Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma

[EN]For patients with smoldering multiple myeloma, the standard of care is observation until symptoms develop. However, this approach does not identify high-risk patients who may benefit from early intervention. In this randomized, open-label, phase 3 trial, we randomly assigned 119 patients with high-risk smoldering myeloma to treatment or observation. Patients in the treatment group received an induction regimen (lenalidomide at a dose of 25 mg per day on days 1 to 21, plus dexamethasone at a dose of 20 mg per day on days 1 to 4 and days 12 to 15, at 4-week intervals for nine cycles), followed by a maintenance regimen (lenalidomide at a dose of 10 mg per day on days 1 to 21 of each 28-day cycle for 2 years). The primary end point was time to progression to symptomatic disease. Secondary end points were response rate, overall survival, and safety. After a median follow-up of 40 months, the median time to progression was significantly longer in the treatment group than in the observation group (median not reached vs. 21 months; hazard ratio for progression, 0.18; 95% confidence interval [CI], 0.09 to 0.32; P<0.001). The 3-year survival rate was also higher in the treatment group (94% vs. 80%; hazard ratio for death, 0.31; 95% CI, 0.10 to 0.91; P=0.03). A partial response or better was achieved in 79% of patients in the treatment group after the induction phase and in 90% during the maintenance phase. Toxic effects were mainly grade 2 or lower. Early treatment for patients with high-risk smoldering myeloma delays progression to active disease and increases overall survival. (Funded by Celgene; ClinicalTrials.gov number, NCT00480363.)

Spanish Cell Therapy Network (TerCel): 15 years of successful collaborative translational research

In the current article we summarize the 15-year experience of the Spanish Cell Therapy Network (TerCel), a successful collaborative public initiative funded by the Spanish government for the support of nationwide translational research in this important area. Thirty-two research groups organized in three programs devoted to cardiovascular, neurodegenerative and immune-inflammatory diseases, respectively, currently form the network. Each program has three working packages focused on basic science, pre-clinical studies and clinical application. TerCel has contributed during this period to boost the translational research in cell therapy in Spain, setting up a network of Good Manufacturing Practice–certified cell manufacturing facilities– and increasing the number of translational research projects, publications, patents and clinical trials of the participating groups, especially those in collaboration. TerCel pays particular attention to the public-private collaboration, which, for instance, has led to the development of the first allogeneic cell therapy product approved by the European Medicines Agency, Darvadstrocel. The current collaborative work is focused on the development of multicenter phase 2 and 3 trials that could translate these therapies to clinical practice for the benefit of patients

Tissue engineered scaffolds for mimetic autografts

Introduction: Despite its regenerative capacity, bone healing can be compromised, leading to delayed fracture regeneration and nonunion. Due to the scarcity of bone tissue that can be used as autograft, novel tissue engineering strategies arise as a promising solution by using biocompatible materials. Methods: Our objective is the development of engineered autografts capable of efficiently treat fracture nonunion. For this purpose, we designed polycaprolactone (PCL) autografts surrounded by a porous membrane mimicking periosteum. To assess their regenerative capacity, these scaffolds were tested in critical size femur defect for ten weeks carrying out μCT and histological analysis. Additionally, we are focusing on the generation of PCL biocomposites, such as poly ethyl-acrylate (PEA) covered PCL membranes which can enhance morphogen functionalization, reducing the effective BMP dose. Results: At the mCT level, structural mimetic PCL scaffolds, showed no significant difference in bone healing (Empty group, 11.47±4.93 mm3; MA, 14.95±3.09 mm3, p=0.1711). Histological analysis demonstrates that MEW PCL mimicking periosteum enhances bone growth, but insufficient for successful healing. However, once functionalized with PEA and BMP-2, these implants showed highly improved regeneration (CTL group, 11,47±4,93 mm3; BMP-2 group, 49,24±13,20 mm3, p = 0.0001). Figure 1. These implants were loaded with BMP-2 solutions previously studied in vitro to estimate morphogen dose, which resulted in 55.64±14.83 ng (n=6). Conclusions and discussion: In conclusion, PEA functionalized mimetic autografts show an important increase in bone healing, enhancing BMP-2 effects, which provide representative regeneration with a 100 folds lower dose than typically described in literature

