dataesr/scientific-paragraphs-categorization huggingface dataset:
They complete the global radiosonde observations and provide an alternative and potentially more reliable reference for the evaluation of satellite retrieval algorithms and of global atmospheric models  17, 18. GNSS measurements are not sensitive to weather conditions and are performed with high temporal resolutions (typically a few minutes). The technique consists in the retrieval of the vertically integrated water vapour column from propagation delay measurements. It is relatively insensitive to instrumentation changes and is thus suitable for trend assessments  19. The present study takes advantage of a recently updated GNSS dataset  20  based on a network of 434 stations with more or less continuous measurements from January 1994 to December 2021. These stations exhibit globally averaged anomalies that are consistent with the global mean values derived from several state-of-the-art atmospheric re-analyses over recent decades (Fig.
It is therefore important to maintain the GNSS network, which will be increasingly useful to constrain the projections of GTPW. Given the much longer GMST record compared to the four GTPW datasets, an alternative strategy could consist in combining the KCC method, to constrain the GSAT response only, and the simple regression technique, to derive the forced GTPW response from the constrained forced GSAT response. Unlike in Fig. SM1d , the regression is now based on the GMST-constrained forced GSAT response (via KCC) rather than the full GSAT anomalies. A best-guess regression coefficient of 7. 0%/°C, derived from the GMST and GNSS annual mean anomalies over the 1994-2021 overlapping period, is now applied to each CMIP6 model. This regression method is however less powerful than KCC for constraining the projections (Fig.
1  includes 237 representative sites with more than 10 years of observations. Gaps in the GNSS time series were filled with ERA5 values to insure consistent temporal representativeness. Some differences with the reanalyses shown in Fig. 1  can arise from spatial representativeness differences as the reanalyses are full global averages. These reanalyses differ in the type of observations assimilated: ERA20C assimilates only surface pressure and marine wind observations, while ERA5, JRA55, and MERRA-2 assimilate a huge amount of conventional and satellite data (millions per day). Finally, a recent update of the HadCRUT5 dataset (https://www. metoffice. gov. uk/hadobs/hadcrut5/), covering the 1850-2021 period, is used to constrain the evolution of the global mean surface air temperature (GSAT).
Although global warming is expected to occur at approximately constant relative humidity, the latest IPCC report remains elusive about the magnitude of observed changes in global mean total precipitable water (GTPW) and their attribution. Here we use a novel quality-controlled dataset of in situ observations, global reanalyses, and a long record of global mean surface temperature (GMST) to constrain both recent and future changes in GTPW. Most state-of-the-art global climate models tend to exaggerate the projected atmospheric moistening, in line with their overestimation of global warming and of the GTPW sensitivity to both anthropogenic greenhouse gases and aerosols across the 20 th century. A 39% narrowing in the range of GTPW projections is obtained after applying the observational constraints, with a best-guess estimate of 7% per °C of global warming.
Acknowledgements: The authors are grateful to all global modelling centres which have contributed to CMIP5 and  CMIP6 , as well as to the people in charge of the ESGF archive (https://esgf-node. llnl. gov/projects/)and of the ESPRI platform (https://mesocentre. ipsl. fr/plate-forme-physique/). The study has been partly supported by the  European Union 's  Horizon 2020 research and innovation program  under the  EUCP (Grant Agreement 776613 ) and the  CONSTRAIN  (Grant Agreement 820829) projects.
Data and script availability: CMIP5 and CMIP6 data are available on the ESGF archive at https://esgf-node. llnl. gov/, GNSS data are available at https://en. aeris-data. fr/, the KCC statistical package for observational constraint is available on gitlab at https://gitlab. com/saidqasmi/KCC, scripts used to plot the figures are available upon request from the corresponding author.
Because of such properties, CAR-T is being investigated as a potential stand-alone treatment in R/R BCP-ALL. Based on the results of the pivotal ELIANA trial (ClinicalTrials. gov identifier: NCT02435849)  (12)  and subsequent approval of tisagenlecleucel, an anti-CD19 CAR-T product, for the treatment of CD19 + R/R BCP-ALL by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) in 2017/18, a rapidly increasing number of paediatric stem cell transplantation centres have been certified to administer tisagenlecleucel to paediatric patients and AYAs, and hundreds of products have been infused worldwide as a novel standard-of-care treatment option. Currently, the three main clinical scenarios in which physicians offer tisagenlecleucel to BCP-ALL patients are: (1) when an HSCT was previously performed but failed to be efficacious (post-HSCT relapse);  (2)  in chemotherapy-resistant ALL patients ineligible for HSCT because minimal residual disease (MRD) remission cannot be achieved (refractory patients); or (3) a belief and hope that CAR-T is as effective as but less toxic than HSCT to eradicate the resistant leukaemic clone and, therefore, is favoured over HSCT (patients with ≥2 relapses who have not been transplanted before and are, per se, eligible for HSCT).
