ABSTRACT
PURPOSE: CAR therapy targeting BCMA is under investigation as treatment for multiple myeloma. However, given the lack of plateau in most studies, pursuing more effective alternatives is imperative. We present the preclinical and clinical validation of a new optimized anti-BCMA CAR (CARTemis-1). In addition, we explored how the manufacturing process could impact CAR-T cell product quality and fitness. METHODS: CARTemis-1 optimizations were evaluated at the preclinical level both, in vitro and in vivo. CARTemis-1 generation was validated under GMP conditions, studying the dynamics of the immunophenotype from leukapheresis to final product. Here, we studied the impact of the manufacturing process on CAR-T cells to define optimal cell culture protocol and expansion time to increase product fitness. RESULTS: Two different versions of CARTemis-1 with different spacers were compared. The longer version showed increased cytotoxicity. The incorporation of the safety-gene EGFRt into the CARTemis-1 structure can be used as a monitoring marker. CARTemis-1 showed no inhibition by soluble BCMA and presents potent antitumor effects both in vitro and in vivo. Expansion with IL-2 or IL-7/IL-15 was compared, revealing greater proliferation, less differentiation, and less exhaustion with IL-7/IL-15. Three consecutive batches of CARTemis-1 were produced under GMP guidelines meeting all the required specifications. CARTemis-1 cells manufactured under GMP conditions showed increased memory subpopulations, reduced exhaustion markers and selective antitumor efficacy against MM cell lines and primary myeloma cells. The optimal release time points for obtaining the best fit product were > 6 and < 10 days (days 8-10). CONCLUSIONS: CARTemis-1 has been rationally designed to increase antitumor efficacy, overcome sBCMA inhibition, and incorporate the expression of a safety-gene. The generation of CARTemis-1 was successfully validated under GMP standards. A phase I/II clinical trial for patients with multiple myeloma will be conducted (EuCT number 2022-503063-15-00).
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BACKGROUND: Kangaroo care (KC) is an evidence-based best practice that can prevent major health complications in preterm infants. However, there is a lack of evidence on the feasibility and safety of placing extremely preterm infants under 28 weeks gestational age in KC position. AIM: To compare thermal stability 60 min after the first KC session in the lateral versus prone position in extremely preterm infants under 28 weeks gestational age. STUDY DESIGN: This is a single-centre, randomized, non-inferiority, parallel clinical trial. The patients were extremely preterm infants during their first 5 days of life. Infants in the intervention group received KC in the lateral position while those in the control group received KC in the prone position. All infants receiving KC were inside their polyethylene bags but maintained skin-to-skin contact. The primary outcome was the axillary temperature of the infants, and the secondary outcome was the development of intraventricular haemorrhage. RESULTS: Seventy infants were randomized (35 per group). The mean gestational age was 26 +1(1+1) in both groups. In the first KC session, the infant temperature at 60 minutes was 36.79°C (0.43) in lateral KC position, and 36.78°C (0.38) in prone KC position (p = .022). In lateral KC position, 7.69% (2) of the children who, according to the cranial ultrasound performed before the first session, had no haemorrhage presented with intraventricular haemorrhage after the first session. In prone KC position, new haemorrhages appeared after the first session in 29.17% (7) (p = .08). CONCLUSIONS: The lateral KC position is an alternative to the conventional prone KC position and maintains normothermia in infants under 28 weeks gestational age. RELEVANCE TO CLINICAL PRACTICE: Extremely preterm infants are candidates for KC. Lateral KC position is an evidence-based best practice that can be applied to preterm infants under 28 weeks GA. This evidence is particularly useful in performing umbilical catheterization on these patients.
