RESUMEN
B-cell lymphoma, clinically, comprises a heterogeneous group of malignancies that encompass various subtypes. CD20 is an optimal target for therapeutic antibodies in B-cell lymphoma immunotherapy since approximately 90% of B-cell malignancies typically exhibit CD20 expression on their surface, while its presence is limited in normal tissues. In this study, we have developed a series of novel non-IgG-like T cell-dependent bispecific antibodies by constructing Fab-FabCH3, referred to as Tandem Antigen-binding Fragment 002 (TFAB002), which specifically target CD20 for the treatment of malignant B-cell lymphoma. TFAB002s display strong binding affinity with CD20 and moderate binding affinity with CD3, thereby triggering target-specific T-cell activation, cytokine release, and tumor cell lysis in vitro. Furthermore, TFAB002s exhibit potent cytotoxicity against B-cell malignancies that express varying levels of CD20. Besides, the TFAB002s show potent pharmacodynamic activity in vivo in the WIL2-S cells CDX mouse model. Collectively, these results underscore the potential of TFAB002s as a highly promising therapeutic approach for selectively depleting CD20-positive B cells, thereby warranting further clinical evaluation as a viable treatment option for CD20-expressing B-cell malignancies.
Asunto(s)
Anticuerpos Biespecíficos , Antígenos CD20 , Fragmentos Fab de Inmunoglobulinas , Linfoma de Células B , Linfocitos T , Animales , Anticuerpos Biespecíficos/farmacología , Anticuerpos Biespecíficos/inmunología , Antígenos CD20/inmunología , Linfoma de Células B/inmunología , Linfoma de Células B/terapia , Linfoma de Células B/tratamiento farmacológico , Ratones , Humanos , Fragmentos Fab de Inmunoglobulinas/inmunología , Linfocitos T/inmunología , Línea Celular Tumoral , Ensayos Antitumor por Modelo de Xenoinjerto , Activación de Linfocitos/inmunología , Activación de Linfocitos/efectos de los fármacos , FemeninoRESUMEN
BACKGROUND: Chimeric antigen receptor (CAR)-T therapy has emerged as a promising treatment for hematologic malignancies. However, cytopenia remains one of the most frequent and challenging adverse effects of this therapy. METHODS: We conducted a retrospective analysis of 26 patients with relapsed/refractory aggressive B-cell lymphoma who received CAR-T therapy at our center. Subsequently, to investigate measures to address cytopenias following CAR-T therapy, we isolated and generated murine CAR-T cells and bone marrow-derived mesenchymal stem cells (MSCs), establishing a murine syngeneic CAR-T therapy model. We assessed the impact of MSC infusion on hematopoietic recovery post-CAR-T therapy by evaluating complete blood count, bone marrow hematopoietic stem cells and their subpopulations, bone marrow histomorphology, and hematopoiesis-related genes. RESULTS: All patients experienced cytopenias to varying degrees, with complete lineage involvement in half of the patients. Grade ≥ 3 cytopenias were observed in 88.46% of the patients. CAR-T therapy was associated with a higher incidence of biphasic, late-onset, or prolonged cytopenias. Survival analysis indicated that neutropenia and lymphopenia tended to be associated with better prognosis, whereas thrombocytopenia tended to be related to poorer outcomes. Through animal experiments, we discovered that MSCs infusion boosted HSCs and their long-term subpopulations, enhancing hematopoietic recovery, particularly in the megakaryocyte lineage, and mitigating bone marrow damage. Importantly, both in vitro and in vivo experiments demonstrated that MSCs did not compromise the activity or antitumor efficacy of CAR-T cells. CONCLUSIONS: Our findings propose MSCs infusion as a promising strategy to address cytopenias, particularly thrombocytopenia, after CAR-T therapy. This approach could help overcome certain limitations of cellular immunotherapy by enhancing hematopoietic recovery without compromising the efficacy of CAR-T cells. HIGHLIGHTS: 1 Cytopenia is a frequently observed adverse effect following CAR-T therapy, and it is often characterized by biphasic and prolonged patterns. 2 MSCs play a critical role in promoting hematopoietic recovery and mitigating bone marrow damage in a murine model of CAR-T therapy 3 The activity and antitumor efficacy of CAR-T cells were not impaired by MSCs.