In exceptional cases, depending on national regulations and the doctor's degree of conviction, the indication to use commercial tisagenlecleucel might be more liberal, for example by stretching the definition of refractory disease to patients not achieving MRD-negativity at certain treatment time points after first relapse. The international multicentre CASSIOPEIA study (NCT03876769) is the only active study evaluating this approach in primary BCP-ALL for National Cancer Institute (NCI)-defined high-risk patients with MRD at end of consolidation. However, randomised studies directly and prospectively comparing HSCT and CAR-T efficacy outcomes have not yet been performed in paediatric ALL, and the longest follow-up post CAR-T to date is in a patient infused with tisagenlecleucel <10 years ago  (13).
Tisagenlecleucel brings considerable costs to healthcare systems but is cost-effective if given as definitive treatment for long-term cure  (14, 15). However, 40-50% of patients initially responding to tisagenlecleucel relapse; a proportion of patients receive HSCT additionally; and 10-20% are primary refractory to tisagenlecleucel. In other trials with different CAR-T products, all responding patients were allocated to HSCT consolidation  (16) (17) (18). Therefore, central and elusive questions are the extent to which CAR-T is a standalone curative treatment, particularly with longer follow-up, and whether patients need additional HSCT either as consolidation for remission or treatment of relapse post CAR-T. Of note, the international ALL SCTped 2012 For Omitting Radiation Under Majority age (FORUM) trial (NCT01949129) recently reported, among patients being in complete remission (CR) 1-3, an excellent 2-year overall survival (OS) rate of FIGURE 1 | Visual summary of different chimeric antigen receptor (CAR) designs to target B-cell malignancies.
Tisagenlecleucel Tisagenlecleucel, formerly known as CTL019 and now commercialised as KYMRIAH R , is an autologous, The first trial investigating tisagenlecleucel in paediatric CD19 + R/R BCP-ALL was a Phase I/IIa single-arm study at the CHOP (NCT01626495 and NCT01029366). The initial publication reported outcomes in 30 patients (including 25 paediatric ALL patients aged 5-22 years at infusion) of whom 18 had relapsed after previous HSCT  (22). The overall remission rate (ORR), including CR and CR with an incomplete haematologic recovery (CRi), at 1 month after infusion was 90%; 22 of the 25 evaluable patients were MRD-negative as assessed by flow cytometry (FCM). Of the 27 patients who achieved CR, 19 remained in remission at a median follow-up of 7 months. Fifteen patients received no further ALL-targeted therapy, while five (19% of all the responders) were allocated to additional post-infusion interventions: three underwent HSCT while in remission; one received bortezomib and an infusion of donor lymphocytes for MRD reappearance; and one received tisagenlecleucel re-infusions due to an early re-appearance of B cells as a marker for CAR T-cell loss.
The probability of persistence of tisagenlecleucel at 6 months for all infused patients was 68%. In an update from the same study with longer follow-up, 59 paediatric patients (aged 20 months to 24 years) including 39 patients with a relapse post HSCT were reported on  (23). Fiftyfive patients (93%) were in CR/CRi 1 month post infusion and 52 were MRD-negative by FCM. Five of 59 patients (8% of all responders) were consolidated by HSCT. Of note, 17 of the 55 responders (31%) received tisagenlecleucel re-infusions 3 and/or 6 months post initial infusion because of the reappearance of CD19 + MRD (three patients), B-cell recovery (seven patients), or appearance of CD19 + haematogones in the bone marrow (seven patients)  (32). In the Phase II ENSIGN trial (NCT02228096), the safety and efficacy of tisagenlecleucel was for the first time investigated in a multicentre setting at 13 US sites with centralised manufacturing of all products at the University of Pennsylvania.
ENSIGN was instrumental in transferring manufacturing from a single-centre academic setting to an industry-based manufacturer (Novartis) and laid the foundation for the global ELIANA trial. ENSIGN enrolled 73 patients of whom 58 had been infused at last available study report  (33). The ORR (CR+CRi) within 6 months of infusion was 69%. Tisagenlecleucel was detected in the peripheral blood for up to 764 days in responders. The global ELIANA Phase II registration trial (NCT02435849) investigated the safety and efficacy of tisagenlecleucel in paediatric patients with R/R BCP-ALL at 25 study sites in 11 countries across North America, Europe, Asia and Australia. In the primary publication, 75 infused patients (aged 3-23 years at enrolment) were reported on, of whom 61% had relapsed after prior HSCT  (12).
