PMC9244693_01
CAR structure and schema of the CAR-T cell therapy. (A) Schematic structure of bispecific BM38 CAR. The bispecific BM38 CAR contains an anti-BCMA scFv and an anti-CD38 scFv in tandem in 4-1BB-containing second-generation formats. (B) Schematic structure of BCMA/CS1 bispecific CAR. The BCMA/CS1 bispecific CAR contains an anti-CS1 scFv and an anti-BCMA scFv in 4-1BB-containing second-generation formats. (C) Diagrammatic sketch of CAR-T cell therapy. After screening for eligibility, PBMCs were collected by leukapheresis for the production of bispecific CAR-T cells, and then patients receive lymphodepleting regimens consisting of CTX (250 mg/m2/day, days -5 to -3) and FLU (25 mg/m2/day, days -5 to -3). Regular follow-up should be continued after the infusion of CAR-T cells. CAR, chimeric antigen receptor; CAR-T, chimeric antigen receptor-modified T cell; BCMA, B-cell maturation antigen; scFv, single-chain variable region; PBMC, peripheral blood mononuclear cell; CTX, cyclophosphamide; FLU, fludarabine.
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The patient took part in the clinical trial of bispecific BM38 CAR-T cells (ChiCTR1800018143) ( Figure 1A ) and was infused with 4 x 106/kg of autologous T cells expressing a bispecific CAR targeting BCMA and CD38 after apheresis and lymphodepletion with fludarabine (30 mg/m2 x 3 days) and cyclophosphamide (250 mg/m2 x 3 days) ( Figure 1C ).
Peripheral blood cell counts and cytokine levels of 3 patients. (A) Patient 1. Early cytopenia occurred on day 10 and recovered soon while isolated thrombocytopenia developed later on day 437. The IL-10 level peaked on day 10 and the IL-6 level fluctuated in accordance with IL-10. (B) Patient 2. Pancytopenia developed after CAR-T cell infusion. His hemoglobin and leukocyte returned to normal levels 1 month later but thrombocytopenia remained with platelet transfusion necessary. His cytokine levels were significantly higher than those of the other two patients, which may be associated with his gastrointestinal bleeding and cardiovascular disorders. (C) Patient 3. His WBC count declined after lymphodepletion chemotherapy. Severe leukopenia and thrombocytopenia occurred 2 weeks after CAR-T cell infusion with blood transfusion inefficacious. At follow-up on day 67, his PLT and WBC returned to normal levels with hemoglobin elevated obviously. IL-6 and IL-10 levels were unstable and fluctuated along with each other.
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However, the PLT count decreased to even lower on day 15, with severe leukopenia and elevated levels of IL-6 and IL-10 ( Figure 2C ). There were only 7 x 109/L PLTs and remained below 20 x 109/L after PLT transfusion ( Figure 2C ). At follow-up on day 67, the patient's PLT and leukocytes returned to normal levels with hemoglobin elevated notably ( Figure 2C ).
Clinical evaluation after CAR-T cell infusion. A. MRD of 3 patients. PT1's MRD turned negative on day 14; PT2's and PT3's MRD turned negative on day 21 and remained negative during follow-up. B. Frequency of CAR-T cells in PB. The frequency of CAR-T cells in PB peaked on day 2 and then declined gradually. (C) Ferritin level of 3 patients. The ferritin level of PT1 was stable within 1 week after CAR-T cell infusion and peaked on day 11. PT2 and PT3 have higher ferritin levels that peaked on day 16 and day 8, respectively. (D) CRP level of 3 patients. PT1's CRP level peaked on day 11; PT2's CRP level peaked on day 8; PT3's CRP level has two peaks on days 9 and 18, respectively. WBC, white blood cells; CAR-T, chimeric antigen receptor-modified T cell; PT, patient; MRD, minimal residual disease; CRP, C-reactive protein; PB, peripheral blood.
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Bone marrow aspirate showed no plasma cells and the MRD was negative on day 21 ( Figure 3A ).