Adipose-derived mesenchymal stromal cells for the treatment of patients with severe SARS-CoV-2 pneumonia requiring mechanical ventilation. A proof of concept study

Background: Identification of effective treatments in severe cases of COVID-19 requiring mechanical ventilation represents an unmet medical need. Our aim was to determine whether the administration of adipose-tissue derived mesenchymal stromal cells (AT-MSC) is safe and potentially useful in these patients. Methods: Thirteen COVID-19 adult patients under invasive mechanical ventilation who had received previous antiviral and/or anti-inflammatory treatments (including steroids, lopinavir/ritonavir, hydroxychloroquine and/or tocilizumab, among others) were treated with allogeneic AT-MSC. Ten patients received two doses, with the second dose administered a median of 3 days (interquartile range-IQR- 1 day) after the first one. Two patients received a single dose and another patient received 3 doses. Median number of cells per dose was 0.98 × 106 (IQR 0.50 × 106) AT-MSC/kg of recipient's body weight. Potential adverse effects related to cell infusion and clinical outcome were assessed. Additional parameters analyzed included changes in imaging, analytical and inflammatory parameters. Findings: First dose of AT-MSC was administered at a median of 7 days (IQR 12 days) after mechanical ventilation. No adverse events were related to cell therapy. With a median follow-up of 16 days (IQR 9 days) after the first dose, clinical improvement was observed in nine patients (70%). Seven patients were extubated and discharged from ICU while four patients remained intubated (two with an improvement in their ventilatory and radiological parameters and two in stable condition). Two patients died (one due to massive gastrointestinal bleeding unrelated to MSC therapy). Treatment with AT-MSC was followed by a decrease in inflammatory parameters (reduction in C-reactive protein, IL-6, ferritin, LDH and d-dimer) as well as an increase in lymphocytes, particularly in those patients with clinical improvement. Interpretation: Treatment with intravenous administration of AT-MSC in 13 severe COVID-19 pneumonia under mechanical ventilation in a small case series did not induce significant adverse events and was followed by clinical and biological improvement in most subjects. Funding: None.We would like to acknowledge the Instituto de Salud Carlos III (ISCIII) through the project “RD16/0011: Red de Terapia Celular”, from the sub-program RETICS, integrated in the “Plan Estatal de I+D+I 2013-2016” and co-financed by the European Regional Development Fund “A way to make Europe”, groups RD16/0011/0001, -/0002, -/005, -/0013, -/0015, -/0029), the Centro en Red de Medicina Regenerativa y Terapia Celular de Castilla y León, Spain and AvanCell-CM (Red de Investigación de Terapia Celular de la Comunidad de Madrid, Spain), for supporting some personnel and networking activities

Loss of the matrix metalloproteinase-10 causes premature features of aging in satellite cells