ABSTRACT
Acute myeloid leukemia (AML) is an aggressive hematologic malignancy with a poor prognosis despite the advent of novel therapies. Consequently, a major need exists for new therapeutic options, particularly for patients with relapsed/refractory (R/R) AML. In recent years, it has been possible to individualize the treatment of a subgroup of patients, particularly with the emergence of multiple targeted therapies. Nonetheless, a considerable number of patients remain without therapeutic options, and overall prognosis remains poor because of a high rate of disease relapse. In this sense, cellular therapies, especially chimeric antigen receptor (CAR)-T cell therapy, have dramatically shifted the therapeutic options for other hematologic malignancies, such as diffuse large B cell lymphoma and acute lymphoblastic leukemia. In contrast, effectively treating AML with CAR-based immunotherapy poses major biological and clinical challenges, most of them derived from the unmet need to identify target antigens with expression restricted to the AML blast without compromising the viability of the normal hematopoietic stem cell counterpart. Although those limitations have hampered CAR-T cell therapy translation to the clinic, there are several clinical trials where target antigens, such as CD123, CLL-1 or CD33 are being used to treat AML patients showing promising results. Moreover, there are continuing efforts to enhance the specificity and efficacy of CAR-T cell therapy in AML. These endeavors encompass the exploration of novel avenues, including the development of dual CAR-T cells and next-generation CAR-T cells, as well as the utilization of gene editing tools to mitigate off-tumor toxicities. In this review, we will summarize the ongoing clinical studies and the early clinical results reported with CAR-T cells in AML, as well as highlight CAR-T cell limitations and the most recent approaches to overcome these barriers. We will also discuss how and when CAR-T cells should be used in the context of AML.
ABSTRACT
INTRODUCTION: Diffuse interstitial lung disease (ILD) describes a broad group of pulmonary inflammatory and fibrosis disorders. Asbestosis and silicosis are the main causes linked to occupational exposure. The aim of this study was to estimate the proportion of cases with possible occupational origin and describe their exposure, clinical, and occupational status. METHOD: We conducted a retrospective longitudinal study of ILD cases between 2017 - 2022 at the University Hospital of Navarra was conducted. Information was supplemented with interviews of cases with possible occupational origin. The occupational proportion was calculated, labor and clinical characteristics analyzed, by statistical comparison of percentages and means. RESULTS: Out of 1067 ILD cases, 56 had a possible occupational origin 5,2% (95% CI 3,9-6,6%). 36 (64,3%) corresponded to asbestosis, 15 (26,8%) to silicosis, and 5 (8,9%) to unspecified pneumoconiosis. The most frequent activities in silicosis were "stone cutting-carving" and in asbestosis "manufacture of iron products". The average age of asbestosis cases was higher than that of silicosis cases (78,2 vs. 67,3 years), as well as their clinical manifestation. Five cases (8,9%) had been recognized as occupational diseases. CONCLUSIONS: The implementation of a computer tool in medical records has made it possible to estimate the magnitude and assess the evolution of occupational ILD treated in the Public Health Service. Economic activities reflect the economic risk structure of the region. However, there is a lack of recognition of these diseases as occupational illnesses and they represent a preventable burden of respiratory disease.
Introducción: La enfermedad pulmonar intersticial difusa (EPID) describe un amplio grupo de trastornos con inflamación y fibrosis pulmonar. La asbestosis y la silicosis son las principales causas por exposición laboral. El objetivo de este trabajo fue estimar la proporción de casos de posible origen laboral y describir la exposición, situación clínica y laboral. Método: Estudio longitudinal retrospectivo de los casos de EPID, en el período 2017-2022 en el Hospital Universitario de Navarra. Se completó la información con entrevista a los casos de posible origen laboral. Resultados: De un total de 1067 casos de EPID, 56 tuvieron un posible origen laboral, 5,2% (3,9-6,6 IC 95%) 36 (64,3%) correspondieron a asbestosis, 15 (26,8%) a silicosis y 5 (8,9%) a neumoconiosis no especificada. Las actividades más frecuentes en silicosis fueron "corte-tallado de piedra" y para asbestosis "fabricación productos hierro". La media de edad de los casos de asbestosis fue superior a los de silicosis (78,2 vs. 67,3 años), así como su afectación clínica. Cinco casos (8,9%) habían sido reconocidos como enfermedad profesional Conclusiones: La implementación de una herramienta informática en historia clínica ha hecho posible estimar la magnitud y valorar la evolución de las EPID laborales atendidas en el servicio nacional de salud. Las actividades económicas reflejan la estructura económica de riesgo de la región. Sin embargo, existe una falta de su reconocimiento como enfermedad profesional y suponen una carga de enfermedad respiratoria evitable.
