Adoptive cellular immunotherapy with chimeric antigen receptor(CAR)T cells has emerged as a novel modality for treating relapsed and/or refractory B-cell non-Hodgkin lymphoma(B-NHL).With increasing approval of CAR T-c...Adoptive cellular immunotherapy with chimeric antigen receptor(CAR)T cells has emerged as a novel modality for treating relapsed and/or refractory B-cell non-Hodgkin lymphoma(B-NHL).With increasing approval of CAR T-cell products and advances in CAR T cell therapy,CAR T cells are expected to be used in a growing number of cases.However,CAR T-cell-associated toxicities can be severe or even fatal,thus compromising the survival benefit from this therapy.Standardizing and studying the clinical management of these toxicities are imperative.In contrast to other hematological malignancies,such as acute lymphoblastic leukemia and multiple myeloma,anti-CD19 CAR T-cell-associated toxicities in B-NHL have several distinctive features,most notably local cytokine-release syndrome(CRS).However,previously published guidelines have provided few specific recommendations for the grading and management of toxicities associated with CAR T-cell treatment for B-NHL.Consequently,we developed this consensus for the prevention,recognition,and management of these toxicities,on the basis of published literature regarding the management of anti-CD19 CAR T-cell-associated toxicities and the clinical experience of multiple Chinese institutions.This consensus refines a grading system and classification of CRS in B-NHL and corresponding measures for CRS management,and delineates comprehensive principles and exploratory recommendations for managing anti-CD19 CAR T-cell-associated toxicities in addition to CRS.展开更多
Although chimeric antigen receptor(CAR)T cells have become an important treatment option for patients with relapsed/refractory B-cell malignancies,more than 60%of patients with diffuse large B-cell lymphoma(DLBCL)trea...Although chimeric antigen receptor(CAR)T cells have become an important treatment option for patients with relapsed/refractory B-cell malignancies,more than 60%of patients with diffuse large B-cell lymphoma(DLBCL)treated with CAR-T cell therapies fail to achieve a durable response.To reveal changes in CAR-T cell therapy and identify response biomarkers,we conducted a retrospective analysis of pre-manufacture source T cells and CAR-T cell products and their association with outcome in 58 patients with r/rDLBCL who received tandem CD19/CD20 CAR-T cell therapy.We performed bulk RNA-Seq,single-cell RNA-Seq,and paired T cell receptor sequencing on CAR-T cell products and pre-manufacture T cells from DLBCL patients.We note that a CD8+stem cell-like memory T cell population with a higher proportion and enhanced activating capacity of the CAR-T cell products was key to achieving durable clinical response.By analysing autologously-derived,pre-manufacture T cells,our data suggest that heterogeneity in the cellular and molecular features of pre-manufacture T cells contribute to the variation in efficacy after CAR-T cell therapy in DLBCL.The differences in anti-tumour efficacy of CAR-T cells among patients with different clinical outcomes appear to be due to the loss of CCR7 gene expression,coupled with increased expression of activation-and inhibitor-related genes in the CD8+naïve-T cell populations among the apheresis T cells from patients with a poor molecular response.These findings significantly advance our understanding of the underlying molecular determinants of pre-manufacture T cell function.展开更多
