***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: New treatments are needed for B-cell malignancies persisting after allogeneic hematopoietic stem cell transplantation ( alloHSCT ) . We conducted a clinical trial of allogeneic T cells genetically modified to express a chimeric antigen receptor ( CAR ) targeting the B-cell antigen CD19 . T cells for genetic modification were obtained from each patient 's alloHSCT donor . All patients had malignancy that persisted after alloHSCT and st and ard donor lymphocyte infusions ( DLIs ) . Patients did not receive chemotherapy  prior to the CAR T-cell infusions and were not lymphocyte depleted at the time of the infusions . The 10 treated patients received a single infusion of allogeneic anti-CD19-CAR T cells . Three patients had regressions of their malignancies . One patient with chronic lymphocytic leukemia ( CLL ) obtained an ongoing complete remission after treatment with allogeneic anti-CD19-CAR T cells , another CLL patient had tumor lysis syndrome as his leukemia dramatically regressed , and a patient with mantle cell lymphoma obtained an ongoing partial remission . None of the 10 patients developed graft-versus-host disease ( GVHD ) . Toxicities included transient hypotension and fever . We detected cells containing the anti-CD19-CAR gene in the blood of 8 of 10 patients . These results show for the first time that donor-derived allogeneic anti-CD19-CAR T cells can cause regression of B-cell malignancies resistant to st and ard DLIs without causing GVHD We conducted a clinical trial to assess adoptive transfer of T cells genetically modified to express an anti-CD19 chimeric Ag receptor ( CAR ) . Our clinical protocol consisted of chemotherapy followed by an infusion of anti-CD19-CAR-transduced T cells and a course of IL-2 .  Six of the 8 patients treated on our protocol obtained remissions of their advanced , progressive B-cell malignancies . Four of the 8 patients treated on the protocol had long-term depletion of normal polyclonal CD19(+ ) B-lineage cells . Cells containing the anti-CD19 CAR gene were detected in the blood of all patients . Four of the 8 treated patients had prominent elevations in serum levels of the inflammatory cytokines IFNγ and TNF . The severity of acute toxicities experienced by the patients correlated with serum IFNγ and TNF levels . The infused anti-CD19-CAR-transduced T cells were a possible source of these inflammatory cytokines because we demonstrated peripheral blood T cells that produced TNF and IFNγ ex vivo in a CD19-specific manner after anti-CD19-CAR-transduced T-cell infusions . Anti-CD19-CAR-transduced T cells have great promise to improve the treatment of B-cell malignancies because of a potent ability to eradicate CD19(+ ) cells in vivo ; however , reversible cytokine-associated toxicities occurred after CAR-transduced T-cell infusions We report the findings from the first 10 patients with chemotherapy-refractory chronic lymphocytic leukemia ( CLL ) or relapsed B-cell acute lymphoblastic leukemia ( ALL ) we have enrolled for treatment with autologous T cells modified to express 19 - 28z , a second-generation chimeric antigen ( Ag ) receptor specific to the B-cell lineage Ag CD19 . Eight of the 9 treated patients tolerated 19 - 28z(+ ) T-cell infusions well . Three of 4 evaluable patients with bulky CLL who received prior conditioning with cyclophosphamide exhibited either a significant reduction or a mixed response in lymphadenopathy without concomitant development of B-cell aplasia . In contrast , one patient with relapsed ALL who was treated in remission with a similar T-cell dose developed a predicted B-cell aplasia . The short-term persistence of infused T cells was enhanced by prior cyclophosphamide administration and inversely proportional to the peripheral blood tumor burden . Further analyses showed rapid trafficking of modified T cells to tumor and retained ex vivo cytotoxic potential of CD19-targeted T cells retrieved 8 days after infusion . We conclude that this adoptive T-cell approach is promising and more likely to show clinical