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Inmunoterapia Adoptiva , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas , Receptores Quiméricos de Antígenos , Animales , Humanos , Ratones , Masculino , Femenino , Persona de Mediana Edad , Inmunoterapia Adoptiva/métodos , Inmunoterapia Adoptiva/efectos adversos , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/metabolismo , Adulto , Trasplante de Células Madre Mesenquimatosas/métodos , Receptores Quiméricos de Antígenos/metabolismo , Anciano , Estudios Retrospectivos , Trombocitopenia/terapia , Hematopoyesis , Linfoma de Células B/terapia , Células Madre Hematopoyéticas/metabolismo , Células Madre Hematopoyéticas/citología , Neutropenia/terapia , CitopeniaAsunto(s)
Antineoplásicos Inmunológicos , Inmunoterapia Adoptiva , Linfoma de Células B , Linfoma de Células T , Neoplasias Primarias Secundarias , Humanos , Antineoplásicos Inmunológicos/administración & dosificación , Antineoplásicos Inmunológicos/efectos adversos , Productos Biológicos/administración & dosificación , Productos Biológicos/efectos adversos , Síndrome de Liberación de Citoquinas/inmunología , Herpesvirus Humano 4/aislamiento & purificación , Inmunoterapia Adoptiva/efectos adversos , Inmunoterapia Adoptiva/métodos , Linfoma de Células B/inmunología , Linfoma de Células B/terapia , Linfoma de Células B/virología , Linfoma de Células T/diagnóstico , Linfoma de Células T/inmunología , Neoplasias Primarias Secundarias/diagnóstico , Neoplasias Primarias Secundarias/inmunología , Receptores Quiméricos de Antígenos/inmunología , RiesgoAsunto(s)
Antineoplásicos Inmunológicos , Hematopoyesis Clonal , Inmunoterapia Adoptiva , Linfoma de Células B , Linfoma de Células T , Neoplasias Primarias Secundarias , Humanos , Inmunoterapia Adoptiva/efectos adversos , Linfoma de Células T/diagnóstico , Linfoma de Células T/genética , Linfoma de Células T/inmunología , Neoplasias Primarias Secundarias/diagnóstico , Neoplasias Primarias Secundarias/genética , Neoplasias Primarias Secundarias/inmunología , Receptores Quiméricos de Antígenos/inmunología , Riesgo , Hematopoyesis Clonal/genética , Hematopoyesis Clonal/inmunología , Linfoma de Células B/genética , Linfoma de Células B/inmunología , Linfoma de Células B/terapia , Linfoma de Células B/virología , Herpesvirus Humano 4/aislamiento & purificación , Antineoplásicos Inmunológicos/administración & dosificación , Antineoplásicos Inmunológicos/efectos adversos , Productos Biológicos/administración & dosificación , Productos Biológicos/efectos adversos , Síndrome de Liberación de Citoquinas/genética , Síndrome de Liberación de Citoquinas/inmunologíaRESUMEN
CAR T-cells is an innovative treatment for relapsed/refractory aggressive B cell lymphomas, initially proposed as third-line therapy and beyond, now allowed as soon as second-line treatment for patients with early relapse after first-line treatment. FDG PET/CT remains the modality of choice to evaluate response to this therapeutic strategy, to detect or confirm treatment failure, and allow for salvage therapy if needed. Correct classification of patients regarding response is thus of the utmost importance. In many cases, metabolic response follows classical known patterns, and Deauville score and Lugano criteria yield accurate characterization of patient status. However, given its specific mode of action, it can result in delayed response or atypical patterns of response. We report here a few examples of response from our experience to illustrate the existence of tricky cases. These atypical cases require multidisciplinary management, with clinical, biological, imaging, and pathological work-up.
