***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 
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    Input: 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 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 . ) Adoptively transferred gene-modified T cells exp and in vivo , eliminate leukemic cells , and form functional memory cells in patients . Go CAR-Ts in the Fast Lane As members of the body ’s police force , cells of the immune system vigilantly pursue bad actors that harm healthy tissues , such as infection or cancer , and then try to deter dangerous activity . Research ers have long sought to harness the power of the immune system to fight cancers such as leukemia ; however , targeting functional immune T cells to the tumor and maintaining these cells in patients remains challenging . Now , Kalos et al. have genetically modified T cells to express a chimeric antigen receptor ( CAR ) to yield so-called CAR T cells that specifically target chronic lymphocytic leukemia ( CLL ) ( a B cell cancer ) . The design er T cells not only exp and ed , persisted , and attacked tumor cells after transfer into patients ; they also mediated cancer remission . Innocent byst and ers were also targeted , as reflected by decreased numbers of B cells and plasma cells and the development of hypogammaglobulinemia . The CAR T cells used in this study expressed an antigen receptor that consists of antibody binding domains that bind in a restricted manner to the CD19 protein ( which is found solely on normal B cells and plasma cells ) attached to both a T cell – specific costimulatory domain and a T cell – specific intracellular signaling domain . The result ing chimeric receptor could activate T cells in response to CD19 in the absence of major histocompatibility complex restriction , allowing for much broader cellular targeting than is obtained with normal T cells . After transfer into three CLL patients , these CAR T cells exp and ed > 1000-fold , persisted for more than 6 months , and eradicated CLL cells . Some of these CAR T cells persisted with a memory phenotype , which would allow them to respond more quickly and on a larger scale with a second exposure to CLL cells . Indeed , two of the three CLL patients who underwent the CAR T cell treatment  had complete remission of their leukemia . Although this is early in the clinical study , these results highlight the potential for CAR-modified T cells to bring cancer therapy up to speed . Tumor immunotherapy with T lymphocytes , which can recognize and destroy malignant cells , has been limited by the ability to isolate and exp and T cells restricted to tumor-associated antigens . Chimeric antigen receptors ( CARs ) composed of antibody binding domains connected to domains that activate T cells could overcome tolerance by allowing T cells to respond to cell surface antigens ; however , to date , lymphocytes engineered to express CARs have demonstrated minimal in vivo expansion and antitumor effects in clinical trials . We report that CAR T cells that target CD19 and contain a costimulatory domain from CD137 and the T cell receptor ζ chain have potent non – cross-resistant clinical activity after infusion in three of three patients treated with advanced chronic lymphocytic leukemia ( CLL ) . The engineered T cells exp and ed > 1000-fold in vivo , trafficked to bone marrow , and continued to express functional CARs at high levels for at least 6 months . Evidence for on-target toxicity included B cell aplasia as well as decreased numbers of plasma cells and hypogammaglobulinemia . On average , each infused CAR-expressing T cell was calculated to eradicate at least 1000 CLL cells . Furthermore , a CD19-specific immune response was demonstrated in the blood and bone marrow , accompanied by complete remission , in two of three patients . Moreover , a portion of these cells persisted as memory CAR+ T cells and retained anti-CD19 effector functionality , indicating the potential of this major histocompatibility complex – independent approach for the effective treatment of B cell malignancies Five adults with chemotherapy-refractory B-ALL were induced into molecular remissions after treatment with CD19 CAR-targeted T cells . CARving a Niche for Cancer Immunotherapy Acute lymphoblastic leukemia ( ALL ) is a cancer of the white blood cells that fend off infection . It ’s most common in children but — as with many diseases that primarily affect children — has a much worse prognosis when it affects adults . Adults with relapsed disease have a very low chance of survival , and new therapies are desperately needed . Now , Brentjens et al. test T cells engineered to target CD19 , which is expressed on both healthy B lymphocytes and B-ALL cells , in five chemotherapy-refractory adult B-ALL patients . Here , the authors treat patients with the patients ’ own T cells  altered to express not only CD19 but also a fusion of the costimulatory molecule CD28 with CD3ζ chain — so-called “ second-generation chimeric antigen receptor ( CAR ) T cells . ” All patients treated with these cells achieved tumor eradication and complete remission . These CAR T cells were well tolerated , although there was substantial cytokine release in some patients that correlated to tumor burden . These patients were treated with steroid therapy . Long-term follow-up in four of these patients was not possible because the CAR T cell therapy allowed these patients to be eligible for subsequent hematopoietic stem cell transplant ( HSCT ) , which result ed in restored hematopoiesis . The remaining patient experienced a relapse of CD19 + cells that coincided with the lack of persistence of the CAR T cells from circulation . These data suggest that subsequent transfusions should be considered for patients unable to undergo HSCT . Adults with relapsed B cell acute lymphoblastic leukemia ( B-ALL ) have a dismal prognosis . Only those patients able to achieve a second remission with no minimal residual disease ( MRD ) have a hope for long-term survival in the context of a subsequent allogeneic hematopoietic stem cell transplantation ( allo-HSCT ) . We have treated five relapsed B-ALL subjects with autologous T cells expressing a CD19-specific CD28/CD3ζ second-generation dual-signaling chimeric antigen receptor ( CAR ) termed 19 - 28z . All patients with persistent morphological disease or MRD+ disease upon T cell infusion demonstrated rapid tumor eradication and achieved MRD− complete remissions as assessed by deep sequencing polymerase chain reaction . Therapy was well tolerated , although significant cytokine elevations , specifically observed in those patients with morphologic evidence of disease at the time of treatment , required lymphotoxic steroid therapy to ameliorate cytokine 
    Output:
    
Conclusion : Lymphodepletion regimen may play a crucial role in predicting the prognosis of patients with hematological malignancies .
Lymphodepletion patients had better progression-free survival than those who did not