Subject(s)
Lung Diseases, Interstitial , Occupational Diseases , Silicosis , Humans , Lung Diseases, Interstitial/epidemiology , Lung Diseases, Interstitial/etiology , Retrospective Studies , Occupational Diseases/epidemiology , Spain/epidemiology , Male , Longitudinal Studies , Aged , Silicosis/epidemiology , Silicosis/complications , Female , Middle Aged , Occupational Exposure/adverse effects , Asbestosis/complications , Asbestosis/epidemiologyABSTRACT
BACKGROUND: non-bismuth sequential therapy (SEQ) was suggested as a first-line anti-Helicobacter pylori treatment alternative to standard triple therapy (STT). METHODS: We conducted a systematic review with a meta-analysis of randomized controlled trials (RCTs) comparing the efficacy of 10-day SEQ vs. STT (of at least 7 days) using bibliographical searches up to July 2021, including treatment-naïve adult or children. The intention-to-treat (ITT) eradication rate and the risk difference (RD) were calculated. RESULTS: Overall, 69 RCTs were evaluated, including 19,657 patients (9486 in SEQ; 10,171 in STT). Overall, SEQ was significantly more effective than STT (82% vs. 75%; RD 0.08; p < 0.001). The results were highly heterogeneous (I2 = 68%), and 38 studies did not demonstrate differences between therapies. Subgroup analyses suggested that patients with clarithromycin resistance only and all geographical areas but South America could benefit more from SEQ. Both therapies have evolved over the years, showing similar results when STT lasted 14 days; however, a tendency toward lower SEQ efficacy was noted from 2010 onwards. CONCLUSIONS: Prior to 2010, SEQ was significantly more effective than STT, notably when 7-day STT was prescribed. A tendency toward lower differences between SEQ and STT has been noted, especially when using 10-day STT. None of the therapies achieved an optimal efficacy and therefore cannot be recommended as a valid first-line H. pylori treatment.
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Unsustainable soil management is one of the drivers of soil degradation, but impact assessment requires the development of indicators. Oribatids might be considered as early indicators of disturbances due to the stability of their community. The aim of this study was to investigate the feasibility of oribatids as bioindicators of sustainable agricultural practices. Under a dry Mediterranean climate, three fertilization experiments - two under a two-crop rotation system and one under maize monoculture and established 12 years earlier - were sampled 3× for oribatid identification during the last annual cropping cycle. The hypothesis was that different nutrient and crop managements affect the number of oribatid species and individuals present, and these parameters could be used as indicators of soil degradation. In total, 18 oribatid species were identified, and 1974 adult individuals were recovered. Maximum abundance was found prior to sowing. Pig slurry (PS) vs. control, and dairy cattle manure (CM) vs. mineral fertilization increased oribatid abundance. This increase was evident when the average applied rates with PS were ca. 2 Mg of organic matter (OM) ha- 1 yr- 1, or higher than ca. 4 Mg OM ha- 1 yr- 1 for CM. When the preceding crop was wheat and PS or CM were used, Oribatula (Zygoribatula) excavata (which reproduces sexually) predominated. In maize monoculture fertilized with CM, Tectocepheus sarekensis and Acrotritia ardua americana (which can reproduce through parthenogenesis) prevailed vs. Oribatula, which indicated a heavily disturbed soil. Under this specific Mediterranean environment, the predominance of certain parthenogenic oribatid species and the number of individuals provide advanced warning on soil degradation.
