Rationally reprogramming single-cell aging trajectories and lifespan through dynamic modulation of environmental inputs.

How do variations in nutrient levels influence cellular lifespan? A dynamical systems model of a core circuit involved in yeast aging suggests principles underlying lifespan extension observed at static and alternating glucose levels that are reminiscent of intermittent fasting regimens.

Increased PVR Expression on Bone Marrow Macrophages May Promote Resistance to TIGIT Blockade in Multiple Myeloma.

PURPOSE: TIGIT blockade in our ex vivo models of bone marrow (BM) reduced the number of malignant plasma cells (PCs) in only half of patients with multiple myeloma (MM). Here we wanted to investigate whether increased expression of TIGIT ligands may inhibit T cell immune response promoting resistance to TIGIT blockade. EXPERIMENTAL DESIGN: We first characterized the number and phenotype of BM macrophages in the different stages of disease by multi-parameter flow cytometry. We assessed the effect of TIGIT ligands on PC survival performing experiments with ex vivo BM model and analyzed changes in gene expression by using Nanostring technology and real-time PCR. RESULTS: Frequency of BM macrophages was significantly decreased in MM which was accompanied by changes in their immunophenotype. Moreover, we found a higher number of malignant PCs in ex vivo BM cells cultured onto PVR and nectin-2 compared to control, suggesting that both ligands may support PC survival. In addition, presence of PVR, but not nectin-2, overcame the therapeutic effect of TIGIT blockade or exogenous IL-2. Furthermore, presence of exogenous IL-2 increased TIGIT expression on both CD4+ and CD8+ T cells and, indirectly, PVR on BM macrophages. Consistently, PVR reduced the number of cytotoxic T cells and promoted a gene signature with reduced effector molecules. CONCLUSIONS: IL-2 induced TIGIT on T cells in the BM where increased PVR expression resulted in cytotoxic T cell inhibition promoting PC survival and resistance to TIGIT blockade.

The evolving pattern of the monoclonal protein improves the IMWG 2/20/20 classification for patients with smoldering multiple myeloma.

The 2/20/20 International Myeloma Working Group (IMWG) score is the most employed risk score in clinical practice to evaluate the risk of progression from smoldering multiple myeloma (SMM) to symptomatic multiple myeloma. However, it faces a serious limitation: The risk score is applied at diagnosis and cannot be reapplied. Since a dynamic accurate patient risk assessment for progression is necessary, we aimed to investigate whether the detection of an evolving pattern in serum M-protein (SMP) improves the identification of high-risk patients. Eighty-three patients diagnosed with SMM between 2011 and 2020 were included. Patients were initially classified applying the 2/20/20 IMWG score at baseline and later reclassified depending on the presence of an SMP evolving pattern into six groups. We regrouped the patients into three final risk groups: low-risk, intermediate-risk, and high-risk. The risk of progression at two years for the high-risk group was 88% and all patients had progressed at 4 years. The performance measurements were superior for the new 2/20/20-Evolving score independently for the detection of high-risk patients. We show that the sequential measurement of the SMP is a noninvasive and widely available test that improves the 2/20/20 IMWG risk score.

Biomarkers of Efficacy and Safety of the Academic BCMA-CART ARI0002h for the Treatment of Refractory Multiple Myeloma.

PURPOSE: B-cell maturation antigen (BCMA)-chimeric antigen receptor T-cells (CART) improve results obtained with conventional therapy in the treatment of relapsed/refractory multiple myeloma. However, the high demand and expensive costs associated with CART therapy might prove unsustainable for health systems. Academic CARTs could potentially overcome these issues. Moreover, response biomarkers and resistance mechanisms need to be identified and addressed to improve efficacy and patient selection. Here, we present clinical and ancillary results of the 60 patients treated with the academic BCMA-CART, ARI0002h, in the CARTBCMA-HCB-01 trial. PATIENTS AND METHODS: We collected apheresis, final product, peripheral blood and bone marrow samples before and after infusion. We assessed BCMA, T-cell subsets, CART kinetics and antibodies, B-cell aplasia, cytokines, and measurable residual disease by next-generation flow cytometry, and correlated these to clinical outcomes. RESULTS: At cut-off date March 17, 2023, with a median follow-up of 23.1 months (95% CI, 9.2-37.1), overall response rate in the first 3 months was 95% [95% confidence interval (CI), 89.5-100]; cytokine release syndrome (CRS) was observed in 90% of patients (5% grades ≥3) and grade 1 immune effector cell-associated neurotoxicity syndrome was reported in 2 patients (3%). Median progression-free survival was 15.8 months (95% CI, 11.5-22.4). Surface BCMA was not predictive of response or survival, but soluble BCMA correlated with worse clinical outcomes and CRS severity. Activation marker HLA-DR in the apheresis was associated with longer progression-free survival and increased exhaustion markers correlated with poorer outcomes. ARI0002h kinetics and loss of B-cell aplasia were not predictive of relapse. CONCLUSIONS: Despite deep and sustained responses achieved with ARI0002h, we identified several biomarkers that correlate with poor outcomes.

Enfermedad del injerto contra el receptor / Graft-versus-host disease

La enfermedad del injerto contra el receptor (EICR) es la complicación más frecuente y potencialmente fatal cuando se realiza un trasplante alogénico de progenitores hematopoyéticos (alo-TPH). Ocurre cuando linfocitos T inmunocompetentes y procedentes del donante (injerto) reconocen estructuras antigénicas del receptor como extrañas. La respuesta inmune resultante activa los linfocitos T del donante y destruye los tejidos del receptor. Las manifestaciones clínicas de esta respuesta inmune dan como resultado la EICR aguda y crónica. La EICR aguda es la principal complicación fatal en la fase precoz del trasplante alogénico de progenitores hematopoyéticos, mientras que la EICR crónica supone una alta morbilidad y mala calidad de vida de los pacientes que sobreviven a largo plazo. En el presente artículo, realizamos una revisión de la EICR desde la frecuencia de aparición, así como las manifestaciones clínicas, diagnóstico, tratamiento y prevención

Graft-versus-host disease (GVHD) is the most frequent and potentially fatal complication of an allogeneic hematopoietic progenitor cell transplantation. It appears when immunocompetent T cells from donor origin recognise antigens from recipient origin as foreign. The immune response activates donor T cells and destroys recipient tissues. The clinical picture of this immune response is called acute and chronic GVHD. Acute GVHD is the main fatal complication during the first months after allogeneic hematopoietic progenitor cell transplantation, while chronic GVHD accounts for a significant long-term fraction of the mortality, morbidity and reduced quality of life of patients. Our goal is to review the frequency, clinical manifestations, diagnosis, treatment and prevention of GVHD