© 2023 Bobadilla Muñoz, Orbe, Abizanda, Machado, Vilas, Ullate-Agote, Extramiana, Baraibar Churio, Aranguren, Cantero, Sáinz Amillo, Rodríguez, Ramos García, Romero Riojas, Vallejo-Illarramendi, Paradas, López de Munain, Páramo, Prósper and Pérez-Ruiz. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Aged muscles accumulate satellite cells with a striking decline response to damage. Although intrinsic defects in satellite cells themselves are the major contributors to aging-associated stem cell dysfunction, increasing evidence suggests that changes in the muscle-stem cell local microenvironment also contribute to aging. Here, we demonstrate that loss of the matrix metalloproteinase-10 (MMP-10) in young mice alters the composition of the muscle extracellular matrix (ECM), and specifically disrupts the extracellular matrix of the satellite cell niche. This situation causes premature features of aging in the satellite cells, contributing to their functional decline and a predisposition to enter senescence under proliferative pressure. Similarly, reduction of MMP-10 levels in young satellite cells from wild type animals induces a senescence response, while addition of the protease delays this program. Significantly, the effect of MMP-10 on satellite cell aging can be extended to another context of muscle wasting, muscular dystrophy. Systemic treatment of mdx dystrophic mice with MMP-10 prevents the muscle deterioration phenotype and reduces cellular damage in the satellite cells, which are normally under replicative pressure. Most importantly, MMP-10 conserves its protective effect in the satellite cell-derived myoblasts isolated from a Duchenne muscular dystrophy patient by decreasing the accumulation of damaged DNA. Hence, MMP-10 provides a previously unrecognized therapeutic opportunity to delay satellite cell aging and overcome satellite cell dysfunction in dystrophic muscles.This work was supported by Red de Terapia Celular (TerCel) RD16-0011-0005 Instituto de Salud Carlos III convocatoria 2016, Convocatoria de Redes Temáticas Cooperativas de Investigación en Salud; CIBERONC; Instituto de Salud Carlos III-FEDER, CIBERONC, Fondo de Investigaciones Sanitarias (PI18/01152), (PI19/00065), and CIBERCV (CB16/11/00371). GC is supported by a postdoctoral fellowship funded by Consejería de Salud y Familias, Junta de Andalucía and Programa Operativo Fondo Social Europeo de Andalucía 2014-2020 (RH0046-2020).Peer reviewe

AG5 is a potent non-steroidal anti-inflammatory and immune regulator that preserves innate immunity

12 pages, 5 figures.-- This is an open access article under the CC BY-NC-ND licenseAn archetypal anti-inflammatory compound against cytokine storm would inhibit it without suppressing the innate immune response. AG5, an anti-inflammatory compound, has been developed as synthetic derivative of andrographolide, which is highly absorbable and presents low toxicity. We found that the mechanism of action of AG5 is through the inhibition of caspase-1. Interestingly, we show with in vitro generated human monocyte derived dendritic cells that AG5 preserves innate immune response. AG5 minimizes inflammatory response in a mouse model of lipopolysaccharide (LPS)-induced lung injury and exhibits in vivo anti-inflammatory efficacy in the SARS-CoV-2-infected mouse model. AG5 opens up a new class of anti-inflammatories, since contrary to NSAIDs, AG5 is able to inhibit the cytokine storm, like dexamethasone, but, unlike corticosteroids, preserves adequately the innate immunity. This is critical at the early stages of any naïve infection, but particularly in SARS-CoV-2 infections. Furthermore, AG5 showed interesting antiviral activity against SARS-CoV-2 in humanized miceThis work has been supported by NextGenerationEU Recovery and Resilience Facility (RRF) through the PTI+ Global Health Platform of Spanish National Research Council, grants SGL2103023 (PBA), SGL2103053 (MMA) and SGL2103015 (MM); by Spanish National Research Council through the program “Ayudas extraodinarias a proyectos de investigacion en el marco de las medidas urgentes extraodinarias para hacer frente al impacto económico y social del COVID-19”, grants CSIC-COV19-093 (PBA) and CSIC-COV19-117 (MM); by Generalitat Valenciana through the program “Ayudas urgentes para proyectos de investigación, desarrollo tecnológico e innovación (I+D+i) por la COVID-19”, grant GVA-COVID19/2021/059 (PBA); by the Conference of Rectors of the Spanish Universities, Spanish National Research Council and Banco Santander through the FONDO SUPERA COVID-19, grant CAPriCORn (JSM, JMB); by Severo Ochoa center of excellence program (grant CEX2021-001230-S) (PBA)Peer reviewe

Fractionated initial infusion and booster dose of ARI0002h, a humanised, BCMA-directed CAR T-cell therapy, for patients with relapsed or refractory multiple myeloma (CARTBCMA-HCB-01): a single-arm, multicentre, academic pilot study

