RESUMEN
Chimeric Antigen Receptor T-cell (CAR T-cell) therapy is an effective treatment for relapsed/refractory (R/R) large B cell lymphoma (LBCL). However, patients with central nervous system (CNS) lymphoma were excluded in most of the CAR T-cell therapy trials. This meta-analysis assesses the efficacy with CAR T-cell therapy in LBCL patients with CNS involvement. Two reviewers independently searched PubMed and Cochrane Library to identify all published literature associated with United States Food and Drug Administration approved CAR T-cell therapies for LBCL. Patients with CNS LBCL were included. Meta-analysis of proportion was performed to evaluate the overall response (ORR), complete response (CR) for efficacy, and cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome for safety assessment. Nineteen studies were qualified for inclusion with 141 CNS LBCL patients. The ORR and CR rates were 61% and 55% respectively. The median overall survival (OS) was 8.8 months, and the median progression free survival (PFS) was 4.4 months. Severe immune effector cell-associated neurotoxicity syndrome (grade≥3) were reported in 25% (32/130) patients and severe cytokine release syndrome (grade≥3) were found in 10% (13/124) of the patients. The safety and efficacy of CAR T-cell therapy in CNS LBCL patients appears comparable to patients without CNS involvement.
Asunto(s)
Neoplasias del Sistema Nervioso Central , Inmunoterapia Adoptiva , Linfoma de Células B Grandes Difuso , Humanos , Inmunoterapia Adoptiva/métodos , Inmunoterapia Adoptiva/efectos adversos , Linfoma de Células B Grandes Difuso/terapia , Linfoma de Células B Grandes Difuso/inmunología , Neoplasias del Sistema Nervioso Central/terapia , Neoplasias del Sistema Nervioso Central/inmunología , Neoplasias del Sistema Nervioso Central/mortalidad , Receptores Quiméricos de Antígenos , Resultado del Tratamiento , MasculinoRESUMEN
The treatment landscape of multiple myeloma (MM) has evolved considerably with the FDA-approval of at least 15 drugs over the past two decades. Together with the use of autologous stem cell transplantation, these novel therapies have resulted in significant survival benefit for patients with MM. In particular, our improved understanding of the BM and immune microenvironment has led to the development of highly effective immunotherapies that have demonstrated unprecedented response rates even in the multiple refractory disease setting. However, MM remains challenging to treat especially in a high-risk setting. A key mediator of therapeutic resistance in MM is the bone marrow (BM) microenvironment; a deeper understanding is necessary to facilitate the development of therapies that target MM in the context of the BM milieu to elicit deeper and more durable responses with the ultimate goal of long-term control or a cure of MM. In this review, we discuss our current understanding of the role the BM microenvironment plays in MM pathogenesis, with a focus on its immunosuppressive nature. We also review FDA-approved immunotherapies currently in clinical use and highlight promising immunotherapeutic approaches on the horizon.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Mieloma Múltiple , Humanos , Mieloma Múltiple/tratamiento farmacológico , Médula Ósea/patología , Microambiente Tumoral , Trasplante AutólogoRESUMEN
The U.S. Food and Drug Administration (FDA) approved 6 CAR T cell (CAR-T) products, including tisagenlecleucel (tisa-cel), axicabtagene ciloleucel (axi-cel), brexucabtagene autoleucel (brexu-cel), lisocabtagene maraleucel (liso-cel), idecabtagene vicleucel (ide-cel), and ciltacabtagene autoleucel (cilta-cel) in the last 5 years. CAR T-cell therapy significantly improved outcomes for patients with B-cell non-Hodgkin lymphoma (NHL) and multiple myeloma (MM). However, recurrence and progression may occur after the initial response due to multiple mechanisms (Zeng and Zhang, 2022) [1]. Furthermore, CAR T-cell therapy is not broadly utilized in solid tumors due to various barriers. This review discusses the evolution of CAR T-cell therapies and how the "younger-generation" CAR T cells counteract these challenges to potentially broaden their applications in the future.