Finally, in the tisagenlecleucel Phase IIIb expandedaccess study (CCTL019B2001X, NCT03123939), an ELIANA confirmatory trial specifically focusing on pre-infusion exposure to blinatumomab and inotuzumab ozogamicin, 67 paediatric and AYA ALL patients (aged 3-33 years at enrolment) received tisagenlecleucel  (35). Fifteen patients received blinatumomab and nine received inotuzumab ozogamicin at any time point before tisagenlecleucel [with a time from last dose of blinatumomab or inotuzumab ozogamicin to infusion of a median 372 days (range, 130-932) and 86 days (range , respectively]. The ORR at 3 months was 85% for the whole cohort, confirming the ELIANA experience. However, the ORR was only 67% for patients who had previously received blinatumomab or inotuzumab ozogamicin. In total, 14 patients relapsed: nine with CD19 - disease (two after blinatumomab) and five with CD19 + disease (three after inotuzumab ozogamicin).
The safety and efficacy of CAT CAR-T were subsequently investigated in the Phase II CARPALL study (NCT02443831) in which 14 R/R BCP-ALL patients were infused, 10 (71%) after post-HSCT relapse  (25). By 3 months, 12 patients (86%) had achieved molecular CR. At a median follow-up of 14 months, five patients (36%) were alive and disease free. Using event-free survival (EFS) criteria in which a molecular relapse was defined as an event, EFS was 55 and 31% at 6 and 12 months, respectively. Importantly, no infused patient underwent consolidative HSCT or re-infusion. CAT CAR T cells were detectable by quantitative polymerase chain reaction (qPCR) in 11 patients (79%) at last follow-up, which was 24 months post infusion in two patients. The median duration of persistence of CAT CAR T cells at data cut-off was 215 days (range, 14-728 days).
Other Anti-CD19 CAR-T Products With a 4-1BB Costimulatory Domain The Seattle group designed a CAR-T product consisting of CD19(FCM63). CD28(transmembrane domain). 4-1BB. CD3ζ transduced autologous CD4 + and CD8 + T cells using a lentivirus platform. These cells were infused in a defined 1:1 CD4 + :CD8 + CAR T-cell ratio  (39). In the PLAT-02 Phase I study (NCT02028455), 43 of 45 enrolled patients with R/R BCP-ALL (median age 12. 3 years, range 1. 3-25. 4) (26)  were infused with the CAR-T product, 28 (62%) for post-HSCT relapse. Seven patients had previously received a CD19-directed therapy: blinatumomab (n = 6) or second-generation CD19-specific CAR T cells with CD28ζ as the costimulatory molecule (n = 1). The rate of MRD-negative CR by FCM on day 28 was 93%. At a median follow-up of 9. 6 months, 18 of the 40 patients who achieved CR subsequently relapsed.
At the Hospital Clínic in Barcelona, a CD19 CAR-T termed ARI-0001 was developed to generate affordable CAR-T in academic institutions. The CAR consists of an scFv derived from the A3B1 antibody, a CD8 hinge and transmembrane region, 4-1BB and CD3ζ. A lentiviral vector and the CliniMACS R Prodigy device were used as the cell production platform. In the CART19-BE-01 trial (NCT03144583)-one of the first European academic clinical trials of CD19 CAR-T-47 patients with Bcell malignancies were infused with ARI-0001, among them 38 with R/R BCP-ALL (including 11 children) of whom 87% had post-HSCT relapse  (28). The MRD-negative CR rate was 84%. Focusing on the paediatric patients, the 1-year PFS and 1-year OS were 82 and 78%, respectively, and 1-year probability of BCA was 48%. No patient underwent consolidative HSCT.
Anti-CD19 CAR-T Products With a CD28 Costimulatory Domain At the NCI, a CAR with a CD28 costimulatory domain (CD19. 28ζ CAR) was developed  (40). This consists of an anti-CD19 scFv derived from FMC63, a portion of the human CD28 molecule as the transmembrane and costimulatory domain, and CD3ζ as the intracellular signalling domain. Utilising γretrovirus for the transduction of autologous T cells, it was clinically tested in a Phase I study (NCT01593696) in which 20 patients with BCP-ALL aged 4-27 years were infused  (18). Fourteen patients (70% of all enrolled and infused BCP-ALL patients, intent-to-treat) responded with CR at day 28; 12 were also MRD-negative. All responders were per protocol candidates for consolidative HSCT. Ten patients underwent HSCT (median time to HSCT, 51 days) while in CARinduced MRD-negative remission.