Asunto(s)
Fluorodesoxiglucosa F18 , Inmunoterapia Adoptiva , Tomografía Computarizada por Tomografía de Emisión de Positrones , Humanos , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Inmunoterapia Adoptiva/métodos , Masculino , Persona de Mediana Edad , Femenino , Recurrencia Local de Neoplasia/diagnóstico por imagen , Linfoma de Células B/terapia , Linfoma de Células B/diagnóstico por imagen , Linfoma de Células B Grandes Difuso/terapia , Linfoma de Células B Grandes Difuso/diagnóstico por imagen , Anciano , Adulto , Radiofármacos , Receptores Quiméricos de Antígenos , Resultado del TratamientoRESUMEN
Background: The non-viral production of CAR-T cells through electroporation of transposon DNA plasmids is an alternative approach to lentiviral/retroviral methods. This method is particularly suitable for early-phase clinical trials involving novel types of CAR-T cells. The primary disadvantage of non-viral methods is the lower production efficiency compared to viral-based methods, which becomes a limiting factor for CAR-T production, especially in chemotherapy-pretreated lymphopenic patients. Methods: We describe a good manufacturing practice (GMP)-compliant protocol for producing CD19 and CD123-specific CAR-T cells based on the electroporation of transposon vectors. The lymphocytes were purified from the blood of patients undergoing chemotherapy for B-NHL or AML and were electroporated with piggyBac transposon encoding CAR19 or CAR123, respectively. Electroporated cells were then polyclonally activated by anti-CD3/CD28 antibodies and a combination of cytokines (IL-4, IL-7, IL-21). The expansion was carried out in the presence of irradiated allogeneic blood-derived mononuclear cells (i.e., the feeder) for up to 21 days. Results: Expansion in the presence of the feeder enhanced CAR-T production yield (4.5-fold in CAR19 and 9.3-fold in CAR123). Detailed flow-cytometric analysis revealed the persistence of early-memory CAR-T cells and a low vector-copy number after production in the presence of the feeder, with no negative impact on the cytotoxicity of feeder-produced CAR19 and CAR123 T cells. Furthermore, large-scale manufacturing of CAR19 carried out under GMP conditions using PBMCs obtained from B-NHL patients (starting number=200x10e6 cells) enabled the production of >50x10e6 CAR19 in 7 out of 8 cases in the presence of the feeder while only in 2 out of 8 cases without the feeder. Conclusions: The described approach enables GMP-compatible production of sufficient numbers of CAR19 and CAR123 T cells for clinical application and provides the basis for non-viral manufacturing of novel experimental CAR-T cells that can be tested in early-phase clinical trials. This manufacturing approach can complement and advance novel experimental immunotherapeutic strategies against human hematologic malignancies.
Asunto(s)
Antígenos CD19 , Elementos Transponibles de ADN , Inmunoterapia Adoptiva , Leucemia Mieloide Aguda , Receptores Quiméricos de Antígenos , Humanos , Inmunoterapia Adoptiva/métodos , Antígenos CD19/inmunología , Antígenos CD19/genética , Receptores Quiméricos de Antígenos/genética , Receptores Quiméricos de Antígenos/inmunología , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/inmunología , Leucemia Mieloide Aguda/genética , Células Nutrientes , Linfoma de Células B/terapia , Linfoma de Células B/inmunología , Linfoma de Células B/genética , Linfocitos T/inmunología , Linfocitos T/metabolismo , Electroporación , Células Alogénicas/inmunologíaRESUMEN
Non-Hodgkin lymphoma (NHL) is a common malignancy in the hematologic system, and traditional therapy has limited efficacy for people with recurrent/refractory NHL (R/R NHL), especially for patients with diffuse large B cell lymphoma (DLBCL). Chimeric antigen receptor (CAR) T-cell therapy is a novel and effective immunotherapy strategy for R/R hematopoietic malignancies, but relapses can occur due to the loss of CAR-T cells in vivo or the loss of antigen. One strategy to avoid antigen loss after CAR-T cell therapy is to target one more antigen simultaneously. Tandem CAR targeting CD19 and CD22 has demonstrated the reliability of tandem CAR-T cell therapy for R/R B-ALL. This study explores the therapeutic potential of tandem CD19/20 CAR-T in the treatment of R/R B cell NHL. The efficacy and safety of autologous CD19/20 CAR-T cells in eleven R/R B cell NHL adult patients were evaluated in an open-label, single-arm trial. Most patients achieved complete response, exhibiting the efficacy and safety of tandem CD19/20 CAR-T cells. The TCR repertoire diversity of CAR-T cells decreased after infusion. The expanded TCR clones in vivo were mainly derived from TCR clones that had increased expression of genes associated with immune-related signaling pathways from the infusion product (IP). The kinetics of CAR-T cells in vivo were linked to an increase in the expression of genes related to immune response and cytolysis/cytotoxicity.