Asunto(s)
Linfoma de Células B Grandes Difuso , Mieloma Múltiple , Receptores Quiméricos de Antígenos , Humanos , Inmunoterapia Adoptiva , Mieloma Múltiple/terapia , Linfocitos TRESUMEN
BACKGROUND AND OBJECTIVE: CAR T-cell therapy has significantly improved the outcomes of patients with relapsed or refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL). However, most clinical trials excluded patients with central nervous system (CNS) involvement due to uncertain efficacy and safety. MATERIAL AND METHODS: On January 1, 2022, we searched PubMed to identify all published literature associated with current commercial CAR T-cell therapies for B-NHL, including tisagenlecleucel (tisa-cel), axicabtagene ciloleucel (axi-cel), brexucabtagene autoleucel (brexu-cel), and lisocabtagene maraleucel (liso-cel). Studies that involved patients with either primary or secondary CNS lymphoma, and evaluated response rate, adverse events (AEs), or survival were included and summarized. RESULT: Herein, we summarize the results of 11 studies qualified for our inclusion criteria, reporting 58 lymphoma patients with CNS Involvement with 44 evaluable for clinical response, 25 for immune effector cell-associated neurotoxicity syndrome (ICANS) and 48 for Cytokine release syndrome (CRS). Objective response was achieved in 62% (16/26) of patients, and CR was achieved in 52% (23/44) of patients. Forty-four percent (11/25) developed ICANS, and 35% (17/48) developed severe ICANS (grade≥3). CRS was reported in 63% (15/24) of patients, while severe CRS (grade≥3) was reported in 7% (3/42) of patients. CONCLUSION: Based on our PubMed literature review, we conclude that CAR T-cell therapy may benefit patients with CNS lymphoma with promising response rates and acceptable AE. However, definite conclusions cannot be drawn until data with a larger sample size is available.
Asunto(s)
Linfoma de Células B Grandes Difuso , Linfoma , Receptores Quiméricos de Antígenos , Humanos , Inmunoterapia Adoptiva/efectos adversos , Linfoma/terapia , Síndrome de Liberación de Citoquinas , Sistema Nervioso Central , Linfocitos T , Linfoma de Células B Grandes Difuso/terapia , Receptores de Antígenos de Linfocitos TRESUMEN
Chimeric antigen receptor (CAR) T-cells targeting CD19 have drastically improved the outcomes of B-cell malignancies; however, the success has not yet extended to myeloid malignancies such as acute myeloid leukemia (AML). Main impediments in the development of CAR T therapy in AML include difficulty in identifying appropriate target antigens that are specific to myeloid leukemia stem cells while sparing the healthy hematopoietic stem progenitor cells (HSPCs). Herein, we discuss the current state of CAR T-cell therapy in AML, highlighting recent progress and limitations in clinical translation. We also discuss novel approaches in CAR T therapy development and potential strategies to enhance anti-leukemic activity while minimizing toxicity to heathy cells to make CAR T-cell therapy a viable option for patients with AML.
Asunto(s)
Leucemia Mieloide Aguda , Receptores Quiméricos de Antígenos , Humanos , Inmunoterapia Adoptiva , Linfocitos T , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/patología , Tratamiento Basado en Trasplante de Células y TejidosRESUMEN
Chimeric antigen receptor T (CAR T) cell therapy has revolutionized the management of lymphoid malignancies. However, it is still in its early phase and is facing many obstacles in solid tumors. Therapeutic challenges in solid tumor lead to tumor target diversification and drive new innovations for the improvement of clinical efficacy. This review showcases early clinical works and sheds light on the most notable successes, drawbacks, and strategies employed to allow CAR T therapy to go full speed ahead.
