Valentín Ortiz-MaldonadoHospital Clínic de Barcelona · Servicio de Hematología
Valentín Ortiz-Maldonado
Doctor of Medicine
About
77
Publications
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Introduction
MD. PhD degree at the University of Barcelona on adoptive immunotherapy with T lymphocytes with chimeric antigen receptors (CAR-T) for the treatment of malignant hemopathies (2022). Since 2017 involved in the development and implementation at a clinical level of the CAR-T unit program for the treatment of malignant hemopathies at the Hospital Clínic de Barcelona.
Publications
Publications (77)
Objectives
In MOG antibody-associated disease (MOGAD), relapse prevention and the treatment approach to refractory symptoms are unknown. We report a patient with refractory MOGAD treated with CD19-directed CAR T-cells.
Methods
CD19-directed CAR T-cells (ARI-0001) were produced in-house by lentiviral transduction of autologous fresh leukapheresis a...
Hematological toxicity is the most common long-term adverse event after CAR T-cell therapy. Severe cytopenias not resolving over time may result in life-threatening infection or bleeding and the best clinical practice to treat this persisting cytopenias after CAR-T is not well established.
Eleven heavily pretreated patients with B-ALL and prolonged...
Background
This study aimed to describe documented infections associated with postinfusion fever after CAR T-cell therapy and to evaluate daily changes in vital signs, laboratory results, and the National Early Warning Score (NEWS) in patients with and without confirmed bacterial infections following fever onset, with the objective of assisting in...
Simple Summary
At least 40% of treated patients with large B-cell lymphoma do not respond to first-line treatment or experience disease recurrence, and less than 50% of patients respond to second-line salvage immunochemotherapy and can proceed to the historical standard of care of autologous stem-cell transplantation (ASCT). This study aimed to ass...
7544
Background: The activity and safety ofARI0002h, an academic autologous CAR T-cell product with a humanized single chain variable fragment targeting BCMA has been reported in a pilot multicenter clinical trial (CARTBCMA-HCB-01) treating 30 patients (pts) with RRMM (NCT04309981) (Oliver-Caldés, Lancet Onc 2023). Here, we describe results of the...
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 overco...
Several products containing chimeric antigen receptor T cells targeting CD19 (CART19) have been approved for the treatment of patients with relapsed/refractory non‐Hodgkin's lymphoma (NHL) and acute lymphoblastic leukaemia (ALL). Despite very impressive response rates, a significant percentage of patients experience disease relapse and die of progr...
How phenotypic, clonal, and functional heterogeneity of the CAR-T-cells impact clinical outcomes remain understudied. Here, we integrated clonal kinetics with transcriptomic heterogeneity resolved by single-cell omics to explore cellular dynamics response of both non-transduced (CARneg) and transduced (CARpos)T-cells. CARneg and CARposT-cells were...
Lymphodepletion (LD) or conditioning is an essential step in the application of currently used autologous and allogeneic chimeric antigen receptor T-cell (CAR-T) therapies as it maximizes engraftment, efficacy and long-term survival of CAR-T. Its main modes of action are the depletion and modulation of endogenous lymphocytes, conditioning of the mi...
Background: Prognosis of relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (ALL) is poor, particularly after allogeneic hematopoietic cell transplantation (alloHCT). In this setting, several CAR T-cell products targeting CD19 (CART19) have been able to achieve complete response (CR) rates of 70 to 90%. However, a significant proportion...
Introduction. Autologous chimeric antigen receptor (CAR) T-cell therapy targeting CD19 is an effective treatment for relapsed or refractory large B-cell lymphoma (LBCL). Real-world studies have reported improved outcomes in terms of safety and efficacy in comparison with pivotal trials. These differences have been associated to a learning curve in...
Background: Median age at diagnosis of diffuse large B cell lymphoma (DLBCL) patients is 66 years; 40% of patients are diagnosed at an age greater than 70 years. CAR-T cell therapy is approved for the treatment of relapsed/refractory DLBCL patients; however, a deeper understanding of outcomes in patients older than 70 years is needed. Our aim was t...