benefit in the setting of prior conditioning chemotherapy and low tumor burden or minimal residual disease . These studies are registered at www . clinical trials.org as # NCT00466531 ( CLL protocol ) and # NCT01044069 ( B-ALL protocol ) Outcomes for patients with refractory diffuse large B cell lymphoma ( DLBCL ) are poor . In the multicenter ZUMA-1 phase 1 study , we evaluated KTE-C19 , an autologous CD3ζ/CD28-based chimeric antigen receptor ( CAR ) T cell therapy , in patients with refractory DLBCL . Patients received low-dose conditioning chemotherapy with concurrent cyclophosphamide ( 500 mg/m2 ) and fludarabine ( 30 mg/m2 ) for 3 days followed by KTE-C19 at a target dose of 2 × 106 CAR T cells/kg . The incidence of dose-limiting toxicity ( DLT ) was the primary endpoint . Seven patients were treated with KTE-C19 and one patient experienced a DLT of grade 4 cytokine release syndrome ( CRS ) and neurotoxicity . Grade ≥3 CRS and neurotoxicity were observed in 14 % ( n = 1/7 ) and 57 % ( n = 4/7 ) of patients , respectively . All other KTE-C19-related grade ≥3 events resolved within 1 month . The overall response rate was 71 % ( n = 5/7 ) and complete response ( CR ) rate was 57 % ( n = 4/7 ) . Three patients have ongoing CR ( all at 12 + months ) . CAR T cells demonstrated peak expansion within 2 weeks and continued to be detectable at 12 + months in patients with ongoing CR . This regimen of KTE-C19 was safe for further study in phase 2 and induced durable remissions in patients with refractory DLBCL BACKGROUND Chimeric antigen receptor ( CAR ) modified T cells targeting CD19 have shown activity in case series of patients with acute and chronic lymphocytic leukaemia and B-cell lymphomas , but feasibility , toxicity , and response rates of consecutively enrolled patients treated with a consistent regimen and assessed on an intention-to-treat basis have not been reported . We aim ed to define feasibility , toxicity , maximum tolerated dose , response rate , and biological correlates of response in children and young adults with refractory B-cell malignancies treated with  CD19-CAR T cells . METHODS This phase 1 , dose-escalation trial consecutively enrolled children and young adults ( aged 1 - 30 years ) with relapsed or refractory acute lymphoblastic leukaemia or non-Hodgkin lymphoma .  Autologous T cells were engineered via an 11-day manufacturing process to express a CD19-CAR incorporating an anti-CD19 single-chain variable fragment plus TCR zeta and CD28 signalling domains . All patients received fludarabine and cyclophosphamide before a single infusion of CD19-CAR T cells . Using a st and ard 3 + 3 design to establish the maximum tolerated dose , patients received either 1 × 10(6 ) CAR-transduced T cells per kg ( dose 1 ) , 3 × 10(6 ) CAR-transduced T cells per kg ( dose 2 ) , or the entire CAR T-cell product if sufficient numbers of cells to meet the assigned dose were not generated . After the dose-escalation phase , an expansion cohort was treated at the maximum tolerated dose . The trial is registered with Clinical Trials.gov , number NCT01593696 . FINDINGS Between July 2 , 2012 , and June 20 , 2014 , 21 patients ( including eight who had previously undergone allogeneic haematopoietic stem-cell transplantation ) were enrolled and infused with CD19-CAR T cells . 19 received the prescribed dose of CD19-CAR T cells , whereas the assigned dose concentration could not be generated for two patients ( 90 % feasible ) . All patients enrolled were assessed for response . The maximum tolerated dose was defined as 1 × 10(6 ) CD19-CAR T cells per kg . All toxicities were fully reversible , with the most severe being grade 4 cytokine release syndrome that occurred in three ( 14 % ) of 21 patients ( 95 % CI 3·0 - 36·3 ) . The most common non-haematological grade 3 adverse events were fever ( nine [ 43 % ] of 21 patients ) , hypokalaemia ( nine [ 43 % ] of 21 patients ) , fever and neutropenia ( eight [ 38 % ] of 21 patients ) , and cytokine release syndrome ( three [ 14 % ) of 21 patients ) . INTERPRETATION CD19-CAR T cell therapy is feasible , safe , and mediates potent anti-leukaemic activity in children and young adults with chemotherapy-resistant B-precursor acute lymphoblastic leukaemia .  