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An excessive immune response during coronavirus disease (COVID-19) can induce cytokine release syndrome (CRS), which is associated with life-threatening complications and disease progression. This retrospective study evaluated the clinical characteristics of severe CRS (sCRS, grade 3-4) induced by severe COVID-19 (40 patients) or chimeric antigen receptor T-cell (CAR-T) therapy as a comparator (41 patients). Grade 4 CRS was significantly more common in the COVID-19 group (15/40 (35.7%) vs. 5/41 (12.2%), P = 0.008). The CAR-T group had more dramatic increase in cytokines, including IL-2, IL-6, IL-10, and IFN-γ. Interestingly, COVID-19 group had significantly higher levels for TNF-α (31.1 pg/ml (16.1-70.0) vs. 3.3 (1.8-9.6), P < 0.001) and lg viral loads were correlated with lg IL-6 (R 2  = 0.101; P < 0.001) and lg IL-10 (R 2  = 0.105; P < 0.001). The independent risk factor for COVID-19-related sCRS was hypertension history (OR: 4.876, 95% CI: 2.038-11.668; P < 0.001). Our study demonstrated that there were similar processes but different intensity of inflammatory responses of sCRS in COVID-19 and CAR-T group. The diagnose and management of severe COVID-19-related sCRS can learn lessons from treatment of sCRS induced by CAR-T therapy.

Background: Sequential CD19 and CD22 chimeric antigen receptor (CAR)-T cell therapy offers a promising approach to antigen-loss relapse in relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL); however, research in adults remains limited. Methods: This study aimed to evaluate the efficacy and safety of sequential CD19 and CD22 CAR-T cell therapy in adult patients with R/R B-ALL between November 2020 and November 2023 (ChiCTR2100053871). Key endpoints included the adverse event incidence, overall survival (OS), and leukemia-free survival (LFS). Results: Twenty-three patients with a median age of 58.1 years (range 25.9–75.0) were enrolled. High-risk cytogenetic and genomic aberrations were identified in 43.5% of patients, and five patients had baseline extramedullary disease (EMD). The median interval between the two infusions was 3.8 months. Grade ≥ 3 hematological adverse events occurred at comparable rates after both infusions. Cytokine release syndrome was observed in 78.3% and 39.1% of patients after CD19 and CD22 CAR-T therapy, respectively. Two patients experienced grade 2 immune effector cell-associated neurotoxicity syndrome (ICANS) during CD19 CAR-T, and no ICANS was reported during CD22 CAR-T. The median OS was not reached with a median follow-up of 19.4 months (range 8.7–45.6), while the median LFS was 20.8 months. OS and LFS rates were 91.3% and 67.1% at 1 year and 58.6% and 47.0% at 2 years, respectively. Eight patients experienced relapse, with the cumulative incidence of relapse being 28.6% at 1 year and 42.5% at 2 years. Higher baseline leukemia burden (≥ 64% bone marrow blasts) and the presence of EMD were significant risk factors for inferior OS and LFS, respectively. Conclusions: Sequential CAR-T cell therapy demonstrated durable efficacy and a manageable safety profile in R/R B-ALL, providing a viable option to address antigen-loss relapse and improve long-term outcomes in high-risk adult patients. [ABSTRACT FROM AUTHOR]

While chimeric antigen receptor (CAR)-T-cell therapy has demonstrated remarkable effectiveness in the treatment of B-cell lymphomas and leukemias, research on T-cell malignancies is still limited. Here, we reported a patient with hepatosplenic d T-cell lymphoma refractory to multiple lines of chemotherapy, who eventually achieved first complete remission with flow cytometry-confirmed minimal residual disease negativity after human leukocyte antigen (HLA) fully-mismatched siblingderived CD7 CAR-T therapy. However, given the allogeneic nature, CAR-T cells dropped rapidly after a peak of 83.4% of circulating T-cells. Cytokine release syndrome, cytopenia, and infections occurred but were manageable after treatments. After the consolidative haploidentical hematopoietic stem cell transplantation (HSCT), the patient remained in remission at the end of the follow-up (13 months post-CAR-T infusion). This is the first case of relapsed/refractory hepatosplenic d T-cell lymphoma who achieved lasting CR after HLA fully-mismatched sibling-derived CD7 CAR-T therapy bridging to haploidentical HSCT. [ABSTRACT FROM AUTHOR]