[Background]: Chimeric antigen receptor (CAR) T-cell therapy is a promising option for patients with heavily treated multiple myeloma. Point-of-care manufacturing can increase the availability of these treatments worldwide. We aimed to assess the safety and activity of ARI0002h, a BCMA-targeted CAR T-cell therapy developed by academia, in patients with relapsed or refractory multiple myeloma.[Methods]: CARTBCMA-HCB-01 is a single-arm, multicentre study done in five academic centres in Spain. Eligible patients had relapsed or refractory multiple myeloma and were aged 18–75 years; with an Eastern Cooperative Oncology Group performance status of 0–2; two or more previous lines of therapy including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 antibody; refractoriness to the last line of therapy; and measurable disease according to the International Myeloma Working Group criteria. Patients received an initial fractionated infusion of 3 × 106 CAR T cells per kg bodyweight in three aliquots (0·3, 0·9, and 1·8 × 106 CAR-positive cells per kg intravenously on days 0, 3, and 7) and a non-fractionated booster dose of up to 3 × 106 CAR T cells per kg bodyweight, at least 100 days after the first infusion. The primary endpoints were overall response rate 100 days after first infusion and the proportion of patients developing cytokine-release syndrome or neurotoxic events in the first 30 days after receiving treatment. Here, we present an interim analysis of the ongoing trial; enrolment has ended. This study is registered with ClinicalTrials.gov, NCT04309981, and EudraCT, 2019-001472-11.[Findings]: Between June 2, 2020, and Feb 24, 2021, 44 patients were assessed for eligibility, of whom 35 (80%) were enrolled. 30 (86%) of 35 patients received ARI0002h (median age 61 years [IQR 53–65], 12 [40%] were female, and 18 [60%] were male). At the planned interim analysis (cutoff date Oct 20, 2021), with a median follow-up of 12·1 months (IQR 9·1–13·5), overall response during the first 100 days from infusion was 100%, including 24 (80%) of 30 patients with a very good partial response or better (15 [50%] with complete response, nine [30%] with very good partial response, and six [20%] with partial response). Cytokine-release syndrome was observed in 24 (80%) of 30 patients (all grade 1–2). No cases of neurotoxic events were observed. Persistent grade 3–4 cytopenias were observed in 20 (67%) patients. Infections were reported in 20 (67%) patients. Three patients died: one because of progression, one because of a head injury, and one due to COVID-19.[Interpretation]: ARI0002h administered in a fractioned manner with a booster dose after 3 months can provide deep and sustained responses in patients with relapsed or refractory multiple myeloma, with a low toxicity, especially in terms of neurological events, and with the possibility of a point-of-care approach.This work has been supported in part by grants from the Instituto de Salud Carlos III (cofunded by the EU), Spanish Ministry of Health (ICI19/00025, FIS PI18/00775, PI19/00669, and PI22/00647), complementary grant for CONCORD-023, RICORS-TERAV network (RD21/0017/0009 and RD21/0017/0019), Red de Terapia Celular TERCEL (RD16/0011/0005), Fondo Europeo de Desarrollo Regional (FEDER), 2017SGR00792 (AGAUR; Generalitat de Catalunya), Centro de Investigación Biomédica en Red de Cáncer CIBERONC (CB16/12/00369 and CB16/12/00489), La Caixa Foundation (CP042702/LCF/PR/GN18/50310007), Asociación Española Contra el Cancer (AECC) LABAE21971FERN, and Fundació Bosch I Aymerich support. AOC received funding from the resident grant Ajut Clínic-La Pedrera 2019, granted by Hospital Clínic de Barcelona.Peer reviewe

In vivo screening characterizes chromatin factor functions during normal and malignant hematopoiesis