Subject(s)
Mites , Cattle , Animals , Swine , Soil , Agriculture , Fertilization , Crop ProductionABSTRACT
Purpose: CAR-T cell therapy has proven to be a disruptive treatment in the hematology field, however, less than 50% of patients maintain long-term response and early predictors of outcome are still inconsistently defined. Here, we aimed to optimize the detection of CD19 CAR-T cells in blood and to identify phenotypic features as early biomarkers associated with toxicity and outcomes. Experimental design: In this study, monitoring by flow cytometry and digital PCR (dPCR), and immunophenotypic characterization of circulating CAR-T cells from 48 patients treated with Tisa-cel or Axi-cel was performed. Results: Validation of the flow cytometry reagent for the detection of CAR-T cells in blood revealed CD19 protein conjugated with streptavidin as the optimal detection method. Kinetics of CAR-T cell expansion in blood confirmed median day of peak expansion at seven days post-infusion by both flow cytometry and digital PCR. Circulating CAR-T cells showed an activated, proliferative, and exhausted phenotype at the time of peak expansion. Patients with increased expansion showed more severe CRS and ICANs. Immunophenotypic characterization of CAR-T cells at the peak expansion identified the increased expression of co-inhibitory molecules PD1 and LAG3 and reduced levels of the cytotoxicity marker CD107a as predictors of a better long-term disease control. Conclusions: These data show the importance of CAR-T cells in vivo monitoring and identify the expression of PD1LAG3 and CD107a as early biomarkers of long-term disease control after CAR-T cell therapy.
Subject(s)
Lymphoma, Large B-Cell, Diffuse , Receptors, Chimeric Antigen , Humans , Receptors, Chimeric Antigen/genetics , Kinetics , B-Lymphocytes/pathology , T-Lymphocytes/pathology , Lymphoma, Large B-Cell, Diffuse/pathologyABSTRACT
B-cell maturation antigen (BCMA) is the lead antigen for chimeric antigen receptor (CAR) T-cell therapy in multiple myeloma (MM). A challenge is inter- and intra-patient heterogeneity in BCMA expression on MM cells and BCMA downmodulation under therapeutic pressure. Accordingly, there is a desire to augment and sustain BCMA expression on MM cells in patients that receive BCMA-CAR T-cell therapy. We used all-trans retinoic acid (ATRA) to augment BCMA expression on MM cells and to increase the efficacy of BCMA-CAR T cells in pre-clinical models. We show that ATRA treatment leads to an increase in BCMA transcripts by quantitative reverse transcription polymerase chain reaction and an increase in BCMA protein expression by flow cytometry in MM cell lines and primary MM cells. Analyses with super-resolution microscopy confirmed increased BCMA protein expression and revealed an even distribution of non-clustered BCMA molecules on the MM cell membrane after ATRA treatment. The enhanced BCMA expression on MM cells after ATRA treatment led to enhanced cytolysis, cytokine secretion and proliferation of BCMA-CAR T cells in vitro, and increased efficacy of BCMA-CAR T-cell therapy in a murine xenograft model of MM in vivo (NSG/MM.1S). Combination treatment of MM cells with ATRA and the γ- secretase inhibitor crenigacestat further enhanced BCMA expression and the efficacy of BCMA-CAR T-cell therapy in vitro and in vivo. Taken together, the data show that ATRA treatment leads to enhanced BCMA expression on MM cells and consecutively, enhanced reactivity of BCMA-CAR T cells. The data support the clinical evaluation of ATRA in combination with BCMA-CAR T-cell therapy and potentially, other BCMA-directed immunotherapies.
