Il-15 enhances the persistence and function of bcma-targeting car-t cells compared to il-2 or il-15/il-7 by limiting car-t cell dysfunction and differentiation

Chimeric antigen receptor (CAR)-T cell immunotherapy has revolutionized the treatment of B-lymphoid malignancies. For multiple myeloma (MM), B-cell maturation antigen (BCMA)-targeted CAR-T cells have achieved outstanding complete response rates, but unfortunately, patients often relapse within a year of receiving the therapy. Increased persistence and reduced dysfunction are crucial features that enhance the durability of CAR-T cell responses. One of the factors that influence CAR-T cell in vivo longevity and loss of function, but which has not yet been extensively studied for BCMA-directed CAR-T cells, are the cytokines used during their production. We here compared the impact of IL-2, IL-15 and a combination of IL-15/IL-7 on the phenotype and function of ARI2h, an academic BCMA-directed CAR-T cell that is currently being administered to MM patients. For this study, flow cytometry, in vitro cytotoxicity assays and analysis of cytokine release were performed. In addition, ARI2h cells expanded with IL-2, IL-15, or IL-15/IL-7 were injected into MM tumor-bearing mice to assess their in vivo efficacy. We demonstrated that each of the cytokine conditions was suitable for the expansion of ARI2h cells, with clear in vitro activity. Strikingly, however, IL-15-produced ARI2h cells had improved in vivo efficacy and persistence. When explored further, it was found that IL-15 drove a less-differentiated ARI2h phenotype, ameliorated parameters related to CAR-T cell dysfunction, and lowered the release of cytokines potentially involved in cytokine release syndrome and MM progression. Moreover, we observed that IL-15 was less potent in inducing T cell senescence and DNA damage accumulation, both of which may contribute to an unfavorable CAR-T cell phenotype. These findings show the superiority of IL-15 to IL-2 and IL-15/IL-7 in the quality of anti-BCMA CAR-T cells, particularly their efficacy and persistence, and as such, could improve the duration of responses if applied to the clinical production of CAR-T cells for patients

The Progress Test of the European Hematology Association: A New Tool for Continuous Learning.

info:eu-repo/semantics/publishedVersio

CAR density influences antitumoral efficacy of BCMA CAR T cells and correlates with clinical outcome

Identification of new markers associated with long-term efficacy in patients treated with CAR T cells is a current medical need, particularly in diseases such as multiple myeloma. In this study, we address the impact of CAR density on the functionality of BCMA CAR T cells. Functional and transcriptional studies demonstrate that CAR T cells with high expression of the CAR construct show an increased tonic signaling with up-regulation of exhaustion markers and increased in vitro cytotoxicity but a decrease in in vivo BM infiltration. Characterization of gene regulatory networks using scRNA-seq identified regulons associated to activation and exhaustion up-regulated in CARHigh T cells, providing mechanistic insights behind differential functionality of these cells. Last, we demonstrate that patients treated with CAR T cell products enriched in CARHigh T cells show a significantly worse clinical response in several hematological malignancies. In summary, our work demonstrates that CAR density plays an important role in CAR T activity with notable impact on clinical response

Chromatin regulation by Histone H4 acetylation at Lysine 16 during cell death and differentiation in the myeloid compartment

Histone H4 acetylation at Lysine 16 (H4K16ac) is a key epigenetic mark involved in gene regulation, DNA repair and chromatin remodeling, and though it is known to be essential for embryonic development, its role during adult life is still poorly understood. Here we show that this lysine is massively hyperacetylated in peripheral neutrophils. Genome-wide mapping of H4K16ac in terminally differentiated blood cells, along with functional experiments, supported a role for this histone post-translational modification in the regulation of cell differentiation and apoptosis in the hematopoietic system. Furthermore, in neutrophils, H4K16ac was enriched at specific DNA repeats. These DNA regions presented an accessible chromatin conformation and were associated with the cleavage sites that generate the 50 kb DNA fragments during the first stages of programmed cell death. Our results thus suggest that H4K16ac plays a dual role in myeloid cells as it not only regulates differentiation and apoptosis, but it also exhibits a non-canonical structural role in poising chromatin for cleavage at an early stage of neutrophil cell death