Asunto(s)
Neoplasias , Receptores Quiméricos de Antígenos , Humanos , Linfocitos T , Neoplasias/terapia , Inmunoterapia Adoptiva , Tratamiento Basado en Trasplante de Células y Tejidos , Receptores de Antígenos de Linfocitos T/genéticaRESUMEN
Autologous chimeric antigen receptor (CAR) T cell therapy has been extensively studied over the past decades. Currently, autologous CAR T products are FDA-approved to treat B cell acute lymphoblastic leukemia (B-ALL), large B cell, mantle cell, and follicular lymphomas, and multiple myeloma. However, this therapy has drawbacks including higher cost, production lead time, logistical complexity, and higher risk of manufacturing failure. Alternatively, allogeneic CAR T cell therapy, currently under clinical trial, has inherent disadvantages, including cell rejection, graft versus host disease, and undetermined safety and efficacy profiles. Different strategies, including modifying HLA and T cell receptor expression using different effector cells, are under investigation to circumvent these issues. Early allogeneic CAR T therapy results for B-ALL and B-NHL have been promising. Large sample clinical trials are ongoing. Here, we discuss the pros and cons of allo-CAR T for hematologic malignancies and review the latest data on this scalable approach.
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Neoplasias Hematológicas , Trasplante de Células Madre Hematopoyéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Receptores Quiméricos de Antígenos , Humanos , Linfocitos T , Neoplasias Hematológicas/terapia , Neoplasias Hematológicas/metabolismo , Receptores de Antígenos de Linfocitos T/metabolismo , Trasplante de Células Madre Hematopoyéticas/métodosRESUMEN
Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) is a high-risk disease subtype with a dismal prognosis. Inhibiting BCR-ABL kinase alone is insufficient to eradicate Ph+ALL clones, and alternative BCR-ABL-dependent and -independent pathways need to be targeted as an effective strategy. Our study revealed that the combination of dasatinib and interferon-α showed synergistic activity against Ph+ALL, inducing mitochondrial dysfunction and causing necrosis-like cell lysis. Mechanistic studies showed that the induced cell death was caspase-3-independent. Canonical necroptosis signals, such as RIP1 and MLKL, were not activated; instead, the pyroptosis executor Gasdermin D was upregulated expression and activated. The expression levels of extracellular ATP and IL-1ß were also upregulated, both of which are markers of pyroptotic cell death. In a murine Ph+ALL model, the dual drug treatment prolonged the survival of tumor-bearing mice. More importantly, we incorporated the dual drugs to maintenance therapy in 39 patients who were unfit for allogeneic stem cell transplantation (allo-HSCT). The median follow-up was 28.5 months, the 4-year disease-free survival and overall survival rates were 52.2% and 65.2%, respectively. Our data suggest that the combination of dasatinib and interferon-α has potential synergistic activity against Ph+ALL and shows promise as a maintenance therapy for Ph+ALL patients who are unfit for allo-HSCT.
RESUMEN
Multiple myeloma (MM) pathogenesis remains incompletely understood and biomarkers predicting treatment response still remain lacking. Here we describe the rational mechanisms of combining targeting glautaminase1 (GLS1) with other chemo-reagents for MM treatment. Gls1 is highly expressed cMYC/KRAS12V-drived plasmacytoma (PCT) cells. Down-regulation of Gls1 with miRNAi in cMYC/KRAS12V-expressing BaF3 cells prevented them from growing independence of interleukin 3 (IL3). By using our cMYC/KRAS12V-transduced adoptive plasmacytoma mouse model, we found that Gls1 is involved in PCT pathogenesis. Down-regulation of Gls1 significantly prolonged the survival of PCT recipients. Knockdown of Gls1 increased the expression of Cdkn1a and Cdkn1b and decreased the expression of some critical oncogenes for cancer cell survival, such as c-Myc, Cdk4, and NfκB, as well as some genes which are essential for MM cell survival, such as Irf4, Prdm1, Csnk1α1, and Rassf5. Combination of Gls1 inhibition with LBH589, Bortezomib, or Lenalidomide significantly impaired tumor growth in a MM xenograft mouse model. Our data strongly suggest that Gls1 plays an important role for MM pathogenesis and that combination of GLS1 inhibitor with other MM therapy agents could benefit to MM patients.