Asunto(s)
Antígenos CD19 , Inmunoterapia Adoptiva , Receptores Quiméricos de Antígenos , Humanos , Masculino , Antígenos CD19/inmunología , Persona de Mediana Edad , Femenino , Inmunoterapia Adoptiva/métodos , Adulto , Receptores Quiméricos de Antígenos/inmunología , Anciano , Linfoma de Células B/terapia , Linfoma de Células B/inmunología , Linfoma no Hodgkin/terapia , Linfoma no Hodgkin/inmunologíaRESUMEN
High upfront cost may be a barrier to adopting chimeric antigen receptor T-cell (CAR-T) therapy for relapsed or refractory B-cell lymphoma. Data on the real-world costs are limited. Using the Blue Cross Blue Shield Axis database, we evaluated 271 commercially insured patients who received CAR-T therapy for B-cell lymphoma (median age = 58 years; men = 68%; diffuse large B-cell lymphoma = 87%; inpatient CAR-T therapy = 85%). Our peri-CAR-T period of interest was from 41 days before to 154 days after CAR-T therapy index divided into seven 28-day intervals. Median total costs were $608â100 (interquartile range, IQR = $534â100-$732â800); 8.5% of patients had total costs exceeding $1 million. The median cost of CAR-T therapy products was $402â500, and the median out-of-pocket copayment was $510. Monthly costs were highest during the month of CAR-T therapy administration (median = $521â500), with median costs below $25â000 in all other 28-day intervals. Costs of CAR-T therapy use were substantial, largely driven by product acquisition. Future studies should examine the relationship between costs, access, and financial outcomes.
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Inmunoterapia Adoptiva , Linfoma de Células B Grandes Difuso , Receptores Quiméricos de Antígenos , Humanos , Inmunoterapia Adoptiva/economía , Masculino , Persona de Mediana Edad , Femenino , Linfoma de Células B Grandes Difuso/terapia , Linfoma de Células B Grandes Difuso/economía , Costos de la Atención en Salud/estadística & datos numéricos , Linfoma de Células B/terapia , Linfoma de Células B/economía , Anciano , Gastos en Salud , Receptores de Antígenos de Linfocitos T/uso terapéuticoAsunto(s)
Inmunoterapia Adoptiva , Linfoma de Células T , Neoplasias Primarias Secundarias , Humanos , Linfocitos B/inmunología , Inmunoterapia Adoptiva/efectos adversos , Linfoma de Células B/epidemiología , Linfoma de Células B/inmunología , Linfoma de Células B/terapia , Receptores Quiméricos de Antígenos/inmunología , Linfocitos T/inmunología , Linfoma de Células T/epidemiología , Linfoma de Células T/inmunología , Incidencia , Factores de Riesgo , Neoplasias Primarias Secundarias/epidemiología , Neoplasias Primarias Secundarias/inmunologíaRESUMEN
CD19-targeted chimeric antigen receptors (CAR) T cells are one of the most remarkable cellular therapies for managing B cell malignancies. However, long-term disease-free survival is still a challenge to overcome. Here, we evaluated the influence of different hinge, transmembrane (TM), and costimulatory CAR domains, as well as manufacturing conditions, cellular product type, doses, patient's age, and tumor types on the clinical outcomes of patients with B cell cancers treated with CD19 CAR T cells. The primary outcome was defined as the best complete response (BCR), and the secondary outcomes were the best objective response (BOR) and 12-month overall survival (OS). The covariates considered were the type of hinge, TM, and costimulatory domains in the CAR, CAR T cell manufacturing conditions, cell population transduced with the CAR, the number of CAR T cell infusions, amount of CAR T cells injected/Kg, CD19 CAR type (name), tumor type, and age. Fifty-six studies (3493 patients) were included in the systematic review and 46 (3421 patients) in the meta-analysis. The overall BCR rate was 56%, with 60% OS and 75% BOR. Younger patients displayed remarkably higher BCR prevalence without differences in OS. The presence of CD28 in the CAR's hinge, TM, and costimulatory domains improved all outcomes evaluated. Doses from one to 4.9 million cells/kg resulted in better clinical outcomes. Our data also suggest that regardless of whether patients have had high objective responses, they might have survival benefits from CD19 CAR T therapy. This meta-analysis is a critical hypothesis-generating instrument, capturing effects in the CD19 CAR T cells literature lacking randomized clinical trials and large observational studies.