This phase I clinical trial （NCT01935843） is to evaluate the safety, feasibility, and activity of chimeric antigen receptor-engineered T cell （CART） immunotherapy tar- geting human epidermal growth factor receptor...This phase I clinical trial （NCT01935843） is to evaluate the safety, feasibility, and activity of chimeric antigen receptor-engineered T cell （CART） immunotherapy tar- geting human epidermal growth factor receptor 2 （HER2） in patients with advanced biliary tract cancers （BTCs） and pancreatic cancers （PCs）. Eligible patients with HER2-positive （〉50%） BTCs and PCs were enrolled in the trial. Well cultured CART-HER2 cells were infused following the conditioning treatment composed of nab- paclitaxel （100-200 mg/m2） and cyclophosphamide （15-35 mglkg）. CAR transgene copy number in the peripheral blood was serially measured to monitor the expansion and persistence of CART-HER2 cells in vivo. Eleven enrolled patients received 1 to 2-cycle CART- HER2 cell infusion （median CAR＋ T cell 2.1× 10^6/kg）. The conditioning treatment resulted in mild-to-moderate fatigue, nausea/vomiting, myalgialarthralgia, and lym- phopenia. Except one grade-3 acute febrile syndrome and one abnormal elevation of transaminase （〉9 ULN）, adverse events related to the infusion of CART-HER2 cells were mild-to-moderate. Post-infusion toxicities included one case of reversible severe upper gastroin- testinal hemorrhage which occurred in a patient with gastric antrum invaded by metastasis 11 days after the CART-HER2 cell infusion, and 2 cases of grade 1-2delayed fever, accompanied by the release of C-reactive protein and interleukin-6. All patients were evaluable for assessment of clinical response, among which 1 obtained a 4.5-months partial response and 5 achieved stable disease. The median progression free survival was 4.8 months （range, 1.5-8.3 months）. Finally, data from this study demonstrated the safety and feasibility of CART-HER2 immunotherapy, and showed encourag- ing signals of clinical activity.展开更多
Programmed cell death protein-1(PD-1)-mediated immunosuppression has been proposed to contribute to the limited clinical efficacy of chimeric antigen receptor T(CAR-T)cells in solid tumors.We generated PD-1 and T cell...Programmed cell death protein-1(PD-1)-mediated immunosuppression has been proposed to contribute to the limited clinical efficacy of chimeric antigen receptor T(CAR-T)cells in solid tumors.We generated PD-1 and T cell receptor(TCR)deficient mesothelin-specific CAR-T(MPTK-CAR-T)cells using CRISPR-Cas9 technology and evaluated them in a dose-escalation study.A total of 15 patients received one or more infusions of MPTK-CAR-T cells without prior lymphodepletion.No dose-limiting toxicity or unexpected adverse events were observed in any of the 15 patients.The best overall response was stable disease(2/15 patients).Circulating MPTK-CAR-T cells peaked at days 7–14 and became undetectable beyond 1 month.TCR-positive CAR-T cells rather than TCR-negative CAR-T cells were predominantly detected in effusion or peripheral blood from three patients after infusion.We further confirmed the reduced persistence of TCR-deficient CAR-T cells in animal models.Our results establish the preliminary feasibility and safety of CRISPR-engineered CAR-T cells with PD-1 disruption and suggest that the natural TCR plays an important role in the persistence of CAR-T cells when treating solid tumors.展开更多
Anti-CD19 chimeric antigen receptor-modified T(CAR-T-19) cells have emerged as a powerful targeted immunotherapy for B-cell lineage acute lymphoblastic leukemia with a remarkable clinical response in recent trials. No...Anti-CD19 chimeric antigen receptor-modified T(CAR-T-19) cells have emerged as a powerful targeted immunotherapy for B-cell lineage acute lymphoblastic leukemia with a remarkable clinical response in recent trials. Nonetheless, few data are available on the subsequent clinical monitoring and treatment of the patients, especially those with disease recurrence after CAR-T-19 cell infusion. Here, we analyzed three patients who survived after our phase I clinical trial and who were studied by means of biomarkers reflecting persistence of CAR-T-19 cells in vivo and predictive factors directing further treatment. One patient achieved 9-week sustained complete remission and subsequently received an allogeneic hematopoietic stem cell transplant. Another patient who showed relapse after 20 weeks without detectable leukemia in the cerebrospinal fluid after CAR-T-19 cell treatment was able to achieve a morphological remission under the influence of stand-alone low-dose chemotherapeutic agents. The third patient gradually developed extensive