Subject(s)
Amyloid Precursor Protein Secretases , Immunotherapy, Adoptive , Multiple Myeloma , Tretinoin , Animals , Humans , Mice , B-Cell Maturation Antigen , Multiple Myeloma/therapy , T-Lymphocytes , Tretinoin/pharmacology , Receptors, Chimeric AntigenABSTRACT
El dolor, y la ansiedad que este produce, son las primeras causas de sufrimiento en los niños que acuden a los servicios de urgencias, motivando un aumento del interés de padres y sanitarios para proporcionar una adecuada analgesia y sedación.Por ello, en los últimos años se ha producido un incremento en el número de procedimientos diagnósticos y terapéuticos en niños que requieren sedoanalgesia en urgencias pediátricas, lo que ha originado una necesidad de formación de personal no anestesiólogo para cubrir ese requisito sin afectar a la seguridad del paciente.El objetivo de este documento de consenso es establecer recomendaciones basadas en la evidencia científica, elaboradas y consensuadas por el Grupo de Trabajo de Sedoanalgesia de la Sociedad Española de Urgencias de Pediatría, sobre las competencias y la capacitación del personal que realiza procedimientos de sedoanalgesia para conseguir un óptimo manejo del paciente pediátrico antes, durante y después del procedimiento en los servicios de urgencias pediátricas.El documento de consenso se ha estructurado en dos partes: la primera hace referencia a las competencias del personal no anestesiólogo que realiza procedimientos de sedoanalgesia, y la segunda, a la forma de obtener la capacitación necesaria. Se ha elaborado un listado de preguntas de investigación, se han definido unas palabras clave y se ha realizado una búsqueda bibliográfica desglosando la evidencia disponible. Los resultados se muestran como conclusiones, sometidas a votación anónima por cada uno de los miembros del Grupo de Trabajo. En cada conclusión se indica el porcentaje obtenido en la votación. (AU)
Pain and the anxiety that it produces are the main sources of suffering in children managed in emergency departments, eliciting a growing interest in parents and health care providers in the adequate provision of sedation and analgesia.In consequence, the number of diagnostic and therapeutic procedures that require sedation and/or analgesia in paediatric emergency departments has increased in recent years, which has generated a need to train non-anaesthesiologists on how to provide this care without affecting patient safety.The objective of this document is to establish evidence-based recommendations, developed by consensus by the Working Group on Sedation and Analgesia of the Sociedad Española de Urgencias de Pediatría, regarding the competencies and training of staff who perform sedation or analgesia procedures to achieve the greatest possible quality in the management of paediatric patients before, during and after these procedures in the paediatric emergency care setting.The consensus document has been structured in two parts: the first addresses the competencies of non-anaesthesiologists who perform sedoanalgesia procedures, and the second how to obtain the necessary training. A list of research questions was prepared, keywords defined and a literature search carried out to break down and summarise the available evidence. The results are presented in the form of conclusions, which were subjected to anonymous voting by each of the members of the working group. For each of the conclusions, we provide the percent agreement obtained in the voting. (AU)
Subject(s)
Humans , Male , Female , Infant, Newborn , Infant , Child, Preschool , Child , Adolescent , Anesthesiologists , Analgesia , Conscious Sedation , Anesthesia , Pain Management , Emergency Service, HospitalABSTRACT
Pain and the anxiety that it produces are the main sources of suffering in children managed in emergency departments, eliciting a growing interest in parents and health care providers in the adequate provision of sedation and analgesia. In consequence, the number of diagnostic and therapeutic procedures that require sedation and/or analgesia in paediatric emergency departments has increased in recent years, which has generated a need to train non-anaesthesiologists on how to provide this care without affecting patient safety. The objective of this document is to establish evidence-based recommendations, developed by consensus by the Working Group on Sedation and Analgesia of the Sociedad Española de Urgencias de Pediatría, regarding the competencies and training of staff who perform sedation or analgesia procedures to achieve the greatest possible quality in the management of paediatric patients before, during and after these procedures in the paediatric emergency care setting. The consensus document has been structured in two parts: the first addresses the competencies of non-anaesthesiologists who perform sedoanalgesia procedures, and the second how to obtain the necessary training. A list of research questions was prepared, keywords defined and a literature search carried out to break down and summarise the available evidence. The results are presented in the form of conclusions, which were subjected to anonymous voting by each of the members of the working group. For each of the conclusions, we provide the percent agreement obtained in the voting.
