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Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment for acute myeloid leukemia (AML). However, most patients experience relapse after allo-HSCT, with a poor prognosis, and treatment options are limited. The lack of an ideal targetable antigen is a major obstacle for treating patients with relapsed AML. CD38 is known to be expressed on most AML and myeloma cells, and its lack of expression on hematopoietic stem cells (HSCs) renders it a potential therapeutic target for relapsed AML. To investigate the clinical therapeutic efficacy and safety of CD38-targeted chimeric antigen receptor T (CAR-T-38) cells, we enrolled 6 AML patients who experienced relapse post-allo-HSCT (clinicaltrials.gov: NCT04351022). Prior to CAR-T-38 treatment, the blasts in the bone marrow of these patients exhibited a median of 95% (92–99%) CD38 positivity. Four weeks after the initial infusion of CAR-T-38 cells, four of six (66.7%) patients achieved complete remission (CR) or CR with incomplete count recovery (CRi); the median CR or CRi time was 191 (range 117–261) days. The cumulative relapse rate at 6 months was 50%. The median overall survival (OS) and leukemia-free survival (LFS) times were 7.9 and 6.4 months, respectively. One case relapsed 117 days after the first CAR-T-38 cell infusion, with remission achieved after the second CAR-T-38 cell infusion. All six patients experienced clinically manageable side effects. In addition, multiparameter flow cytometry (FCM) revealed that CAR-T-38 cells eliminated CD38 positive blasts without off-target effects on monocytes and lymphocytes. Although this prospective study has a limited number of cases and a relatively short follow-up time, our preliminary data highlight the clinical utility and safety of CAR-T-38 cell therapy in treating relapsed AML post-allo-HSCT.

CAR-T cell therapy is a novel approach in the treatment of hematological tumors. However, it is associated with life-threatening side effects, such as the severe cytokine release syndrome (sCRS). Therefore, predicting the occurrence and development of sCRS is of great significance for clinical CAR-T therapy. The study of existing clinical data by artificial intelligence may bring useful information. By analyzing the heat map of clinical factors and comparing them between severe and non-severe CRS, we can identify significant differences among these factors and understand their interrelationships. Ultimately, a decision tree approach was employed to predict the timing of severe CRS in both children and adults, considering variables such as the same day, the day before, and initial values. We measured cytokines and clinical biomarkers in 202 patients who received CAR-T therapy. Peak levels of 25 clinical factors, including IFN-γ, IL6, IL10, ferritin, and D-dimer, were highly associated with severe CRS after CAR T cell infusion. Using the decision tree model, we were able to accurately predict which patients would develop severe CRS consisting of three clinical factors, classified as same-day, day-ahead, and initial value prediction. Changes in serum biomarkers, including C-reactive protein and ferritin, were associated with CRS, but did not alone predict the development of severe CRS. Our research will provide significant information for the timely prevention and treatment of sCRS, during CAR-T immunotherapy for tumors, which is essential to reduce the mortality rate of patients.

This study aimed to determine whether intermuscular adipose tissue (IMAT) or intramuscular adipose tissue content (IMAC) has a greater effect on skeletal muscle density (SMD) and to explore the underlying mechanisms. We recruited 292 inpatients without musculoskeletal system disease, all of whom underwent abdominal CT. Muscle parameters, including skeletal muscle area (SMA), skeletal muscle index (SMI), SMD, IMAC, and IMAT, as well as fat parameters—subcutaneous fat area (SFA) and subcutaneous fat density (SFD) in the abdominal wall—were measured by two musculoskeletal radiologists using ImageJ software at the third lumbar vertebra (L3) level. One-way ANOVA with LSD (chi-square test for group comparisons where p  > 0.05) or Dunnett’s T3 test ( p  < 0.05) was employed to compare muscle parameters between genders and across age groups. The relationship between SMD and muscle measurements was analyzed using Spearman’s correlation coefficient. Multiple regression analysis identified and compared factors influencing SMD. SMD was highly correlated with IMAT and IMAC ( p  < 0.05), moderately correlated with gender, age, and SFA ( p  < 0.05). Multiple linear regression analysis indicated that IMAC, IMAT, and age significantly affected SMD ( p  < 0.05), with the order of influence being IMAT (β = -0.616), IMAC (β = -0.429), and age (β = -0.098). SFA and gender did not significantly affect SMD ( p  > 0.05). The findings revealed that age, IMAT, and IMAC influence SMD, with IMAT exerting the most significant impact.