The trial demonstrated that sequential therapy with CD19. 28ζ-CAR T cells and HSCT in responding patients can mediate durable disease control. At the Memorial Sloan Kettering Cancer Centre, another second-generation CD28-based CAR was developed (termed 19-28ζ); this gene is retrovirally transduced into autologous T cells and infused after lymphodepletion with cyclophosphamide alone  (41). In a paediatric and AYA Phase I study (NCT01860937), 25 patients with a median age of 13. 5 years (range, 1-22. 5) were infused, five for post-HSCT relapse  (16). The overall CR rate at day 28 was 75% (18 of 24 evaluable patients) with 16 (89%) being MRD-negative. All 18 responders were per protocol candidates for consolidative HSCT and 15 (83%) underwent HSCT. With a median follow-up of 8 months (29 months in responders), eight patients (53%) were alive and disease free after CAR-T consolidated by HSCT; the three responders who did not undergo HSCT relapsed and died.
Finally, in a report from the Sheba Medical Centre in Israel, CAR T cells with a FMC63-derived scFv, a CD28 costimulatory domain and a CD3ζ signalling domain were produced inhouse and infused into 21 patients after lymphodepletion with fludarabine and cyclophosphamide (Phase Ib/II study, NCT02772198)  (17). Median age was 11 years (range, 5-48), and 10 patients had relapsed after prior HSCT. All responding patients were per protocol candidates for consolidative HSCT, irrespective of previous HSCT. Eighteen of the 20 patients (90%) who survived until day 28 after CAR-T infusion were in CR; 11 of the 14 evaluable patients were MRD-negative. The median persistence of CAR T cells (measured by qPCR in peripheral blood) was 23 days. Fourteen of the 18 responders underwent consolidative HSCT. With a median follow-up of 9 months from cell infusion, 14 patients were alive and disease free, 12 had received HSCT, and two were not transplanted.
CD22-Targeted CAR-T Products The NCI and other groups have developed CARs targeting CD22 as an alternative antigen in BCP-ALL patients not responding to or relapsing after CD19-targeted strategies, particularly those with CD19 -disease. In a Phase I trial at the NCI (NCT02315612), a CAR containing a fully humanised anti-CD22 scFv region, a CD8α transmembrane domain, a 4-1BB costimulatory domain and CD3ζ (CD22. BB. z) was transduced by lentivirus into autologous T cells. Twenty-one patients were infused; the median age was 19 years (range, 7-30 years)  (29). Importantly, all patients had undergone ≥1 prior HSCT; 17 had received prior CD19directed immunotherapies, including 15 who had received CD19 CAR-T; and 10 patients had CD19 -or CD19-diminished disease. The CD22 CAR T cells were detectable in the blood of 19 of 21 infused patients, peaking on day 14 and remaining detectable in seven of nine patients evaluated 3 months post infusion, in two of three patients evaluated at 6 months, one patient evaluated at 9 months, and one patient evaluated at 18 months.
Two of four ALL patients responded. Interestingly, in a Phase I clinical trial in R/R CD19 + adult B-cell non-Hodgkin lymphoma (NHL), two different cellular products were simultaneously infused in each patient: one transduced with a second-generation CD19 CAR containing one costimulatory domain (CD28) and another with a third-generation CD19 CAR encoding CD28 and 4-1BB costimulatory domains (NCT01853631). Cells containing the third-generation CAR had superior expansion and longer persistence than did cells containing the second-generation CAR. This difference was most pronounced in patients with low disease burden at infusion and few normal circulating CD19 + B cells, a group in which the second-generation CD19 CAR T cells had limited expansion and persistence. As of now, in the very limited number of BCP-ALL patients treated with third-  (62)  or fourth-generation (63-66) CAR T cells (mainly in Phase I studies), 1-year PFS was substantially lower than that observed with single 4-1BB or CD28 costimulatory domain constructs.
Some groups have focused on B-cell targets other than CD19, e. g. , CD20  (94, 110)  and CD22 (Figure  1C ). As discussed in a previous section, Shah et al. recently reported the results of a clinical trial exploring the efficacy of CD22 CAR-T encoding 4-1BB as the costimulatory molecule in patients who failed treatment with a CD19 CAR-T (NCT02315612)  (30). To avoid tumour escape mechanisms by antigen loss  (111) (112) (113) , several groups are now investigating the use of bispecific CARs to target BCP-ALL (CD19/CD20 and CD19/CD22)  (94, 114, 115)  (Figure  1D ). Until now, no validated data have been obtained in paediatric patients or AYA with BCP-ALL to prove the safety or superiority in terms of the long-term outcome of targeting another antigen in addition to CD19; however, data in adult ALL and lymphoma have emerged  (94, 115).