extramedullary involvement in tissues with scarce immune-cell infiltration during a long period of hematopoietic remission after CAR-T-19 cell therapy. Long-term and discontinuous increases in serum cytokines(mainly interleukin 6 and C-reactive protein) were identified in two patients(Nos. 1 and 6) even though only a low copy number of CAR molecules could be detected in their peripheral blood. This finding was suggestive of persistent functional activity of CAR-T-19 cells. Combined analyses of laboratory biomarkers with their clinical manifestations before and after salvage treatment showed that the persistent immunosurveillance mediated by CAR-T-19 cells would inevitably potentiate the leukemia-killing effectiveness of subsequent chemotherapy in patients who showed relapse after CAR-T-19-induced remission.展开更多
(CAR)T cells and immune checkpoint blockade therapies has shown remarkable outcomes in the field of cancer treatment.1,2 In particular,great success has been achieved in B cell acute lymphocytic leukemia(B-ALL)treated...(CAR)T cells and immune checkpoint blockade therapies has shown remarkable outcomes in the field of cancer treatment.1,2 In particular,great success has been achieved in B cell acute lymphocytic leukemia(B-ALL)treated with anti-CD19 CAR T cells.2 However,the loss,mutation,and reduced expression of CD19 are crucial causes for the failure of CAR T cell treatment in leukemia patients.3,4 CD38,a 45-kDa type II glycoprotein,is detectable in BALL,and several studies have indicated the efficacy and safety of CD38 monoclonal antibodies in clinical applications,suggesting that CD38 represents a suitable therapeutic target for the treatment of B-ALL.5,6 In addition,we developed a CAR against CD38,and our preclinical study indicated that anti-CD38 CAR T(CAR T-38)cells could specifically lyse CD38-positive tumor cells.7 Herein,we present the anti-leukemia ability of CAR T-38 cells in an adult relapsed B-ALL patient after failure of bi-specific CD19/CD22 CAR T cell treatment,and this administration of CAR T-38 cells was accompanied by the occurrence of target-mediated toxicities and severe and uncontrollable cytokine release syndrome(CRS).展开更多
基金supported by funds from the National Natural Science Foundation of China(Grant Nos.81830002,81830004,82070168,and 32070951)the Translational Research grant of NCRCH(Grant No.2020ZKZC04)National Key R&D Program of China(Grant No.2021YFA1100800)。
文摘Adoptive cellular immunotherapy with chimeric antigen receptor(CAR)T cells has emerged as a novel modality for treating relapsed and/or refractory B-cell non-Hodgkin lymphoma(B-NHL).With increasing approval of CAR T-cell products and advances in CAR T cell therapy,CAR T cells are expected to be used in a growing number of cases.However,CAR T-cell-associated toxicities can be severe or even fatal,thus compromising the survival benefit from this therapy.Standardizing and studying the clinical management of these toxicities are imperative.In contrast to other hematological malignancies,such as acute lymphoblastic leukemia and multiple myeloma,anti-CD19 CAR T-cell-associated toxicities in B-NHL have several distinctive features,most notably local cytokine-release syndrome(CRS).However,previously published guidelines have provided few specific recommendations for the grading and management of toxicities associated with CAR T-cell treatment for B-NHL.Consequently,we developed this consensus for the prevention,recognition,and management of these toxicities,on the basis of published literature regarding the management of anti-CD19 CAR T-cell-associated toxicities and the clinical experience of multiple Chinese institutions.This consensus refines a grading system and classification of CRS in B-NHL and corresponding measures for CRS management,and delineates comprehensive principles and exploratory recommendations for managing anti-CD19 CAR T-cell-associated toxicities in addition to CRS.
基金This work was supported in part by the National Natural Science Foundation of China(Nos.81830002,31991171,82150108 and 82102892)Translational Research Grant of NCRCH(2021WWC04).