Introduction
Recent studies have shown the potential implication of sexual disparity on the immune system, emphasizing the significant roles of androgens and estrogens in immune cell function and their potential implications for immune responses and antitumor immunity. Anti-CD19 CART therapy is a new immunotherapy pillar for patients with relapsed/...
Background: We reported the safety and activity ofARI0002h, an academic autologous 4-1BB-based CAR T-cell product with a humanized scFv targeting BCMA in a pilot multicenter clinical trial (CARTBCMA-HCB-01) in 30 patients (pts) with relapsed/refractory multiple myeloma (RRMM) (NCT04309981) (Oliver-Caldés, Lancet Onc 2023). Here, we report results o...
Background: The prognosis of CLL patients that do not respond to targeted therapy is unfavourable, especially in the case of adverse genomic aberrations (e.g. TP53 alterations or complex karyotype) or after transformation to aggressive B lymphoma (Richter transformation, RT). In patients with refractory CLL, anti-CD19 CAR-T (CART19) therapy has ach...
Background
Despite treatment advances, chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) remain incurable. Patients (pts) with concurrent Richter's transformation (RT) have poor prognoses with limited treatment options. Chimeric antigen receptor (CAR) T-cell products targeting CD19 have shown activity in pts with CLL/SLL or RT...
Varnimcabtagene autoleucel (var‐cel) is an academic anti‐CD19 chimeric antigen receptor (CAR) product used for the treatment of non‐Hodgkin lymphoma (NHL) in the CART19‐BE‐01 trial. Here we report updated outcomes of patients with NHL treated with var‐cel. B‐cell recovery was compared with patients with acute lymphoblastic leukaemia (ALL). Forty‐fi...
Background
We described the real‐life epidemiology and causes of infections on the different therapy phases in patients undergoing chimeric antigen receptor (CAR) T‐cells directed towards CD19+ or BCMA+ cells.
Methods
All consecutive patients receiving CAR T‐cell therapy at our institution were prospectively followed‐up. We performed various compa...
Background:
In the pre-chimeric antigen receptor (CAR)-T cell therapy era, the SCHOLAR-1 study identified a group of patients with refractory aggressive B-cell lymphoma (ABCL) with particularly poor prognoses. We recently published our real-world data from Spain, focused on this SHOLAR-1 refractory group, and compared patients who underwent CAR-T...
Objectives
To estimate the readiness of Spanish National Health Service (NHS) hospitals to provide chimeric antigen receptor T cell (CAR-T), and to identify and quantify the different resources needed to provide CAR-T considering three scenarios defined by 10, 25 and 50 patients per centre per year.
Design
Targeted literature review and quantitati...
Background: We described the real-life epidemiology and causes of infections on the different therapy phases in patients with haematological malignancies undergoing chimeric antigen receptor (CAR) T-cells directed towards CD19+ or BCMA+ cells.
Methods: All consecutive patients receiving CAR T-cell therapy at our institution were prospectively follo...
Key Clinical Message
The prognosis of patients with relapsed or refractory (R/R) BL is poor with limited response to salvage therapy, especially for patients with early relapse (<6 months) or refractory disease. Novel therapies may be promising but need refinement.
Abstract
The prognosis of patients with relapsed or refractory (R/R) BL is poor wit...
Objectives:
We aimed to describe the clinical outcomes and duration of viral shedding in high-risk patients with haematological malignancies hospitalized with COVID-19 during Omicron variant predominance who received early treatment with antivirals.
Methods:
We conducted a prospective observational study on high-risk haematological patients admi...
Background
Chimeric antigen receptor (CAR)-T cell-based immunotherapy constitutes a revolutionary advance for treatment of relapsed/refractory hematological malignancies. Nevertheless, cytokine release and immune effector cell-associated neurotoxicity syndromes are life-threatening toxicities in which the endothelium could be a pathophysiological s...
Background:
Chimeric antigen receptor-engineered (CAR) T-cell therapy remains limited by significant toxicities such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). The optimal management of severe and/or refractory CRS/ICANS remains ill-defined. Anakinra has emerged as a promising agent based...
Anti-CD19 chimeric antigen receptor T cells (CART) has rapidly been adopted as the standard third-line therapy to treat aggressive B-cell lymphomas (ABCL) after failure of second-line therapy despite the lack of direct comparisons with allogeneic hematopoietic cell transplantation (alloHCT)-based strategies. Using the Grupo Español de Trasplante y...