A search on ClinicalTrial. gov revealed two ongoing trials using donor-derived CD19 CAR T cells after HSCT (NCT02050347 and NCT01430390). While both trials will administer CD19 CAR T cells harbouring CD28 as the costimulatory domain, only one will use Epstein-Barr virusspecific T cells as the starting material to reduce the risk of GvHD. Few data are available addressing the GvHD risk associated with infusion of donor-derived allogeneic CAR T cells. The first study using donor-derived multi-virus-specific CD19 CAR T cells was published by Cruz et al. (106). The idea was to reduce the alloreactive potential of donor-derived T cells by selecting and expanding T cells with an endogenous virus-specific TCR, which, due to their TCR specificity and experienced phenotype, would both reduce the risk of GvHD and promote CAR Tcell persistence.
Third-Party CAR Cells The use of third-party immune effector cells as the starting material derived from, for example, natural killer (NK) cells (NCT03056339, NCT04245722), invariant NK T cells (NCT03774654), γ/δ T cells (139) (NCT04107142), and α/β T cells knocked-out for the TCR α-chain and CD52 (NCT04150497, NCT03398967) represents an attractive and readily available ("universal") option for all patients whose lymphocytes could not be collected (in time) or for whom autologous production failed. Moreover, the transduction of a leukaemic cell and, as a result, expansion of CD19 CARexpressing leukaemic blasts post-infusion has been described as a rare event following autologous leukapheresis  (140). Different groups are working on the development and validation of allogeneic third-party CAR cell platforms with the aim to overcome some of the main clinical and economical limitations observed using autologous T cells, including the challenges of leukapheresis and ad hoc manufacturing.
Re-infusion induced BCA for a second time in one of seven children treated for B-cell recovery, while six of seven children re-infused for CD19 + haematogones continued to have BCA 6-21 months later. A systematic study on tisagenlecleucel re-infusion is ongoing (NCT04225676). Another approach reported from the same group at the CHOP/University of Pennsylvania (  109 ) is the infusion of a humanised CAR construct (huCART19 or CTL119) in attempt to overcome the possibility of an anti-murine immune response. In a pilot trial (NCT02374333), 33 R/R BCP-ALL patients with either partial or no response to prior tisagenlecleucel, CD19 + relapse or early B-cell recovery (defined as occurring within 6 months of prior CAR T-cell infusion), were infused with huCART19  (109). The ORR 1 month after infusion was 64% in the re-treatment cohort.
ONGOING AND PLANNED STUDIES TO CLOSE THE GAPS Further Research on Approved CAR-T Indications Currently, as of September 2021, tisagenlecleucel is the only CAR-T with market authorisation for paediatric patients and AYAs with BCP-ALL. As discussed above, the approved indications are ≥2 BCP-ALL relapse or a relapse after HSCT (Figure  2 ). In addition, refractory disease to standard chemotherapy, either in a primary or relapsed setting, is an indication for tisagenlecleucel. As a post-market requirement applied by the regulatory authorities, data on patients receiving commercial tisagenlecleucel are collected in registries such as the CIBMTR  (24) , European Society for Blood and Marrow Transplantation (EBMT) registry  (175, 176)  or national registries  (37). These "real-world" databases collecting data on a rapidly increasing number of patients will be valuable (but yet not monitored) resources to begin to evaluate in more detail (retrospectively and prospectively) multiple aspects of CAR-T planning, delivery, and outcome (Table  4 ).
Research in Primary BCP-ALL The important question of whether CAR-T can circumvent the long-term adverse effects of HSCT is currently not being addressed in a randomised study design in any ALL disease stage. However, the CASSIOPEIA study (NCT03876769), a single arm, multi-centre, Phase II trial, will determine the efficacy and safety of tisagenlecleucel in paediatric patients and AYAs with de novo NCI-defined high-risk BCP-ALL who have received a four-drug induction and subsequent consolidation (∼3 months of therapy in total) yet remain MRD positive at the end of consolidation, defined as an MRD of >0. 01% by centralised FCM assessment  (177). Such patients have a dismal prognosis with conventional high-intensive chemotherapy blocks consolidated by HSCT  (178, 179) , and experience substantial therapy-related toxicity  (180).