文摘Although chimeric antigen receptor(CAR)T cells have become an important treatment option for patients with relapsed/refractory B-cell malignancies,more than 60%of patients with diffuse large B-cell lymphoma(DLBCL)treated with CAR-T cell therapies fail to achieve a durable response.To reveal changes in CAR-T cell therapy and identify response biomarkers,we conducted a retrospective analysis of pre-manufacture source T cells and CAR-T cell products and their association with outcome in 58 patients with r/rDLBCL who received tandem CD19/CD20 CAR-T cell therapy.We performed bulk RNA-Seq,single-cell RNA-Seq,and paired T cell receptor sequencing on CAR-T cell products and pre-manufacture T cells from DLBCL patients.We note that a CD8+stem cell-like memory T cell population with a higher proportion and enhanced activating capacity of the CAR-T cell products was key to achieving durable clinical response.By analysing autologously-derived,pre-manufacture T cells,our data suggest that heterogeneity in the cellular and molecular features of pre-manufacture T cells contribute to the variation in efficacy after CAR-T cell therapy in DLBCL.The differences in anti-tumour efficacy of CAR-T cells among patients with different clinical outcomes appear to be due to the loss of CCR7 gene expression,coupled with increased expression of activation-and inhibitor-related genes in the CD8+naïve-T cell populations among the apheresis T cells from patients with a poor molecular response.These findings significantly advance our understanding of the underlying molecular determinants of pre-manufacture T cell function.
基金We would like to thank all patients who participated in this trial. This study was supported by the grants from the National Natural Science Foundation of China （Grant No. 81230061 to WDH）, the Science and Technology Planning Project of Beijing City （No. Z151100003915076 to WDH）, the National Key Research and Development Program of China （Nos. 2016YFC1303501 and 2016YFC1303504 to WDH）.
文摘This phase I clinical trial （NCT01935843） is to evaluate the safety, feasibility, and activity of chimeric antigen receptor-engineered T cell （CART） immunotherapy tar- geting human epidermal growth factor receptor 2 （HER2） in patients with advanced biliary tract cancers （BTCs） and pancreatic cancers （PCs）. Eligible patients with HER2-positive （〉50%） BTCs and PCs were enrolled in the trial. Well cultured CART-HER2 cells were infused following the conditioning treatment composed of nab- paclitaxel （100-200 mg/m2） and cyclophosphamide （15-35 mglkg）. CAR transgene copy number in the peripheral blood was serially measured to monitor the expansion and persistence of CART-HER2 cells in vivo. Eleven enrolled patients received 1 to 2-cycle CART- HER2 cell infusion （median CAR＋ T cell 2.1× 10^6/kg）. The conditioning treatment resulted in mild-to-moderate fatigue, nausea/vomiting, myalgialarthralgia, and lym- phopenia. Except one grade-3 acute febrile syndrome and one abnormal elevation of transaminase （〉9 ULN）, adverse events related to the infusion of CART-HER2 cells were mild-to-moderate. Post-infusion toxicities included one case of reversible severe upper gastroin- testinal hemorrhage which occurred in a patient with gastric antrum invaded by metastasis 11 days after the CART-HER2 cell infusion, and 2 cases of grade 1-2delayed fever, accompanied by the release of C-reactive protein and interleukin-6. All patients were evaluable for assessment of clinical response, among which 1 obtained a 4.5-months partial response and 5 achieved stable disease. The median progression free survival was 4.8 months （range, 1.5-8.3 months）. Finally, data from this study demonstrated the safety and feasibility of CART-HER2 immunotherapy, and showed encourag- ing signals of clinical activity.
基金This research was supported by grants from the National Key Research and Development Program of China(No.2019YFC1316205 to J.N.)National Natural Science Foundation of China(Nos.31991171 and 81830002 to W.D.H.,81773269 and 31722036 to H.Y.W.)Strategic Priority Research Program of the Chinese Academy of Sciences(No.XDA16010503 to H.Y.W.).
文摘Programmed cell death protein-1(PD-1)-mediated immunosuppression has been proposed to contribute to the limited clinical efficacy of chimeric antigen receptor T(CAR-T)cells in solid tumors.We generated PD-1 and T cell receptor(TCR)deficient mesothelin-specific CAR-T(MPTK-CAR-T)cells using CRISPR-Cas9 technology and evaluated them in a dose-escalation study.A total of 15 patients received one or more infusions of MPTK-CAR-T cells without prior lymphodepletion.No dose-limiting toxicity or unexpected adverse events were observed in any of the 15 patients.The best overall response was stable disease(2/15 patients).Circulating MPTK-CAR-T cells peaked at days 7–14 and became undetectable beyond 1 month.TCR-positive CAR-T cells rather than TCR-negative CAR-T cells were predominantly detected in effusion or peripheral blood from three patients after infusion.We further confirmed the reduced persistence of TCR-deficient CAR-T cells in animal models.Our results establish the preliminary feasibility and safety of CRISPR-engineered CAR-T cells with PD-1 disruption and suggest that the natural TCR plays an important role in the persistence of CAR-T cells when treating solid tumors.