Background and Objectives
Data about collection efficiency 1 (CE1), which takes into account blood cell counts before and after collection, thus providing a more accurate estimate, in the collection of autologous T lymphocytes by apheresis for chimeric antigen receptor (CAR) T-cells remain scarce. We evaluated donor- and procedure-related character...
Introduction: Chimeric antigen receptor (CAR) T-cell therapy is a promising immunotherapy for the treatment of refractory hematopoietic malignancies. Adverse events are common, and neurotoxicity is one of the most important. However, the physiopathology is unknown and neuropathologic information is scarce. Materials and methods: Post-mortem examina...
CD19-directed immunotherapies have revolutionized the treatment of advanced B-ALL. Despite initial impressive rates of complete remission (CR) many patients ultimately relapse. The fact that B-ALL patients successfully treated with CD19-directed T-cells eventually relapse, coupled with the early onset of CD22 expression during B-cell development su...
Chimeric antigen receptor T-cells targeting the CD19 antigen have achieved impressive results in patients with relapsed/refractory (R/R) B-cell malignancies, leading to their approval in the European Union and other jurisdictions. In Spain, the 100% academic anti-CD19 CART-cell product varnimcabtagene autoleucel (var-cel, ARI-0001 cells) has been e...
Real-world evidence comparing the efficacy of chimeric antigen receptor (CAR) T-cell therapy against that of the previous standard of care (SOC) for refractory large B-cell lymphoma (LBCL) is scarce. We retrospectively collected data from patients with LBCL according to SCHOLAR-1 criteria treated with commercial CAR T-cell therapy in Spain (204 pat...
Axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) are CD19-targeted chimeric antigen receptor (CAR) T-cells approved for relapsed/refractory (R/R) large B-cell lymphoma (LBCL). We performed a retrospective study to evaluate safety and efficacy of axi-cel and tisa-cel outside the setting of a clinical trial. Data from consecutive pat...
CD19-directed immunotherapies have revolutionized the treatment of advanced B-ALL. Despite initial impressive rates of complete remission (CR) many patients ultimately relapse. B-ALL patients successfully treated with CD19-directed T-cells eventually relapse, which coupled with the early onset of CD22 expression during B-cell development suggests t...
We evaluated outcomes of 18 patients with isolated extramedullary disease (iEMD) relapsed/refractory (R/R) B‐cell acute lymphoblastic leukemia (B‐ALL) treated with the CD19‐directed CAR T cells ARI‐0001 in two centers (adult and pediatric), including patients treated in the CART19‐BE‐01 trial and the consecutive compassionate use program. iEMD was...
CART19 cells are emerging as an alternative therapy for patients with chronic lymphocytic leukemia (CLL). Here we report the outcome of nine consecutive patients with CLL treated with ARI-0001 CART19 cells, six of them with Richter’s transformation (RT). One patient with RT never received therapy. The cytokine release syndrome rate was 87.5% (12.5%...
Multiple myeloma (MM) remains incurable despite the number of novel therapies that have become available in recent years. Occasionally, a patient with MM will develop an amyloid light-chain (AL) amyloidosis with organ dysfunction. Chimeric antigen receptor T-cell (CART) therapy has become a promising approach in treating hematological malignancies....
Introduction.
The prognosis of patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) is poor. Chimeric antigen receptor (CAR) T-cell therapy is approved for R/R DLBCL (≥3 rd line) in Spain since April 2019, based on data from single-arm phase 2 trials that showed complete response (CR) rates between 40-50% and prolonged r...
Background: ARI0002h is an academic lentiviral autologous second-generation CAR T-cell product with a 4-1BB co-stimulatory domain and a humanized single chain variable fragment targeting BCMA. In pre-clinical studies, ARI0002h has demonstrated potent in vitro and in vivo activity. Here, we report the first safety and efficacy results of the CARTBCM...
Introduction: Axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) are the two autologous anti-CD19 chimeric antigen receptors T cells commercially approved in Europe for relapsed/refractory (R/R) DLBCL. We performed a retrospective study to evaluate patients characteristics, efficacy and safety for axi-cel and tisa-cel in a large coho...