RICORS2040 : The need for collaborative research in chronic kidney disease

Chronic kidney disease (CKD) is a silent and poorly known killer. The current concept of CKD is relatively young and uptake by the public, physicians and health authorities is not widespread. Physicians still confuse CKD with chronic kidney insufficiency or failure. For the wider public and health authorities, CKD evokes kidney replacement therapy (KRT). In Spain, the prevalence of KRT is 0.13%. Thus health authorities may consider CKD a non-issue: very few persons eventually need KRT and, for those in whom kidneys fail, the problem is 'solved' by dialysis or kidney transplantation. However, KRT is the tip of the iceberg in the burden of CKD. The main burden of CKD is accelerated ageing and premature death. The cut-off points for kidney function and kidney damage indexes that define CKD also mark an increased risk for all-cause premature death. CKD is the most prevalent risk factor for lethal coronavirus disease 2019 (COVID-19) and the factor that most increases the risk of death in COVID-19, after old age. Men and women undergoing KRT still have an annual mortality that is 10- to 100-fold higher than similar-age peers, and life expectancy is shortened by ~40 years for young persons on dialysis and by 15 years for young persons with a functioning kidney graft. CKD is expected to become the fifth greatest global cause of death by 2040 and the second greatest cause of death in Spain before the end of the century, a time when one in four Spaniards will have CKD. However, by 2022, CKD will become the only top-15 global predicted cause of death that is not supported by a dedicated well-funded Centres for Biomedical Research (CIBER) network structure in Spain. Realizing the underestimation of the CKD burden of disease by health authorities, the Decade of the Kidney initiative for 2020-2030 was launched by the American Association of Kidney Patients and the European Kidney Health Alliance. Leading Spanish kidney researchers grouped in the kidney collaborative research network Red de Investigación Renal have now applied for the Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS) call for collaborative research in Spain with the support of the Spanish Society of Nephrology, Federación Nacional de Asociaciones para la Lucha Contra las Enfermedades del Riñón and ONT: RICORS2040 aims to prevent the dire predictions for the global 2040 burden of CKD from becoming true

Future prospects of chimeric antigen receptor T‐cell therapy for multiple myeloma

Although multiple myeloma (MM) remains an incurable hematological malignancy, the introduction of autologous stem cell transplantation, proteasome inhibitors, and immunomodulatory agents has increased the survival of patients. However, most patients will become refractory to available therapeutic regimens. Moreover, conventional strategies have shown limited benefit in high‐risk patients with adverse cytogenetics. Therefore, novel strategies including immunotherapy are needed to improve the outcomes of these patients. Immunotherapy includes a range of strategies to redirect the immune system to attack tumor cells. Here, we review the most promising immunotherapy strategy published to date for many hematologic malignancies, chimeric antigen receptor (CAR) T cells. Most clinical studies of CAR T cell therapy for MM target B‐cell maturation antigen (BCMA) on malignant plasma cells. The initial studies using BCMA targeted CAR T cells are devoted to patients with advanced relapsed/refractory MM. Eventual relapse after CAR T‐cell therapy remains an issue. We present the most recent clinical data, as well as relevant preclinical data demonstrating novel strategies with the potential to improve clinical outcomes of cellular therapy for MM. Further, we present a proposal for how CAR T‐cell therapy may fit into the future therapeutic landscape of MM as adoptive cellular therapy moves beyond the currently studied multiply relapsed/refractory setting

Atlas municipal de mortalidade por cancro em Portugal e Espanha (2003–2012), AMOCAPE

El 'Atlas of Cancer Mortality in Portugal and Spain 2003–2012', muestra la distribución espacial de la mortalidad municipal por distintos tipos cáncer para el periodo 2003-2012. Ha sido desarrollado por la Unidad de Epidemiología del Cáncer y Ambiental del Centro Nacional de Epidemiología del ISCIII, que forma parte del CIBERESP, y por el Departamento de Epidemiología del Instituto Nacional De Saúde Doutor Ricardo Jorge de Portugal. El estudio de la distribución geográfica del riesgo de fallecer por cáncer es una de las herramientas que se usan en epidemiología para generar hipótesis sobre la posible implicación de factores ambientales en el origen de los tumores.This project is partially supported by research grant from the Spanish Health Research Fund (FIS) of the National Institute of Health Carlos III (ISCIII), Spain (Project PI17CIII/00040: “Spatial distribution of municipal cancer mortality in Spain (SICAMSA)” (“Distribución Espacial de la Mortalidad municipal por CÁncer en ESpaña (DEMOCAES)”).Introduction. Methods. Results: Oesophagus (ICD-10 C15) Stomach (ICD-10 C16) Colorectal (ICD-10 C18–C21) Pancreas (ICD-10 C25) Larynx (ICD-10 C32) Lung (ICD-10 C33–C34) Female Breast (ICD-10 C50) Prostate (ICD-10 C61) Bladder (ICD-10 C67) Leukaemia (ICD-10 C91–C95) References. Annexes: Annex I and Annex IIN

The proteasome: mechanisms of biology and markers of activity and response to treatment in multiple myeloma

Since the early 1990s, the synthesis and subsequent clinical application of small molecule inhibitors of the ubiquitin proteasome pathway (UPP) has revolutionized the treatment and prognosis of multiple myeloma. In this review, we summarize important aspects of the biology of the UPP with a focus on its structure and key upstream/downstream regulatory components. We then review current knowledge of plasma cell sensitivity to proteasome inhibition and highlight new proteasome inhibitors that have recently entered clinical development. Lastly, we address the putative role of circulating proteasomes as a novel biomarker in multiple myeloma and provide guidance for future clinical trials using proteasome inhibitors