基金supported by the National Science Foundation for Young Scientists of China (81402567, 81402566, 81472612)Bejing Nova Program (XX2016086)+3 种基金China Postdoctoral Science Foundation Grant (201150M1533)Science and Technology Planning Project of Beijing City (Z151100003915076 to Weidong Han)National Natural Science Foundation of China (31270820, 81230061 to Weidong Han)People’s Republic of China Support Fund (2015PC-TSYS-2013 to Suxia Li)
文摘Anti-CD19 chimeric antigen receptor-modified T(CAR-T-19) cells have emerged as a powerful targeted immunotherapy for B-cell lineage acute lymphoblastic leukemia with a remarkable clinical response in recent trials. Nonetheless, few data are available on the subsequent clinical monitoring and treatment of the patients, especially those with disease recurrence after CAR-T-19 cell infusion. Here, we analyzed three patients who survived after our phase I clinical trial and who were studied by means of biomarkers reflecting persistence of CAR-T-19 cells in vivo and predictive factors directing further treatment. One patient achieved 9-week sustained complete remission and subsequently received an allogeneic hematopoietic stem cell transplant. Another patient who showed relapse after 20 weeks without detectable leukemia in the cerebrospinal fluid after CAR-T-19 cell treatment was able to achieve a morphological remission under the influence of stand-alone low-dose chemotherapeutic agents. The third patient gradually developed extensive extramedullary involvement in tissues with scarce immune-cell infiltration during a long period of hematopoietic remission after CAR-T-19 cell therapy. Long-term and discontinuous increases in serum cytokines(mainly interleukin 6 and C-reactive protein) were identified in two patients(Nos. 1 and 6) even though only a low copy number of CAR molecules could be detected in their peripheral blood. This finding was suggestive of persistent functional activity of CAR-T-19 cells. Combined analyses of laboratory biomarkers with their clinical manifestations before and after salvage treatment showed that the persistent immunosurveillance mediated by CAR-T-19 cells would inevitably potentiate the leukemia-killing effectiveness of subsequent chemotherapy in patients who showed relapse after CAR-T-19-induced remission.
基金supported by the grants from the National Natural Science Foundation of China for the Grants 81830002(W.H.),81903151(Y.G.)the National Key Research and Development Program of China for the Grant 2017YFC0909803(Y.W.).
文摘(CAR)T cells and immune checkpoint blockade therapies has shown remarkable outcomes in the field of cancer treatment.1,2 In particular,great success has been achieved in B cell acute lymphocytic leukemia(B-ALL)treated with anti-CD19 CAR T cells.2 However,the loss,mutation,and reduced expression of CD19 are crucial causes for the failure of CAR T cell treatment in leukemia patients.3,4 CD38,a 45-kDa type II glycoprotein,is detectable in BALL,and several studies have indicated the efficacy and safety of CD38 monoclonal antibodies in clinical applications,suggesting that CD38 represents a suitable therapeutic target for the treatment of B-ALL.5,6 In addition,we developed a CAR against CD38,and our preclinical study indicated that anti-CD38 CAR T(CAR T-38)cells could specifically lyse CD38-positive tumor cells.7 Herein,we present the anti-leukemia ability of CAR T-38 cells in an adult relapsed B-ALL patient after failure of bi-specific CD19/CD22 CAR T cell treatment,and this administration of CAR T-38 cells was accompanied by the occurrence of target-mediated toxicities and severe and uncontrollable cytokine release syndrome(CRS).