Immunotherapy utilizing chimeric antigen receptor T cell (CAR-T) therapy holds promise for hematologic malignancies, however, response rates and associated immune-related adverse effects widely vary among patients. Here we show, by comparing diversity and composition of the gut microbiome during different CAR-T therapeutic phases in the clinical trial ChiCTR1800017404, that the gut flora characteristically differs among patients and according to treatment stages, and might also reflect patient response to therapy in relapsed/refractory multiple myeloma (MM; n = 43), acute lympholastic leukemia (ALL; n = 23) and non-Hodgkin lymphoma (NHL; n = 12). We observe significant temporal differences in diversity and abundance of Bifidobacterium, Prevotella, Sutterella, and Collinsella between MM patients in complete remission (n = 24) and those in partial remission (n = 11). Furthermore, we find that patients with severe cytokine release syndrome present with higher abundance of Bifidobacterium, Leuconostoc, Stenotrophomonas, and Staphylococcus, which is reproducible in an independent cohort of 38 MM patients. This study has important implications for understanding the biological role of the microbiome in CAR-T treatment responsiveness of hematologic malignancy patients, and may guide therapeutic intervention to increase efficacy. The success rate of CAR-T cell therapy is high in blood cancers, yet individual patient characteristics might reduce therapeutic benefit. Here we show that therapeutic response in MM, ALL and NHL, and occurrence of severe cytokine release syndrome in multiple myeloma are associated with specific gut microbiome alterations. The success rate of chimeric antigen receptor T cell therapy is high in blood cancers, yet individual patient characteristics might reduce therapeutic benefit. Here authors show that therapeutic response in multiple myeloma, acute lymphoblastic leukemia and non-Hodgkin lymphoma, and occurrence of severe cytokine release syndrome in multiple myeloma are associated with specific gut microbiome alterations. [ABSTRACT FROM AUTHOR]

Twenty patients with relapsed B-ALL after HSCT were treated with CAR T cell therapy and were evaluated for efficacy and safety. Twelve patients previously received haploidentical transplantation, while 8 patients received HLA-matched transplantation. The median relapse time was 12 months (range, 4 to 72). Thirteen patients received autologous CAR T cells, and 7 patients received allogeneic CAR T cells, which were derived from transplant donors. The median infusion dose was 2.9×106/kg (range, 0.33 to 12×106/kg). Nineteen patients were evaluated for efficacy, among which 17 patients (89.5%) achieved MRD negative. The CR rates in the HLA-matched transplantation group and haploidentical transplantation group were 100% (7/7) and 83.3% (10/12), respectively. The median follow-up time was 9.80 months (range, 2.40 to 64.97). Ten patients (50%) died of relapse, 3 patients (15%) died of infection, and 1 patient (5%) died of aGVHD. Fifteen patients (75%) developed CRS, including 3 (20%) grade 1 CRS, 6 (40%) grade 2 CRS, and 6 (40%) grade 3 CRS. Ten patients (50%) developed aGVHD, including 1 (10%) grade I aGVHD, 6 (60%) grade II aGVHD, and 3 (30%) grade III aGVHD. The log rank test showed that CAR T cell origin was correlated with aGVHD occurrence in the haploidentical transplantation group (P = 0.005). The authors' study indicated that the initial efficacy and safety of CAR T cell therapy for patients with post-transplant relapse were satisfactory. However, aGVHD was a concern in patients with a history of haploidentical transplantation occupied with allogeneic CAR T cells, which warrants clinical attention. [ABSTRACT FROM AUTHOR]

Background: Chimeric antigen receptor T cell (CAR-T) therapy is successful in improving treatment outcomes for relapsed/refractory acute lymphoblastic leukemia (R/R ALL). However, toxicities associated with CAR-T therapy are being increasingly identified. Pancytopenia is one of the most common complications after CAR-T therapy, and platelet transfusions are an essential part of its supportive care. Study Design and Methods: This study aimed to assess the effectiveness of platelet transfusions for R/R ALL patients at our single center and identify associated risk factors. Overall, 44 R/R ALL patients were enrolled in this study, of whom 26 received CAR-T therapy and 18 received salvage chemotherapy. Result: Patients in the CAR-T group had a higher incidence of platelet transfusion refractoriness (PTR) (15/26, 57.7%) than those in the chemotherapy group (3/18, 16.7%) (p = 0.007). For patients receiving CAR-T therapy, multivariate analysis showed that the grade of cytokine release syndrome (CRS) was the only independent risk factor associated with PTR (p = 0.007). Moreover, higher peak serum IL-6 and IFN-γ levels suggested a higher risk of PTR (p = 0.024 and 0.009, respectively). Patients with PTR received more platelet infusion doses than those without PTR (p = 0.0426). Patients with PTR had more grade 3–4 bleeding events than those without PTR (21.4 vs. 0%, p = 0.230), and the cumulative incidence of grade 3–4 bleeding event was different (p = 0.023). Conclusion: We found for the first time that PTR is associated with the CRS grade. Improved knowledge on the mechanisms of PTR after CAR-T therapy is needed to design a rational therapeutic strategy that aims to improve the efficiency of transfusions. [ABSTRACT FROM AUTHOR]