Bulk ex vivo and single-cell in vivo CRISPR knockout screens are used to characterize 680 chromatin factors during mouse hematopoiesis, highlighting lineage-specific and normal and leukemia-specific functions. Cellular differentiation requires extensive alterations in chromatin structure and function, which is elicited by the coordinated action of chromatin and transcription factors. By contrast with transcription factors, the roles of chromatin factors in differentiation have not been systematically characterized. Here, we combine bulk ex vivo and single-cell in vivo CRISPR screens to characterize the role of chromatin factor families in hematopoiesis. We uncover marked lineage specificities for 142 chromatin factors, revealing functional diversity among related chromatin factors (i.e. barrier-to-autointegration factor subcomplexes) as well as shared roles for unrelated repressive complexes that restrain excessive myeloid differentiation. Using epigenetic profiling, we identify functional interactions between lineage-determining transcription factors and several chromatin factors that explain their lineage dependencies. Studying chromatin factor functions in leukemia, we show that leukemia cells engage homeostatic chromatin factor functions to block differentiation, generating specific chromatin factor-transcription factor interactions that might be therapeutically targeted. Together, our work elucidates the lineage-determining properties of chromatin factors across normal and malignant hematopoiesis

Supplementary Figure S1 from Biomarkers of Efficacy and Safety of the Academic BCMA-CART ARI0002h for the Treatment of Refractory Multiple Myeloma [Dataset]

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. 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. 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. Despite deep and sustained responses achieved with ARI0002h, we identified several biomarkers that correlate with poor outcomes.Instituto de Salud Carlos III (ISCIII) 'la Caixa' Foundation ('la Caixa') Fundación Científica Asociación Española Contra el Cáncer (AECC)Peer reviewe

LncRNAs: Novel therapeutic targets to treat Multiple Myeloma with RNA-based therapies

Insights into B-cell development and plasma cell biology are essential for understanding the disease known as Multiple Myeloma (MM). The differentiation from a precursor cell into a terminally differentiated, antibody producing plasma cell (PC) is a complex and tightly regulated process, guided by maturation-specific transcriptional programs and external cues such as cytokines present in the bone marrow and secondary lymphoid organs1,2. B lymphocytes develop in the bone marrow (BM) from precursor hematopoietic stem cells (HSC) (Figure 1A), which are the origin of all blood cells3 HSCs differentiate into common lymphoid progenitors that commit to the B-cell lineage due to the expression of lineage-specific transcription factors such as EBF1, PAX5 and E2A3,4. Early BM-dependent stages of B-cell development are structured along the functional rearrangement of immunoglobulin genes, where heavy chain (H- chain) VH-DH-JH segments and light-chain (L-chain) VL-JL segments are rearranged. Finally, early B-cell development is finalized when immature B-cells expressing IgM molecules leave the BM and migrate to secondary lymphoid organs where they further differentiate into Naïve (NBC), follicular or marginal zone B cells1,5. Naïve B cells circulate through peripheral blood and the lymphatic system and enter secondary lymphoid tissues where they can be activated upon exogenous antigen encountering and T cell interaction1,6. Activated B cells can either develop directly into extrafollicular short-lived plasma cells or can mature into germinal center (GC) precursor B-cells6,7. GC microenvironments are formed by proliferating B cells in the follicles of peripheral lymphoid tissues, and are the main site of antibody diversification and affinity maturation (Figure 1B) 6,7. In GCs, B cells are subjected to repeated rounds of somatic hypermutation (SHM) and affinity selection, together with the class-switch recombination (CSR) of heavy chain isotypes, resulting in progressive increase of antibody affinity during immune responses6,7. In brief, SHM is a process that modifies the immunoglobulin variable region (IgV) of the rearranged antibody genes during an immune response, creating a repertoire of diverse B cell receptors whose affinity is “tested” and the best ones are selected. On the other hand, CSR is an irreversible somatic recombination mechanism by which B cells change their immunoglobulin heavy chain expression to gain distinct effector functions6 Finally, clonally selected high-affinity antibody producing GC B cells are terminally differentiated into memory B cells or PCs6,7. Mature PCs are specialized in the production and secretion of high amounts of protective high-affinity antibodies, and they migrate to the BM to turn into long-lived PCs and become central elements of the adaptive immune system1,4. In contrast, the mechanisms that drive memory B cell development are less clear, but they comprise a group of pathogen-experienced cells which are rapidly reactivated upon re- infection4,8