Background Chimeric antigen receptor T-cell (CAR-T) therapy is a new and efficient cellular immunotherapy. The therapy shows significant efficacy, but also has serious side effects, collectively known as cytokine release syndrome (CRS). At present, some CRS-related cytokines and their roles in CAR-T therapy have been confirmed by experimental studies. However, the mechanism of CRS remains to be fully understood. Methods Based on big data for human protein interactions and meta-learning graph neural network, we employed known CRS-related cytokines to comprehensively investigate the CRS associated cytokines in CAR-T therapy through protein interactions. Subsequently, the clinical data for 119 patients who received CAR-T therapy were examined to validate our prediction results. Finally, we systematically explored the roles of the predicted cytokines in CRS occurrence by protein interaction network analysis, functional enrichment analysis, and pathway crosstalk analysis. Results We identified some novel cytokines that would play important roles in biological process of CRS, and investigated the biological mechanism of CRS from the perspective of functional analysis. Conclusions 128 cytokines and related molecules had been found to be closely related to CRS in CAR-T therapy, where several important ones such as IL6, IFN-γ, TNF-α, ICAM-1, VCAM-1 and VEGFA were highlighted, which can be the key factors to predict CRS.

Background Patients with refractory/relapsed (R/R) B-cell acute lymphoblastic leukemia (B-ALL) harboring TP53 alterations have a dismal prognosis due to profound chemoresistance. While CD19 chimeric antigen receptor T-cell (CAR-T) therapy has shifted the treatment landscape, long-term efficacy in this high-risk subset remains limited. The dual-target CD19/22 CAR-T has been developed to enhance anti-tumor activity; however, its comparative efficacy and long-term survival relative to CD19 CAR-T in this high-risk population remain unclear and require further elucidation to inform clinical decision-making. Methods This study included 55 patients with TP53 -altered R/R B-ALL who were enrolled in clinical trials (NCT03919240, NCT03275493, and NCT03614858) and treated with either CD19 ( n  = 27) or CD19/22 ( n  = 28) CAR-T therapy. The outcomes assessed included the complete remission (CR) rate, minimal residual disease (MRD)-negative CR rate, overall survival (OS), leukemia-free survival (LFS), and cumulative incidence of relapse (CIR). Multivariable Cox regression models were used to estimate hazard ratios (HRs) for OS and LFS. Results The CR rate was high in both groups (CD19/22: 100%; CD19: 88.89%). Notably, the MRD-negative CR rate was higher with CD19/22 CAR-T therapy (75.00% vs. 29.63%, p  = 0.0011), and was confirmed as an independent favorable prognostic factor. The CD19/22 CAR-T also demonstrated markedly better long-term survival, with 3-year OS (59.55% vs. 25.49%, p  = 0.0050) and LFS (57.29% vs. 17.64%, p  = 0.0047) rates. Among the 32 patients who underwent consolidative allo-HSCT after CAR-T, the CD19/22 CAR-T group achieved superior 3-year survival (OS: 72.34% vs. 30.77%, p  = 0.0089; LFS: 76.69% vs. 23.07%, p  = 0.0041) and lower CIR (23.30% vs. 75.00%, p  = 0.0182). Multivariable analysis established CD19/22 CAR-T therapy and bridging to allo-HSCT as independent predictors of improved LFS. Conclusion CD19/22 CAR-T immunotherapy, particularly when followed by allo-HSCT, represents a promising and clinically effective treatment paradigm for R/R B-ALL with TP53 alterations. Trial registration A single-center retrospective clinical study.

