RESUMEN
Extracellular vesicles (EVs) are membrane-surrounded cellular particles released by virtually any cell type, containing numerous bioactive molecules, including lipids, proteins, and nucleic acids. EVs act as a very efficient intercellular communication system by releasing their content into target cells, thus affecting their fate and influencing several biological processes. EVs are released both in physiological and pathological conditions, including several types of cancers. In hematological malignancies (HM), EVs have emerged as new critical players, contributing to tumor-to-stroma, stroma-to-tumor, and tumor-to-tumor cell communication. Therefore, EVs have been shown to play a crucial role in the pathogenesis and clinical course of several HM, contributing to tumor development, progression, and drug resistance. Furthermore, tumor EVs can reprogram the bone marrow (BM) microenvironment and turn it into a sanctuary, in which cancer cells suppress both the normal hematopoiesis and the immunological antitumor activity, conferring a therapy-resistant phenotype. Due to their physicochemical characteristics and pro-tumor properties, EVs have been suggested as new diagnostic biomarkers, therapeutic targets, and pharmacological nanocarriers. This review aims to provide an update on the pathogenetic contribution and the putative therapeutic utility of EVs in hematological diseases.
Asunto(s)
Vesículas Extracelulares , Neoplasias Hematológicas , Neoplasias , Médula Ósea/patología , Comunicación Celular , Vesículas Extracelulares/metabolismo , Neoplasias Hematológicas/patología , Neoplasias Hematológicas/terapia , Humanos , Neoplasias/patología , Microambiente TumoralAsunto(s)
Receptor del Factor Activador de Células B/genética , Inmunoterapia Adoptiva/métodos , Leucemia de Células B/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Humanos , Receptores Quiméricos de Antígenos/genética , Linfocitos T/inmunología , Células Tumorales CultivadasAsunto(s)
Factor Activador de Células B/análisis , Receptor del Factor Activador de Células B/análisis , Crisis Blástica/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patología , Enfermedad Aguda , Factor Activador de Células B/metabolismo , Receptor del Factor Activador de Células B/metabolismo , Niño , Femenino , Humanos , Masculino , RecurrenciaRESUMEN
Chimeric antigen receptor (CAR)-modified T-cell adoptive immunotherapy is a remarkable therapeutic option proven effective in the treatment of hematological malignancies. In order to optimize cell manufacturing, we sought to develop a novel clinical-grade protocol to obtain CAR-modified cytokine-induced killer cells (CIKs) using the Sleeping Beauty (SB) transposon system. Administration of irradiated PBMCs overcame cell death of stimulating cells induced by non-viral transfection, enabling robust gene transfer together with efficient T-cell expansion. Upon single stimulation, we reached an average of 60% expression of CD123- and CD19- specific 3rd generation CARs (CD28/OX40/TCRzeta). Furthermore, modified cells displayed persistence of cell subsets with memory phenotype, specific and effective lytic activity against leukemic cell lines and primary blasts, cytokine secretion, and proliferation. Adoptive transfer of CD123.CAR or CD19.CAR lymphocytes led to a significant anti-tumor response against acute myelogenous leukemia (AML) and acute lymphoblastic leukemia (ALL) disseminated diseases in NSG mice. Notably, we found no evidence of integration enrichment near cancer genes and transposase expression at the end of the differentiation. Taken all together, our findings describe a novel donor-derived non-viral CAR approach that may widen the repertoire of available methods for T cell-based immunotherapy.
Asunto(s)
Terapia Genética/métodos , Inmunoterapia Adoptiva/métodos , Leucemia/patología , Leucemia/terapia , Receptores de Antígenos de Linfocitos T/metabolismo , Linfocitos T/trasplante , Transposasas/genética , Enfermedad Aguda , Adolescente , Animales , Antígenos CD19/genética , Antígenos CD19/metabolismo , Línea Celular Tumoral , Niño , Preescolar , Terapia Combinada , Femenino , Humanos , Lactante , Subunidad alfa del Receptor de Interleucina-3/genética , Subunidad alfa del Receptor de Interleucina-3/metabolismo , Leucemia/inmunología , Ratones , Ratones Endogámicos NOD , Ratones SCID , Ratones Transgénicos , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/inmunología , Linfocitos T/metabolismo , Transposasas/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Despite the survival of pediatric patients affected by hematological malignancies being improved in the last 20 years by chemotherapy and hematopoietic stem cell transplantation, a significant amount of patients still relapses. Treatment intensification is limited by toxic side effects and is constrained by the plateau of efficacy, while the pipeline of new chemotherapeutic drugs is running short. Therefore, novel therapeutic strategies are essential and researchers around the world are testing in clinical trials immune and gene-therapy approaches as second-line treatments. The aim of this review is to give a glance at these novel promising strategies of advanced medicine in the field of pediatric leukemias. Results from clinical protocols using new targeted "smart" drugs, immunotherapy, and gene therapy are summarized, and important considerations regarding the combination of these novel approaches with standard treatments to promote safe and long-term cure are discussed.