Subject(s)
Analgesia , Conscious Sedation , Humans , Child , Conscious Sedation/methods , Analgesia/methods , Pain Management , Emergency Service, Hospital , PainABSTRACT
BACKGROUND: It is unclear whether the insertion of an axis-orienting double-pigtail plastic stent (DPS) through biliary lumen-apposing meal stent (LAMS) in EUS-guided choledochoduodenostomy (CDS) improves the stent patency. The aim of this study is to determine whether this technical variant offers a clinical benefit in EUS-guided biliary drainage (BD) for the management of distal malignant biliary obstruction. METHODS/DESIGN: This is a multicenter open-label, randomized controlled trial with two parallel groups. Eighty-four patients with malignant biliary obstruction will undergo EUS-BD (CDS type) using LAMS in 7 tertiary hospitals in Spain and will be randomized to the LAMS and LAMS plus DPS groups. The primary endpoint is the rate of recurrent biliary obstruction, as a stent dysfunction parameter, detected during follow-up. Secondary endpoints: technical and clinical success (reduction in bilirubin > 50% within 14 days of stent placement), safety, and others (number of reinterventions, time to biliary obstruction, prognostic factors, survival rate). DISCUSSION: The BAMPI trial has been designed to determine whether the addition of a coaxial axis-orienting DPS through LAMS is superior to LAMS alone to prevent stent dysfunction. TRIAL REGISTRATION: ClinicalTrials.gov NCT04595058 . Registered on October 14, 2020.
Subject(s)
Cholestasis , Endosonography , Cholestasis/diagnostic imaging , Cholestasis/etiology , Cholestasis/surgery , Drainage/methods , Endosonography/methods , Humans , Multicenter Studies as Topic , Randomized Controlled Trials as Topic , Stents , Ultrasonography, Interventional/methodsABSTRACT
El manejo de la infección por Helicobacter pylori en los niños es un dilema permanente en la práctica clínica. A lo largo de los años se han ido creando multitud de interrogantes respecto a los síntomas ligados a la infección, los métodos diagnósticos y los modos de tratamiento, siendo la más controvertida la indicación diagnóstica.En los últimos 10 años el colectivo pediátrico ha dispuesto de una guía elaborada por expertos de las Sociedades de Gastroenterología Pediátrica de Europa (ESPGHAN) y Estados Unidos (NASPGHAN) publicada en 2011 y actualizada en 2017 que nos ha orientado en el manejo de la infección por H.pylori en la edad pediátrica.El presente documento pretende unificar los criterios de indicación de estudio así como las pautas de diagnóstico y tratamiento de la infección por H.pylori en los niños y adolescentes para que puedan ser utilizadas tanto en atención primaria como en la clínica hospitalaria. (AU)
The management of Helicobacter pylori infection in children is a consistent problem in clinical practice. Over the years, many questions have been raised regarding symptoms associated with the infection, the diagnostic methods and type of treatment. What is most controversial is determining the criteria that enable us to initiate and carry out the study in children.In the last 10 years, pediatricians have followed the joint ESPGHAN/NASPGHAN guidelines published in 2011 and updated in 2017 in the management of H.pylori in children.This document aims to unify the study indication criteria as well as the diagnosis and treatment recommendations for H.pylori infection in children and adolescents, so they can be used in both Primary and Hospital care. (AU)
Subject(s)
Humans , Infant, Newborn , Infant , Child, Preschool , Child , Adolescent , Helicobacter pylori , Gastritis , Spain , GastroscopyABSTRACT
The management of Helicobacter pylori infection in children is a consistent problem in clinical practice. Over the years, many questions have been raised regarding symptoms associated with the infection, the diagnostic methods and type of treatment. What is most controversial is determining the criteria that enable us to initiate and carry out the study in children. In the last 10 years, pediatricians have followed the joint ESPGHAN/NASPGHAN guidelines published in 2011 and updated in 2017 in the management of H. pylori in children. This document aims to unify the study indication criteria as well as the diagnosis and treatment recommendations for H. pylori infection in children and adolescents, so they can be used in both Primary and Hospital care.
