CD19- is still controversial.
The coping strategies for recurrence after CAR-T treatment are based on the above recurrence mechanism, and the researchers have also adopted corresponding coping strategies.
Humanized CAR-T can greatly reduce the human body’s immune response to heterologous sequences, but the remaining small amount of murine sequences can still make the human body produce a certain immune response.
Therefore, the development of fully humanized CAR-T has become a CAR -T is one of the development trends of clinical application.
At present, fully human CAR-T such as CD19 and CD22 have been used in clinical research. In addition, in order to kill tumor stem cells, researchers have tried CAR-T bridging allogeneic hematopoietic stem cell transplantation.
The results of the study show that CAR-T treatment of adult ALL patients reaches minimal residual disease negative (MRD-) CR and then bridging allogeneic hematopoietic stem cells Transplantation can significantly improve the survival of patients.
In addition, in order to better simulate the activation process of natural T cells, the researchers tried to express 12 different costimulatory factors in parallel on the structure of CD20 CAR.
Preclinical studies have confirmed that CD20 CAR-T cells expressing OX40 in parallel have more Good proliferation and expansion ability, and reduced apoptosis after antigen stimulation, can effectively eliminate CD20+ B cells, and significantly extend the survival time of tumor-bearing mice.
The clinical trial results of the CAR-T cells for the treatment of R/R diffuse large B-cell lymphoma (DLBCL) patients showed that all 5 patients in the group achieved remission, 2 patients received CR, and 3 patients received partial remission (PR ), no severe cytokine release syndrome (CRS) occurred, and no neurotoxicity.
Professor Kailin Xu said that he looks forward to the results of the study of CD20 CAR-T cells expressing OX40 in parallel for the treatment of ALL.
The results of most studies have shown that patients who relapse after remission of CD19 CAR-T treatment have poor curative effect after re-infusion of the original CAR-T cell therapy, and the CR rate is less than 30%.
Professor Kailin Xu said that after CD19 CAR-T treatment relapses, you can consider changing the treatment target, dual-target CAR-T treatment, changing humanized or fully humanized CAR-T therapy, or replacing CAR-T with other costimulatory molecules.
Treatment etc.
In addition to the exploration in the CAR-T field, the researchers also combined CD19CAR-T with other monoclonal antibodies and small molecule drugs, including PD1/PD-L1 inhibitors, lenalidomide, demethylation drugs, and ritual Ciximab, 4-1BB agonist, PI3K inhibitor, BTK inhibitor, etc.
Professor Kailin Xu said that the combination of CD19 CAR-T and other drugs is a direction that is very worth exploring.
There are many related clinical trials and good research results have been achieved.
But at present, whether the combination of CD19 CAR-T and other drugs can help ALL patients There is a lack of head-to-head research to verify the benefits. Professor Kailin Xu Director of the Institute of Hematology, Xuzhou Medical University Director of the Hematopoietic Stem Cell Transplantation Center of Xuzhou Medical University The chairman of the Jiangsu Provincial Hematology Branch National Natural Science Foundation, the first review and final review expert, the Ministry of Health, and the young and middle-aged experts with outstanding contributions from Jiangsu Province stamp "read the original text", and we will make progress together