Chimeric antigen receptor T cell (CAR-T) therapy has emerged as highly effective in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), but only about 40% patients have achieved sustained responses. Here, we conducted a phase II clinical trial testing efficacy and toxicities of CAR-T therapy in R/R non-Hodgkin’s lymphoma patients (NCT03196830). Among enrolled patients, 33 R/R DLBCL patients pretreated with DFC (decitabine, fludarabine plus cyclophosphamide) lymphodepletion chemotherapy and infused with tandem CD19-CD22 based CAR-T cells were drawn out for efficacy and toxicities of CAR-T therapy evaluation. With a median follow-up of 10.9(0.6-29.0) months, the best overall response and complete remission (CR) rates were 90.9% and 63.6%, respectively. The median progression-free survival (PFS) was 10.2 months and overall survival (OS) was undefined. The 2-year OS and PFS rates were 54.3% and 47.2%, respectively. No severe grade 4 cytokine release syndrome (CRS) was observed and grade 3 CRS was observed in only 7 patients; 3 patients developed mild immune effect or cell-associated neurotoxic syndrome. All toxicities were transient and reversible and no CAR-T-related mortality. Further subgroup analysis showed that achieving CR was an independent prognostic factor associated with favorable PFS and OS. The 2-year OS and PFS for patients who achieved CR within 3 months (undefined versus undefined P =0.021 and undefined versus undefined P =0.036) or during the follow-up period were significantly longer than those who did not (undefined versus 4.6 months P < 0.0001 and undefined versus 2.0months P <0.001). While severe CRS was also an independent prognostic factor but associated with inferior PFS and OS. The 2-year OS and PFS for patients with grade 3 CRS were significantly shorter than those with grade 0-2 CRS (4.1 months versus undefined P <0.0001 and 1.7 months versus undefined P =0.0002). This study indicated that CD19/CD22 dual-targeted CAR-T therapy under a decitabine-containing lymphodepletion regimen may be a safe, potent effective approach to R/R DLBCL patients.

The tumor burden (TB) is significantly related to the severity of cytokine release syndrome (CRS) caused by CAR-T cells, but its correlation with therapeutic efficacy has not been systematically studied. This study focused on the effects of the TB level on both the safety and efficacy of ssCART-19 as a treatment for r/r B-ALL. Taking the 5% tumor burden as the boundary, the study participants were divided into 2 groups, high and low tumor burden groups. Under this grouping strategy, the impacts of differential r/r B-ALL TBs on the clinical therapeutic efficacy (CR rate and long-term survival) and safety profiles after ssCART-19 cell treatment were analysed. 78 patients were reported in this study. The differential B-ALL TBs significantly affected the complete remission (CR) rates of patients treated with ssCART-19, with rates of 93.94% and 75.56% in the low and high TB groups, respectively ( P  = 0.0358). The effects of TBs on long-term therapeutic efficacy were further studied based on event-free survival (EFS) and overall survival (OS) profiles; both the OS and EFS of the low TB group were better than those of the high TB group, but the differences were not statistically significant. Importantly, the time points of TB measurement did not significantly affect the OS and EFS profiles regardless of whether the TBs were measured before or after fludarabine-cyclophosphamide (FC) preconditional chemotherapy. On the other hand, the severity of CRS was significantly correlated with the TB level ( P  = 0.0080), and the incidence of sCRS was significantly related to the TB level (the sCRS incidence increased as the TB level increased, P  = 0.0224). Unexpectedly, the ssCART-19 cell expansion peaks were not significantly different ( P  = 0.2951) between the study groups. Patients with a low r/r B-ALL TB yield more net benefits from CAR-T treatment than those with a high TB in terms of safety and CR rate. These findings are critical and valuable for determining the optimal CAR-T cell treatment window for r/r B-ALL patients and will further the development of comprehensive and reasonable CAR-T cell treatment plans for r/r B-ALL patients with differential TBs. Trial registration: ClinicalTrials.gov identifier, NCT03919240.