Asunto(s)
Seno Cavernoso , Humanos , Seno Cavernoso/diagnóstico por imagen , Seno Cavernoso/patología , Neoplasias del Sistema Nervioso Central/complicaciones , Neoplasias del Sistema Nervioso Central/diagnóstico por imagen , Masculino , Imagen por Resonancia Magnética , Femenino , Linfoma/diagnóstico por imagen , Linfoma/complicaciones , Linfoma/diagnóstico , Persona de Mediana Edad , Síndromes del Seno CavernosoRESUMEN
PURPOSE: This study was to perform preclinical evaluation of a novel class I and IIb HDAC-selective inhibitor, purinostat mesylate, for the treatment of Ph+ B-cell acute lymphoblastic leukemia (B-ALL). EXPERIMENTAL DESIGN: Biochemical assays were used to test enzymatic activity inhibition of purinostat mesylate. Ph+ leukemic cell lines and patient cells were used to evaluate purinostat mesylate activity in vitro. BL-2 secondary transplantation Ph+ B-ALL mouse model was used to validate its efficacy, mechanism, and pharmacokinetics properties in vivo. BCR-ABL(T315I)-induced primary B-ALL mouse model and PDX mouse model derived from relapsed Ph+ B-ALL patient post TKI treatment were used to determine the antitumor effect of purinostat mesylate for refractory or relapsed Ph+ B-ALL. Long-term toxicity and hERG blockade assays were used to safety evaluation of purinostat mesylate. RESULTS: Purinostat mesylate, a class I and IIb HDAC highly selective inhibitor, exhibited robust antitumor activity in hematologic cancers. Purinostat mesylate at low nanomolar concentration induced apoptosis, and downregulated BCR-ABL and c-MYC expression in Ph+ leukemia cell lines and primary Ph+ B-ALL cells from relapsed patients. Purinostat mesylate efficiently attenuated Ph+ B-ALL progression and significantly prolonged the survival both in BL-2 secondary transplantation model with clinical patient symptoms of Ph+ B-ALL, BCR-ABL(T315I)-induced primary B-ALL mouse model, and PDX model derived from patients with relapsed Ph+ B-ALL post TKI treatment. In addition, purinostat mesylate possesses favorable pharmacokinetics and low toxicity properties. CONCLUSIONS: Purinostat mesylate provides a new therapeutic strategy for patients with Ph+ B-ALL, including those who relapse after TKI treatment.
Asunto(s)
Apoptosis , Resistencia a Antineoplásicos , Proteínas de Fusión bcr-abl/genética , Inhibidores de Histona Desacetilasas/farmacología , Histona Desacetilasas/química , Mesilatos/farmacología , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Animales , Línea Celular Tumoral , Proliferación Celular , Perros , Inhibidores de Histona Desacetilasas/química , Humanos , Mesilatos/química , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones SCID , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Ratas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The regulation of mRNA translation is of fundamental importance in biological mechanisms ranging from embryonic axis specification to the formation of long-term memory. POS-1 is one of several CCCH zinc-finger RNA-binding proteins that regulate cell fate specification during C. elegans embryogenesis. Paradoxically, pos-1 mutants exhibit striking defects in endo-mesoderm development but have wild-type distributions of SKN-1, a key determinant of endo-mesoderm fates. RNAi screens for pos-1 suppressors identified genes encoding the cytoplasmic poly(A)-polymerase homolog GLD-2, the Bicaudal-C homolog GLD-3, and the protein NEG-1. We show that NEG-1 localizes in anterior nuclei, where it negatively regulates endo-mesoderm fates. In posterior cells, POS-1 binds the neg-1 3' UTR to oppose GLD-2 and GLD-3 activities that promote NEG-1 expression and cytoplasmic lengthening of the neg-1 mRNA poly(A) tail. Our findings uncover an intricate series of post-transcriptional regulatory interactions that, together, achieve precise spatial expression of endo-mesoderm fates in C. elegans embryos.