PMC9244693_02
CAR structure and schema of the CAR-T cell therapy. (A) Schematic structure of bispecific BM38 CAR. The bispecific BM38 CAR contains an anti-BCMA scFv and an anti-CD38 scFv in tandem in 4-1BB-containing second-generation formats. (B) Schematic structure of BCMA/CS1 bispecific CAR. The BCMA/CS1 bispecific CAR contains an anti-CS1 scFv and an anti-BCMA scFv in 4-1BB-containing second-generation formats. (C) Diagrammatic sketch of CAR-T cell therapy. After screening for eligibility, PBMCs were collected by leukapheresis for the production of bispecific CAR-T cells, and then patients receive lymphodepleting regimens consisting of CTX (250 mg/m2/day, days -5 to -3) and FLU (25 mg/m2/day, days -5 to -3). Regular follow-up should be continued after the infusion of CAR-T cells. CAR, chimeric antigen receptor; CAR-T, chimeric antigen receptor-modified T cell; BCMA, B-cell maturation antigen; scFv, single-chain variable region; PBMC, peripheral blood mononuclear cell; CTX, cyclophosphamide; FLU, fludarabine.
fimmu-13-898341-g001.jpg
PMC9244693_03_fimmu-13-898341-g001.jpg
f1
The patient took part in the clinical trial of bispecific BM38 CAR-T cells (ChiCTR1800018143) ( Figure 1A ) and was infused with 4 x 106/kg of autologous T cells expressing a bispecific CAR targeting BCMA and CD38 after apheresis and lymphodepletion with fludarabine (30 mg/m2 x 3 days) and cyclophosphamide (250 mg/m2 x 3 days) ( Figure 1C ).
Peripheral blood cell counts and cytokine levels of 3 patients. (A) Patient 1. Early cytopenia occurred on day 10 and recovered soon while isolated thrombocytopenia developed later on day 437. The IL-10 level peaked on day 10 and the IL-6 level fluctuated in accordance with IL-10. (B) Patient 2. Pancytopenia developed after CAR-T cell infusion. His hemoglobin and leukocyte returned to normal levels 1 month later but thrombocytopenia remained with platelet transfusion necessary. His cytokine levels were significantly higher than those of the other two patients, which may be associated with his gastrointestinal bleeding and cardiovascular disorders. (C) Patient 3. His WBC count declined after lymphodepletion chemotherapy. Severe leukopenia and thrombocytopenia occurred 2 weeks after CAR-T cell infusion with blood transfusion inefficacious. At follow-up on day 67, his PLT and WBC returned to normal levels with hemoglobin elevated obviously. IL-6 and IL-10 levels were unstable and fluctuated along with each other.
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However, the PLT count decreased to even lower on day 15, with severe leukopenia and elevated levels of IL-6 and IL-10 ( Figure 2C ). There were only 7 x 109/L PLTs and remained below 20 x 109/L after PLT transfusion ( Figure 2C ). At follow-up on day 67, the patient's PLT and leukocytes returned to normal levels with hemoglobin elevated notably ( Figure 2C ).
Clinical evaluation after CAR-T cell infusion. A. MRD of 3 patients. PT1's MRD turned negative on day 14; PT2's and PT3's MRD turned negative on day 21 and remained negative during follow-up. B. Frequency of CAR-T cells in PB. The frequency of CAR-T cells in PB peaked on day 2 and then declined gradually. (C) Ferritin level of 3 patients. The ferritin level of PT1 was stable within 1 week after CAR-T cell infusion and peaked on day 11. PT2 and PT3 have higher ferritin levels that peaked on day 16 and day 8, respectively. (D) CRP level of 3 patients. PT1's CRP level peaked on day 11; PT2's CRP level peaked on day 8; PT3's CRP level has two peaks on days 9 and 18, respectively. WBC, white blood cells; CAR-T, chimeric antigen receptor-modified T cell; PT, patient; MRD, minimal residual disease; CRP, C-reactive protein; PB, peripheral blood.
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Bone marrow aspirate showed no plasma cells and the MRD was negative on day 21 ( Figure 3A ).
