Refractory or relapsed B lymphoblastic leukemia (B-ALL) patients have a dismal outcome with current therapy. We treated 42 primary refractory/hematological relapsed (R/R) and 9 refractory minimal residual disease by flow cytometry (FCM-MRD) B-ALL patients with optimized second generation CD19-directed CAR-T cells. The CAR-T-cell infusion dosages were initially ranged from 0.05 to 14 × 10/kg and were eventually settled at 1 × 10/kg for the most recent 20 cases. 36/40 (90%) evaluated R/R patients achieved complete remission (CR) or CR with incomplete count recovery (CRi), and 9/9 (100%) FCM-MRD patients achieved MRD. All of the most recent 20 patients achieved CR/CRi. Most cases only experienced mild to moderate CRS. 8/51 cases had seizures that were relieved by early intervention. Twenty three of twenty seven CR/CRi patients bridged to allogeneic hematopoietic stem cell transplantation (allo-HCT) remained in MRD with a median follow-up time of 206 (45-427) days, whereas 9 of 18 CR/CRi patients without allo-HCT relapsed. Our results indicate that a low CAR-T-cell dosage of 1 × 10/kg, is effective and safe for treating refractory or relapsed B-ALL, and subsequent allo-HCT could further reduce the relapse rate.
Despite worldwide promising clinical outcome of CD19 CART therapy, relapse after this therapy is associated with poor prognosis and has become an urgent problem to be solved. We conducted a CD22 CAR T-cell therapy in 34 relapsed or refractory (r/r) BALL pediatric and adult patients who failed from previous CD19 CAR T-cell therapy. Complete remission (CR) or CR with incomplete count recovery (CRi) was achieved in 24 of 30 patients (80%) that could be evaluated on day 30 after infusion, which accounted for 70.5% of all 34 enrolled patients. Most patients only experienced mild cytokine-release syndrome and neurotoxicity. Seven CR patients received no further treatment, and 3 of them remained in remission at 6, 6.6, and 14 months after infusion. Eleven CR patients were promptly bridged to transplantation, and 8 of them remained in remission at 4.6 to 13.3 months after transplantation, resulted in 1-year leukemia-free survival rate of 71.6% (95% CI, 44.2-99.0). CD22 antigen loss or mutation was not observed to be associated with relapsed patients. Our study demonstrated that our CD22 CAR T-cells was highly effective in inducing remission in r/r BALL patients, and also provided a precious window for subsequent transplantation to achieve durable remission.
The prognosis of relapsed acute lymphoblastic leukemia (ALL) after allogeneic transplantation is dismal when treated with conventional approaches. While single‐target CD19 or CD22 chimeric antigen receptor (CAR) T‐cell therapy has achieved high complete remission (CR) rates in refractory/relapsed B‐ALL, it could not maintain a durable remission in most patients. To prolong relapse‐free survival, we sequentially combined CD19 and CD22 CAR‐T cells to treat post‐transplant relapsed B‐ALL patients with both CD19/CD22 antigen expression on lymphoblasts. Patient‐derived donor cells were collected to produce CAR‐T cells that were transfected by lentiviral vectors encoding second generation CARs composed of CD3ζ and 4–1BB. The second T‐cell infusion was scheduled at least 1 month, and usually within 6 months after the first CAR‐T treatment. Twenty‐seven adult and pediatric patients, including 11 (41%) with extramedullary diseases (EMD), received the first CD19 CAR‐T and 23 (85%) achieved CR. Subsequently, 21 out of 27 patients received the second CD22 CAR‐T and were followed‐up for a median of 19.7 (range, 5.6–27.3) months; 14 cases remained in CR, seven relapsed and two of them died from disease progression; Kaplan–Meier survival analysis showed overall survival and event‐free survival rates of 88.5% and 67.5%, respectively, at both 12 months and 18 months. CAR‐T associated graft‐versus‐host disease (GVHD) occurred in 23% of patients, with 8% new‐onset acute GVHD and 15% persistent or worsened pre‐existing cGVHD before CAR‐T. This combination strategy of sequential CD19 and CD22 CAR‐T therapy significantly improved the long‐term survival in B‐ALL patients who relapsed after transplantation.
The antihypertensive drug amiloride is being considered as a tactic to improve cancer therapy including that for chronic myelogenous leukemia. In this study, we show that amiloride modulates the alternative splicing of various cancer genes, including Bcl-x, HIPK3, and BCR/ABL, and that this effect is not mainly related to pH alteration, which is a known effect of the drug. Splice modulation involved various splicing factors, with the phosphorylation state of serine-arginine-rich (SR) proteins also altered during the splicing process. Pretreatment with okadaic acid to inhibit protein phosphatase PP1 reversed partially the phosphorylation levels of SR proteins and also the amiloride-modulated yields of Bcl-x s and HIPK3 U(-) isoforms. Genome-wide detection of alternative splicing further revealed that many other apoptotic genes were regulated by amiloride, including APAF-1, CRK, and SURVIVIN. Various proteins of the Bcl-2 family and MAPK kinases were found to be involved in amiloride-induced apoptosis. Moreover, the effect of amiloride on mRNA levels of Bcl-x was demonstrated to translate to the protein levels. Cotreatment of K562 and BaF3/Bcr-AblT315I cells with amiloride and imatinib induced more loss of cell viability than either agent alone. Our findings suggest that amiloride may offer a potential treatment option for chronic myelogenous leukemia either alone or in combination with imatinib.Cancer Res; 71(2); 383-92. Ó2011 AACR.
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