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Antígenos CD19 , Inmunoterapia Adoptiva , Receptores Quiméricos de Antígenos , Humanos , Factores de Edad , Antígenos CD19/inmunología , Inmunoterapia Adoptiva/métodos , Leucemia de Células B/terapia , Leucemia de Células B/inmunología , Leucemia de Células B/mortalidad , Linfoma de Células B/inmunología , Linfoma de Células B/terapia , Linfoma de Células B/mortalidad , Receptores de Antígenos de Linfocitos T/inmunología , Receptores Quiméricos de Antígenos/inmunología , Linfocitos T/inmunología , Resultado del TratamientoRESUMEN
ABSTRACT: Little is known about the central nervous system (CNS) risk in high-grade B-cell lymphoma, not otherwise specified (HGBL NOS). Hence, we sought to describe the rates of baseline CNS involvement, risk of CNS recurrence after primary therapy, and management strategies in HGBL NOS. In this multicenter retrospective study, we included 160 adults with newly diagnosed HGBL NOS treated between 2016 and 2021 at 20 US institutions. Eleven patients (7%) had baseline CNS involvement at diagnosis (leptomeningeal = 6, parenchymal = 4, and both = 1). Baseline CNS involvement was significantly associated only with MYC rearrangement (OR = 3.5) and testicular (in men) or female pelvic (in women) involvement (OR = 8.1). There was no significant difference in survival outcomes between patients with HGBL NOS with (median PFS = 4 years) or without (median PFS = 2.4 years) baseline CNS involvement (P = 0.45). The cumulative incidence of CNS recurrence at 3 years was 11%. Patients with baseline CNS involvement were at the highest risk (48.5% vs 8% for those without baseline CNS involvement) and were excluded from the risk factors analysis for CNS recurrence. The risk for CNS recurrence was significantly associated with blood or bone marrow involvement, CD5 expression, non-germinal center B-cell subtype, and "dual-expresser lymphoma" phenotype, however, high CNS IPI was not. The prognosis of relapsed HGBL NOS was poor, regardless of whether recurrence was systemic or limited to the CNS, and with currently available salvage strategies, including autologous transplantation and chimeric antigen receptor T-cell modalities, almost all patients with CNS recurrence ultimately succumbed to their disease.
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Neoplasias del Sistema Nervioso Central , Linfoma de Células B , Humanos , Femenino , Masculino , Persona de Mediana Edad , Adulto , Neoplasias del Sistema Nervioso Central/terapia , Neoplasias del Sistema Nervioso Central/diagnóstico , Neoplasias del Sistema Nervioso Central/mortalidad , Anciano , Estudios Retrospectivos , Linfoma de Células B/terapia , Linfoma de Células B/mortalidad , Linfoma de Células B/patología , Clasificación del Tumor , Anciano de 80 o más Años , Adulto Joven , Pronóstico , Resultado del TratamientoRESUMEN
Primary cutaneous B-cell lymphomas represent a type of non-Hodgkin's lymphoma of the skin without evidence of extracutaneous involvement at the time of diagnosis. According to the 2018 World Health Organization-the European Organization for Research and Treatment of Cancer classification, primary cutaneous B-cell lymphomas include primary cutaneous marginal zone lymphoma, primary cutaneous follicle center lymphoma, primary cutaneous diffuse large B-cell lymphoma, leg type, intravascular large B-cell lymphoma, and Epstein-Barr virus+ mucocutaneous ulcer (provisional). Herein, we provide a comprehensive review of the updated literature on these entities, including clinical presentation, histopathology, immunophenotype, molecular genetics, prognosis, and treatment.
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Neoplasias Cutáneas , Humanos , Neoplasias Cutáneas/terapia , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/diagnóstico , Linfoma de Células B/terapia , Linfoma de Células B/patología , Linfoma de Células B/diagnóstico , Linfoma de Células B/etiología , Pronóstico , Infecciones por Virus de Epstein-Barr/complicaciones , Infecciones por Virus de Epstein-Barr/diagnósticoRESUMEN
Immunotherapy has emerged as a promising approach to cancer treatment that utilizes the potential of the immune system to precisely identify and eradicate cancerous cells. Despite significant progress in immunotherapy, innovative approaches are required to enhance the effectiveness and safety of these treatments. Interleukin-12 (IL-12), widely recognized for its essential function in immune responses, has been explored as a potential candidate for treating cancer. However, early attempts involving the systemic administration of IL-12 were ineffective, with significant adverse effects, thus underscoring the need for innovation. To address these challenges, we developed a therapeutic molecule that utilizes a single-chain IL-12 mutant (IL-12mut) linked to a tumor-targeting arm. Here, we describe the development of a highly effective IL-12-based TMEkine™ platform by employing a B-cell lymphoma model (termed CD20-IL-12mut). CD20-IL-12mut combined the attenuated activities of IL-12 with targeted delivery to the tumor, thereby maximizing therapeutic potential while minimizing off-target effects. Our results revealed that CD20-IL-12mut exhibited potent anticancer activity by inducing complete regression and generating immunological memory for tumor antigens. Collectively, our data provide a basis for additional research on CD20-IL-12mut as a potential treatment choice for patients with B-cell lymphomas such as non-Hodgkin's lymphoma.