Background:
Chimeric antigen receptor-engineered (CAR) T-cell therapy remains associated with significant toxicities including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Recently, the recombinant IL-1 receptor antagonist anakinra has emerged as a promising approach after failure of tocilizuma...
Background
The ongoing Coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is having an enormous impact on society worldwide and is especially posing a threat to health in vulnerable patients, such as patients with immune deficiencies. It is expected that patients who received Ch...
Background
Chimeric antigen receptor (CAR) T-cells directed against CD19 (CART19) are effective in B-cell malignancies, but little is known about the molecular factors predicting clinical outcome of CART19 therapy. The increasingly recognized relevance of epigenetic changes in cancer immunology prompted us to determine the impact of the DNA methyla...
Allogenic hematopoietic stem cell transplantation (allo-HSCT) is one of the standard treatments for B-cell lymphoproliferative disorders; however, deep relapses are common after an allo-HSCT, and it is associated with poor prognosis. A successful approach to overcome these relapses is to exploit the body’s own immune system with chimeric antigen re...
Background
Chimeric antigen receptor (CAR) T-cell therapy can induce side-effects such as cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome (ICANS), which often require intensive care unit admission. The aim of this study was to describe management of critically ill CAR T-cell recipients in intensive care.
Method...
Chimeric antigen receptor (CAR) T-cell therapy is one of the most promising emerging treatments for B-cell malignancies. Recently, two CAR T-cell products (axicabtagene ciloleucel and tisagenlecleucel) have been approved for patients with aggressive B-cell lymphoma and acute lymphoblastic leukemia; many other CAR-T constructs are in research for bo...
The COVID-19 pandemic, caused by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), has generated a significant repercussion on the administration of adoptive cell therapies, including chimeric antigen receptor (CAR) T-cells. The closing of borders, the reduction of people transit and the confinement of the population has affected the su...
Background
Chimeric Antigen Receptor (CAR)-T cells directed against CD19 have induced high rates of response in patients with relapsed/refractory (R/R) B-cell malignancies. Two CD19-targeting constructs have been approved by the FDA and EMA (Yescarta ®, Kymriah ®) for B lymphoblastic leukemia (B-ALL) and aggressive lymphoma. Despite deep remissions...
Development of semi-automated devices that can reduce the hands-on time and standardize the production of clinical-grade CAR T-cells, such as CliniMACS Prodigy from Miltenyi, is key to facilitate the development of CAR T-cell therapies, especially in academic institutions. However, the feasibility of manufacturing CAR T-cell products from heavily p...
Background
Several chimeric antigen receptor products targeting CD19 are either approved or in development for the treatment of acute lymphoblastic leukemia (ALL) and non‐Hodgkin's lymphoma (NHL). Nevertheless, information on infections and immune impairment caused by this procedure (lymphodepletion chemotherapy, neutropenia, B‐cell aplasia and hyp...
Background
Cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS) are major adverse events in patients receiving CART cell therapy. Forecasting the in vivo toxicity of “living drugs” like CART cells is complex and multifactorial. Some of these factors might be disease burden and CART cell dose, so adjusti...
Genetically modifying autologous T cells to express an anti-CD19 chimeric antigen receptor (CAR) has shown impressive response rates for the treatment of CD19+ B cell malignancies in several clinical trials (CTs). Making this treatment available to our patients prompted us to develop a novel CART19 based on our own anti-CD19 antibody (A3B1), follow...
B-cell lymphoma 2 (BCL2)-type proteins are key regulators of the intrinsic or mitochondrial pathway for apoptosis. Since escape from apoptosis is one the main ‘hallmarks of cancer’, BCL2 inhibitors have emerged as promising therapeutic agents for diverse lymphoid malignancies, particularly chronic lymphocytic leukemia (CLL). Multiple clinical trial...
Phosphoinositide 3'-kinase (PI3K) is a key component of both chronic active and tonic B-cell receptor-signalling pathways. As such, PI3K inhibitors have emerged as promising therapeutic agents for diverse lymphoid malignancies, particularly chronic lymphocytic leukaemia. Multiple in vitro experiments and clinical trials have shown efficacy of these...