This document is a correction notice for an article titled "CAR-T cell therapy-related cytokine release syndrome and therapeutic response is modulated by the gut microbiome in hematologic malignancies" published in Nature Communications. The original version of the article contained numerical mistakes in the source data and missing or incorrect values in figure 1a. Additionally, column B of the source data corresponding to Supplementary Table 1 was deleted due to confidentiality concerns. The correction also includes revised information in the "Clinical trial outcomes" section of the Results. The corrected article provides updated and accurate data on the outcomes of the clinical trial. [Extracted from the article]

With the increasing application of chimeric antigen receptor (CAR)-T cell therapy in various malignancies, an extra toxicity profile has been revealed, including a severe complication resembling hemophagocytic lymphohistiocytosis (HLH), which is usually disguised by severe cytokine release syndrome (CRS). In a clinical trial in whom 99 patients received B-cell maturation antigen CAR-T cells, we identified 20 (20.20%) cases of CAR-T cell–associated HLH (carHLH), most of whom possessed a background of severe CRS (grade ≥3). The overlapping features of carHLH and severe CRS attracted us to further explore the differences between them. We showed that carHLH can be distinguished by extreme elevation of interferon-γ, granzyme B, interleukin-1RA and interleukin-10, which can be informative in developing prevention and management strategies of this toxicity. Moreover, we developed a predictive model of carHLH with a mean area under the curve of 0.81 ± 0.07, incorporating serum lactate dehydrogenase at day 6 post-CRS and serum fibrinogen at day 3 post-CRS. The incidence of carHLH in CAR-T recipients might be relatively higher than we previously thought. relatively higher than we previously. A cytokine network distinguished from CRS is responsible for carHLH. And corresponding cytokine-directed therapies, especially targeting IL-10, are worth trying. [ABSTRACT FROM AUTHOR]

The considerable efficacy of B-cell maturation antigen–targeted chimeric antigen receptor (CAR)–T-cell therapy has been extensively demonstrated in the treatment of relapsed or refractory multiple myeloma. Nevertheless, in clinical practice, prolonged hematologic toxicity (PHT) extends hospital stay and impairs long-term survival. This retrospective study reviewed 99 patients with relapsed or refractory multiple myeloma who underwent B-cell maturation antigen CAR–T-cell therapy at our institution between April 2018 and September 2021 (ChiCTR1800017404). Among 93 evaluable patients, the incidence of prolonged hematologic toxicities was high after CAR–T-cell infusion, including 38.71% (36/93) of patients with prolonged neutropenia, 22.58% (21/93) with prolonged anemia and 59.14% (55/93) with prolonged thrombocytopenia. In addition, 9.68% (9/93) of patients experienced prolonged pancytopenia. Our multivariate analyses identified that cytokine profiles were independent risk factors for PHTs, whereas a sufficient baseline hematopoietic function and high CD4/CD8 ratio of CAR-T cells were protective factors for PHTs after CAR–T-cell infusion. Subgroup analyses found that the kinetics of post-CAR-T hematologic parameters were primarily determined by the collective effects of cytokine release syndrome and baseline hematopoietic functions, and showed influential weights for the three lineages. Our findings improve the understanding of the impact of cytokines on hematopoietic functions, which could contribute to the mechanism investigation and exploration of potential intervention strategies. [ABSTRACT FROM AUTHOR]

The pandemic of coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is spreading rapidly across the world. Currently, the COVID-19 pandemic is affecting the continuity of essential routine healthcare services and procedures, including chimeric antigen receptor T-cell (CAR-T) therapy, a life-saving option for patients with relapsed/refractory (R/R) hematologic malignancies. Due to the rapid disease progression of hematological malignancies, there is an urgent need to manufacture and utilize CAR T-cells. However, CAR-T treatment has become extraordinarily challenging during this COVID-19 pandemic. Thus, many medical and technical factors must now be taken into consideration before, during, and after CAR-T therapy. The purpose of this review is to provide brief suggestions for rational decision-making strategies in evaluating and selecting CAR T-cell treatment and appropriate CAR T-cell products, and protective strategies for medical staff and patients to prevent infection in the midst of the current COVID-19 pandemic. [ABSTRACT FROM AUTHOR]