BackgroundDespite the encouraging outcome of chimeric antigen receptor T cell (CAR-T) targeting B cell maturation antigen (BCMA) in managing relapsed or refractory multiple myeloma (RRMM) patients, the therapeutic side effects and dysfunctions of CAR-T cells have limited the efficacy and clinical application of this promising approach.MethodsIn this study, we incorporated a short hairpin RNA cassette targeting PD-1 into a BCMA-CAR with an OX-40 costimulatory domain. The transduced PD-1KD BCMA CAR-T cells were evaluated for surface CAR expression, T-cell proliferation, cytotoxicity, cytokine production, and subsets when they were exposed to a single or repetitive antigen stimulation. Safety and efficacy were initially observed in a phase I clinical trial for RRMM patients.ResultsCompared with parental BCMA CAR-T cells, PD-1KD BCMA CAR-T cell therapy showed reduced T-cell exhaustion and increased percentage of memory T cells in vitro. Better antitumor activity in vivo was also observed in PD-1KD BCMA CAR-T group. In the phase I clinical trial of the CAR-T cell therapy for seven RRMM patients, safety and efficacy were initially observed in all seven patients, including four patients (4/7, 57.1%) with at least one extramedullary site and four patients (4/7, 57.1%) with high-risk cytogenetics. The overall response rate was 85.7% (6/7). Four patients had a stringent complete response (sCR), one patient had a CR, one patient had a partial response, and one patient had stable disease. Safety profile was also observed in these patients, with an incidence of manageable mild to moderate cytokine release syndrome and without the occurrence of neurological toxicity.ConclusionsOur study demonstrates a design concept of CAR-T cells independent of antigen specificity and provides an alternative approach for improving the efficacy of CAR-T cell therapy.

Background B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor T-cell (CAR T-cell) therapy has exhibited remarkable efficacy in refractory or relapsed multiple myeloma (R/R MM), but recurrence and rapid progression of disease are still observed within a short time after treatment. Long-term pomalidomide therapy, which potentiates T-cell functionality, might enhance the efficacy of BCMA CAR T-cell therapy. Methods We performed a single-center retrospective clinical study. Patients with relapsed or refractory multiple myeloma who received BCMA CAR T-cell infusion were enrolled in our study, and were followed by long-term pomalidomide treatment (4 mg/day) or not one month after infusion. The response and adverse events were assessed after infusion. The effect of pomalidomide on BCMA CAR T-cells was assessed in vitro. Results The objective response rate (ORR) of BCMA-CART was 100%. Three months following CAR T-cell infusion, of the 8 patients receiving pomalidomide, except for 2 patients who stopped maintenance therapy and were lost to follow-up, all patients (6/6) achieved VGPR (very good partial response) or CR (complete response), while only 5 patients (5/8) who did not receive pomalidomide treatment achieved VGPR or better. At a median follow-up of 27 months, for the 8 patients who did not receive pomalidomide administration, the median TTP (time to progression) was 5.85 (1–14) months, while the OS (overall survival) was 10.7 (1.2–16) months. Of the 8 patients who received pomalidomide therapy after CAR T-cell infusion, the median TTP was 13 (7–13) months, while the OS was not reached. Moreover, neither long-term hematological toxicity nor drug-induced liver damage was observed during the follow-up period. Mechanistically, pomalidomide promotes antimyeloma efficacy of BCMA CAR T-cells by inhibiting cell apoptosis and enhancing cytoxicity. Conclusions Our results confirmed that BCMA CAR T-cell therapy combined with long-term pomalidomide had a low recurrence rate and manageable therapy-related side effects, providing a promising option for treating R/R MM. Graphical Abstract

The chimera antigen receptor (CAR) T cell therapy is a novel and potential targeted therapy and has achieved satisfactory efficacy in patients with relapsed or refractory multiple myeloma (MM) in recent years. However, cytokine release syndrome (CRS) and clinical efficacy have become the major obstacles which limit the application of CAR-T in clinics. To explore the potential biomarkers in plasma for evaluating CRS and clinical efficacy, we performed metabolomic and lipidomic profiling of plasma samples from 17 relapsed or refractory MM patients received CAR-T therapy. Our study showed that glycerophosphocholine (GPC), an intermediate of platelet-activating factor (PAF)-like molecule, was significantly decreased when the participants underwent CRS, and the remarkable elevation of lysophosphatidylcholines (lysoPCs), which were catalyzed by lysoPC acyltransferase (LPCAT) was a distinct metabolism signature of relapsed or refractory MM patients with prognostic value post-CAR-T therapy. Both GPC and lysoPC are involved in platelet-activating factor (PAF) remodeling pathway. Besides, these findings were validated by LPCAT1 expression, a key factor in the PAF pathway, associated with poor outcome in three MM GEP datasets of MM. In conclusion, CAR-T therapy alters PAF synthesis in MM patients, and targeting PAF remodeling may be a promising strategy to enhance MM CAR-T therapy.