Subject(s)
Helicobacter Infections , Helicobacter pylori , Adolescent , Child , Helicobacter Infections/diagnosis , HumansABSTRACT
The management of Helicobacter pylori infection in children is a consistent problem in clinical practice. Over the years, many questions have been raised regarding symptoms associated with the infection, the diagnostic methods and type of treatment. What is most controversial is determining the criteria that enable us to initiate and carry out the study in children. In the last 10 years, pediatricians have followed the joint ESPGHAN/NASPGHAN guidelines published in 2011 and updated in 2017 in the management of H.pylori in children. This document aims to unify the study indication criteria as well as the diagnosis and treatment recommendations for H.pylori infection in children and adolescents, so they can be used in both Primary and Hospital care.
ABSTRACT
No disponible
Subject(s)
Humans , Pandemics/ethics , Coronavirus Infections/epidemiology , Refusal to Treat/ethics , Health Priorities/ethics , Surge Capacity/ethics , 36448 , Critical Care/ethics , Decision Making/ethics , Bioethical IssuesABSTRACT
Environmental impacts and consumer concerns have necessitated the study of bio-based materials as alternatives to petrochemicals for packaging applications. The purpose of this review is to summarize synthetic and non-synthetic materials feasible for packaging and textile applications, routes of upscaling, (industrial) applications, evaluation of sustainability, and end-of-life options. The outlined bio-based materials include polylactic acid, polyethylene furanoate, polybutylene succinate, and non-synthetically produced polymers such as polyhydrodyalkanoate, cellulose, starch, proteins, lipids, and waxes. Further emphasis is placed on modification techniques (coating and surface modification), biocomposites, multilayers, and additives used to adjust properties especially for barriers to gas and moisture and to tune their biodegradability. Overall, this review provides a holistic view of bio-based packaging material including processing, and an evaluation of the sustainability of and options for recycling. Thus, this review contributes to increasing the knowledge of available sustainable bio-based packaging material and enhancing the transfer of scientific results into applications.
ABSTRACT
Multiple myeloma (MM) remains an incurable disease regardless of recent advances in the field. Therefore, a substantial unmet need exists to treat patients with relapsed/refractory myeloma. The use of novel agents such as daratumumab, elotuzumab, carfilzomib, or pomalidomide, among others, usually cannot completely eradicate myeloma cells. Although these new drugs have had a significant impact on the prognosis of MM patients, the vast majority ultimately become refractory or can no longer be treated due to toxicity of prior treatment, and thus succumb to the disease. Cellular therapies represent a novel approach with a unique mechanism of action against myeloma with the potential to defeat drug resistance and achieve long-term remissions. Genetic modification of cells to express a novel receptor with tumor antigen specificity is currently being explored in myeloma. Chimeric antigen receptor gene-modified T-cells (CAR T-cells) have shown to be the most promising approach so far. CAR T-cells have shown to induce durable complete remissions in other advanced hematologic malignancies like acute lymphocytic leukemia (ALL) and diffuse large B-cell lymphoma (DLBCL). With this background, significant efforts are underway to develop CAR-based therapies for MM. Currently, several antigen targets, including CD138, CD19, immunoglobulin kappa (Ig-Kappa) and B-cell maturation antigen (BCMA), are being used in clinical trials to treat myeloma patients. Some of these trials have shown promising results, especially in terms of response rates. However, the absence of a plateau is observed in most studies which correlates with the absence of durable remissions. Therefore, several potential limitations such as lack of effectiveness, off-tumor toxicities, and antigen loss or interference with soluble proteins could hamper the efficacy of CAR T-cells in myeloma. In this review, we will focus on clinical outcomes reported with CAR T-cells in myeloma, as well as on CAR T-cell limitations and how to overcome them with next generation of CAR T-cells.