Pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) has achieved an 80% cure rate as a result of a risk-adapted therapy largely based on minimal residual disease (MRD) monitoring. However, relapse is still the most frequent adverse event, occurring mainly in the patients with intermediate MRD levels (intermediate risk, IR), emphasizing the need for new prognostic markers. We analyzed the prognostic impact of cytokine receptor-like factor 2 (CRLF2) over-expression and P2RY8-CRLF2 fusion in 464 BCP-ALL patients (not affected by Down syndrome and BCR-ABL negative) enrolled in the AIEOP-BFM ALL2000 study in Italy. In 22/464 (4.7%) samples, RQ-PCR showed CRLF2 over-expression (X20 times higher than the overall median). P2RY8-CRLF2 fusion was detected in 22/365 (6%) cases, with 10/22 cases also showing CRLF2 over-expression. P2RY8-CRLF2 fusion was the most relevant prognostic factor independent of CRLF2 over-expression with a threefold increase in risk of relapse. Significantly, the cumulative incidence of relapse of the P2RY8-CRLF2 þ patients in the IR group was high (61.1% ± 12.9 vs 17.6% ± 2.6, Po0.0001), similar to high-risk patients in AIEOP-BFM ALL2000 study. These results were confirmed in a cohort of patients treated in Germany. In conclusion, P2RY8-CRLF2 identifies a subset of BCP-ALL patients currently stratified as IR that could be considered for treatment intensification.
Exposure to microgravity generates alterations that are similar to those involved in age-related diseases, such as cardiovascular deconditioning, bone loss, muscle atrophy, and immune response impairment. Endothelial dysfunction is the common denominator. To shed light on the underlying mechanism, we participated in the Progress 40P mission with Spaceflight of Human Umbilical Vein Endothelial Cells (HUVECs): an Integrated Experiment (SPHINX), which consisted of 12 in-flight and 12 ground-based control modules and lasted 10 d. Postflight microarray analysis revealed 1023 significantly modulated genes, the majority of which are involved in cell adhesion, oxidative phosphorylation, stress responses, cell cycle, and apoptosis. Thioredoxin-interacting protein was the most up-regulated (33-fold), heat-shock proteins 70 and 90 the most down-regulated (5.6-fold). Ion channels (TPCN1, KCNG2, KCNJ14, KCNG1, KCNT1, TRPM1, CLCN4, CLCA2), mitochondrial oxidative phosphorylation, and focal adhesion were widely affected. Cytokine detection in the culture media indicated significant increased secretion of interleukin-1α and interleukin-1β. Nitric oxide was found not modulated. Our data suggest that in cultured HUVECs, microgravity affects the same molecular machinery responsible for sensing alterations of flow and generates a prooxidative environment that activates inflammatory responses, alters endothelial behavior, and promotes senescence.
Design and Methods PatientsThe study cohort was constituted by 410 non-Down syndrome, non-T, Philadelphia chromosome-negative, B-cell precursor ALL patients consecutively enrolled in the AIEOP-BFM ALL2000 study in AIEOP Centers from February 2003 to July 2005, who were included in the previous study on CRLF2 alterations and for whom DNA was still available. 18 Data on recurrent genomic aberrations were available for most patients.19 P2RY8-CRLF2 rearrangement was tested by reverse transcriptase polymerase chain reaction analysis in 372 (90.7%) patients. 18 As shown in Online Supplementary Table S1, there was an unbalance toward more unfavorable features with respect to treatment response (prednisone-poor response and high minimal residual disease levels) in the non-investigated group. Despite this difference, the event-free survival curve of the analyzed patients was not different from that of the not analyzed patients diagnosed in AIEOP centers in the study period (2003)(2004)(2005) (Online Supplementary Figure S1).The project was approved by the AIEOP ALL Scientific Committee.Risk group definitions and treatment outlines have already been reported 17 and are summarized in the Online Supplementary Material. DNA copy number variationsIKZF1 deletions, together with deletions in other genes (CDKN2A/B, PAX5, ETV6, BTG1, RB1 and EBF1) were investigated by multiplex ligation-dependent probe amplification (MLPA) using the Salsa MLPA P335-A3 ALL-IKZF1 kit (MRC-Holland, Amsterdam, the Netherlands) according to the manufacturer's instructions. 7,18,20 Patients positive for IKZF1 deletions were further analyzed by the more specific Salsa MLPA P202-A1 IKZF1 kit (MRC-Holland, Amsterdam, the Netherlands) to confirm and better define the extension of the alteration.Samples from pediatric ALL patients in complete remission were used as wild-type controls. Statistical analysisEvent-free survival time was calculated from the date of diagnosis to the date of an event, which was resistance, relapse, death or second neoplasm, whichever occurred first. Patients were censored at last follow-up if no events occurred. Event-free survival was estimated according to Kaplan-Meier, and compared using the log-rank test. The cumulative incidence of relapse at 5 years was estimated by adjusting for competing risks of other events and compared using Gray's test. 18 Multivariate Cox models for eventfree survival and cause-specific hazard of relapse were applied to assess, with the Wald test, the impact of IKZF1 deletions, after accounting for the risk group, age and white blood cell count at diagnosis, and the presence of P2RY8-CRLF2 aberration. The Cox model was also applied for each variable separately (univariate analysis). Results IKZF1 deletions at diagnosisIKZF1 deletions were detected in 54/410 cases (13.2%), in keeping with incidence data reported in the literature. 3,13 In 25 cases (6.1%) the deletion was intra-genic, involving only some exons of the IKZF1 gene, while in 29 cases (7.1%) the deletion encompassed the whole IKZF1 gene. In ...
BackgroundThe cancer-testis antigen MAGE-A4 is an attractive target for T-cell-based immunotherapy, especially for indications with unmet clinical need like non-small cell lung or triple-negative breast cancer.MethodsAn unbiased CD137-based sorting approach was first used to identify an immunogenic MAGE-A4-derived epitope (GVYDGREHTV) that was properly processed and presented on human leukocyte antigen (HLA)-A2 molecules encoded by the HLA-A*02:01 allele. To isolate high-avidity T cells via subsequent multimer sorting, an in vitro priming approach using HLA-A2-negative donors was conducted to bypass central tolerance to this self-antigen. Pre-clinical parameters of safety and activity were assessed in a comprehensive set of in vitro and in vivo studies.ResultsA MAGE-A4-reactive, HLA-A2-restricted T-cell receptor (TCR) was isolated from primed T cells of an HLA-A2-negative donor. The respective TCR-T-cell (TCR-T) product bbT485 was demonstrated pre-clinically to have a favorable safety profile and superior in vivo potency compared with TCR-Ts expressing a TCR derived from a tolerized T-cell repertoire to self-antigens. This natural high-avidity TCR was found to be CD8 co-receptor independent, allowing effector functions to be elicited in transgenic CD4+ T helper cells. These CD4+ TCR-Ts supported an anti-tumor response by direct killing of MAGE-A4-positive tumor cells and upregulated hallmarks associated with helper function, such as CD154 expression and release of key cytokines on tumor-specific stimulation.ConclusionThe extensive pre-clinical assessment of safety and in vivo potency of bbT485 provide the basis for its use in TCR-T immunotherapy studies. The ability of this non-mutated high-avidity, co-receptor-independent TCR to activate CD8+ and CD4+ T cells could potentially provide enhanced cellular responses in the clinical setting through the induction of functionally diverse T-cell subsets that goes beyond what is currently tested in the clinic.
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