All toxicities were reversible and prolonged B-cell aplasia did not occur . FUNDING National Institutes of Health Intramural funds and St Baldrick 's Foundation BACKGROUND Relapsed acute lymphoblastic leukemia ( ALL ) is difficult to treat despite the availability of aggressive therapies . Chimeric antigen receptor-modified T cells targeting CD19 may overcome many limitations of conventional therapies and induce remission in patients with refractory disease . METHODS We infused autologous T cells transduced with a CD19-directed chimeric antigen receptor ( CTL019 ) lentiviral vector in patients with relapsed or refractory ALL at doses of 0.76 × 10(6 ) to 20.6 × 10(6 ) CTL019 cells per kilogram of body weight . Patients were monitored for a response , toxic effects , and the expansion and persistence of circulating CTL019 T cells . RESULTS A total of 30 children and adults received  CTL019 .  Complete remission was achieved in 27 patients ( 90 % ) , including 2 patients with blinatumomab-refractory disease and 15 who had undergone stem-cell transplantation . CTL019 cells proliferated in vivo and were detectable in the blood , bone marrow , and cerebrospinal fluid of patients who had a response . Sustained remission was achieved with a 6-month event-free survival rate of 67 % ( 95 % confidence interval [ CI ] , 51 to 88 ) and an overall survival rate of 78 % ( 95 % CI , 65 to 95 ) . At 6 months , the probability that a patient would have persistence of CTL019 was 68 % ( 95 % CI , 50 to 92 ) and the probability that a patient would have relapse-free B-cell aplasia was 73 % ( 95 % CI , 57 to 94 ) . All the patients had the cytokine-release syndrome . Severe cytokine-release syndrome , which developed in 27 % of the patients , was associated with a higher disease burden before infusion and was effectively treated with the anti-interleukin-6 receptor antibody tocilizumab . CONCLUSIONS Chimeric antigen receptor-modified T-cell therapy against CD19 was effective in treating relapsed and refractory ALL . CTL019 was associated with a high remission rate , even among patients for whom stem-cell transplantation had failed , and durable remissions up to 24 months were observed . ( Funded by Novartis and others ; CART19 Clinical Trials.gov numbers , NCT01626495 and NCT01029366 . ) BACKGROUND T cells that have been modified to express a CD19-specific chimeric antigen receptor ( CAR ) have antitumor activity in B cell malignancies ; however , identification of the factors that determine toxicity and efficacy of these T cells has been challenging in prior studies in which phenotypically heterogeneous CAR-T cell products were prepared from unselected T cells . METHODS We conducted a clinical trial to evaluate CD19 CAR-T cells that were manufactured from defined CD4 + and CD8 + T cell subsets and administered in a defined CD4+:CD8 + composition to adults with B cell acute lymphoblastic leukemia after lymphodepletion chemotherapy .  RESULTS The defined composition product was remarkably potent , as 27 of 29 patients ( 93 % ) achieved BM remission , as determined by flow cytometry . We established that high CAR-T cell doses and tumor burden increase the risks of severe cytokine release syndrome and neurotoxicity . Moreover , we identified serum biomarkers that allow testing of early intervention strategies in patients at the highest risk of toxicity . Risk-stratified CAR-T cell dosing based on BM disease burden decreased toxicity . CD8 + T cell-mediated anti-CAR transgene product immune responses developed after CAR-T cell infusion in some patients , limited CAR-T cell persistence , and increased relapse risk . Addition of fludarabine to the lymphodepletion regimen improved CAR-T cell persistence and disease-free survival . CONCLUSION Immun 
    Output:
    
Tumor burden was strongly associated with the severity of CRS in B-ALL .
Besides , post-HSCT CD19 CAR-T cell infusion represented lower severe CRS incidence .