PMC9244693_03
CAR structure and schema of the CAR-T cell therapy. (A) Schematic structure of bispecific BM38 CAR. The bispecific BM38 CAR contains an anti-BCMA scFv and an anti-CD38 scFv in tandem in 4-1BB-containing second-generation formats. (B) Schematic structure of BCMA/CS1 bispecific CAR. The BCMA/CS1 bispecific CAR contains an anti-CS1 scFv and an anti-BCMA scFv in 4-1BB-containing second-generation formats. (C) Diagrammatic sketch of CAR-T cell therapy. After screening for eligibility, PBMCs were collected by leukapheresis for the production of bispecific CAR-T cells, and then patients receive lymphodepleting regimens consisting of CTX (250 mg/m2/day, days -5 to -3) and FLU (25 mg/m2/day, days -5 to -3). Regular follow-up should be continued after the infusion of CAR-T cells. CAR, chimeric antigen receptor; CAR-T, chimeric antigen receptor-modified T cell; BCMA, B-cell maturation antigen; scFv, single-chain variable region; PBMC, peripheral blood mononuclear cell; CTX, cyclophosphamide; FLU, fludarabine.
fimmu-13-898341-g001.jpg
PMC9244693_03_fimmu-13-898341-g001.jpg
f1
The patient took part in the clinical trial of bispecific BM38 CAR-T cells (ChiCTR1800018143) ( Figure 1A ) and was infused with 4 x 106/kg of autologous T cells expressing a bispecific CAR targeting BCMA and CD38 after apheresis and lymphodepletion with fludarabine (30 mg/m2 x 3 days) and cyclophosphamide (250 mg/m2 x 3 days) ( Figure 1C ).
Peripheral blood cell counts and cytokine levels of 3 patients. (A) Patient 1. Early cytopenia occurred on day 10 and recovered soon while isolated thrombocytopenia developed later on day 437. The IL-10 level peaked on day 10 and the IL-6 level fluctuated in accordance with IL-10. (B) Patient 2. Pancytopenia developed after CAR-T cell infusion. His hemoglobin and leukocyte returned to normal levels 1 month later but thrombocytopenia remained with platelet transfusion necessary. His cytokine levels were significantly higher than those of the other two patients, which may be associated with his gastrointestinal bleeding and cardiovascular disorders. (C) Patient 3. His WBC count declined after lymphodepletion chemotherapy. Severe leukopenia and thrombocytopenia occurred 2 weeks after CAR-T cell infusion with blood transfusion inefficacious. At follow-up on day 67, his PLT and WBC returned to normal levels with hemoglobin elevated obviously. IL-6 and IL-10 levels were unstable and fluctuated along with each other.
fimmu-13-898341-g002.jpg
PMC9244693_03_fimmu-13-898341-g002.jpg
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However, the PLT count decreased to even lower on day 15, with severe leukopenia and elevated levels of IL-6 and IL-10 ( Figure 2C ). There were only 7 x 109/L PLTs and remained below 20 x 109/L after PLT transfusion ( Figure 2C ). At follow-up on day 67, the patient's PLT and leukocytes returned to normal levels with hemoglobin elevated notably ( Figure 2C ).
Clinical evaluation after CAR-T cell infusion. A. MRD of 3 patients. PT1's MRD turned negative on day 14; PT2's and PT3's MRD turned negative on day 21 and remained negative during follow-up. B. Frequency of CAR-T cells in PB. The frequency of CAR-T cells in PB peaked on day 2 and then declined gradually. (C) Ferritin level of 3 patients. The ferritin level of PT1 was stable within 1 week after CAR-T cell infusion and peaked on day 11. PT2 and PT3 have higher ferritin levels that peaked on day 16 and day 8, respectively. (D) CRP level of 3 patients. PT1's CRP level peaked on day 11; PT2's CRP level peaked on day 8; PT3's CRP level has two peaks on days 9 and 18, respectively. WBC, white blood cells; CAR-T, chimeric antigen receptor-modified T cell; PT, patient; MRD, minimal residual disease; CRP, C-reactive protein; PB, peripheral blood.
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Bone marrow aspirate showed no plasma cells and the MRD was negative on day 21 ( Figure 3A ).