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Inmunoterapia , Interleucina-12 , Linfoma de Células B , Interleucina-12/genética , Interleucina-12/inmunología , Animales , Linfoma de Células B/terapia , Linfoma de Células B/inmunología , Inmunoterapia/métodos , Humanos , Línea Celular Tumoral , Antígenos CD20/inmunología , Ratones , Ratones Endogámicos BALB C , Femenino , Memoria InmunológicaRESUMEN
ABSTRACT: T-cell engaging-therapies have transformed the treatment landscape of relapsed and refractory B-cell non-Hodgkin lymphomas by offering highly effective treatments for patients with historically limited therapeutic options. This review focuses on the advances in chimeric antigen receptor-modified T cells and bispecific antibodies, first providing an overview of each product type, followed by exploring the primary data for currently available products in large B-cell lymphoma, follicular lymphoma, and mantle cell lymphoma. This review also highlights key logistical and sequencing considerations across diseases and product types that can affect clinical decision-making.
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Anticuerpos Biespecíficos , Inmunoterapia Adoptiva , Linfoma de Células B , Linfocitos T , Humanos , Anticuerpos Biespecíficos/uso terapéutico , Linfoma de Células B/terapia , Linfoma de Células B/inmunología , Linfocitos T/inmunología , Linfocitos T/metabolismo , Inmunoterapia Adoptiva/métodos , Receptores Quiméricos de Antígenos/inmunologíaRESUMEN
ABSTRACT: Unirradiated patients with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (NHL) who undergo anti-CD19 chimeric antigen receptor T-cell therapy (CART) have a predominant localized pattern of relapse, the significance of which is heightened in individuals with limited/localized disease before CART. This study reports on the outcomes of patients with R/R NHL and limited (<5 involved sites) disease bridged with or without radiotherapy. A multicenter retrospective review of 150 patients with R/R NHL who received CART with <5 disease sites before leukapheresis was performed. Bridging treatment, if any, was administered between leukapheresis and CART infusion. Study end points included relapse-free survival (RFS), event-free survival (EFS), and overall survival. Before CART infusion, 48 patients (32%) received bridging radiotherapy (BRT), and 102 (68%) did not. The median follow-up was 21 months. After CART infusion, BRT patients had higher objective response (92% vs 78%; P = .046) and sustained complete response rates (54% vs 33%; P = .015). Local relapse in sites present before CART was lower in the BRT group (21% vs 46%; P = .003). BRT patients had improved 2-year RFS (53% vs 44%; P = .023) and 2-year EFS (37% vs 34%; P = .039) compared with patients who did not receive BRT. The impact of BRT was most prominent in patients who had ≤2 pre-CART involved disease sites, with 2-year RFS of 62% in patients who received BRT compared with 42% in those who did not (P = .002). BRT before CART for patients with limited (<5 involved disease sites) R/R NHL improves response rate, local control, RFS, and EFS without causing significant toxicities.
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Linfoma de Células B , Humanos , Masculino , Femenino , Persona de Mediana Edad , Adulto , Anciano , Resultado del Tratamiento , Estudios Retrospectivos , Linfoma de Células B/radioterapia , Linfoma de Células B/mortalidad , Linfoma de Células B/terapia , Inmunoterapia Adoptiva/métodos , Adulto JovenRESUMEN
BACKGROUND: Chimeric antigen receptor (CAR) T-cell therapy has improved the historically poor outcomes for relapsed and refractory (R/R) large B-cell non-Hodgkin's lymphoma (LBCL). However, nearly 60% of patients will either fail to respond or relapse after CAR T-cell therapy. Currently, PET/CT scans are used to assess response. Cell-free circulating tumor DNA (ctDNA) is released by tumor cells into the peripheral blood and can be measured for minimal residual disease (MRD) assessment. METHODS: In this retrospective, IRB approved pilot study, archived lymphoma tissue and ctDNA from peripheral blood samples on day 0, 14, 28, 56, 90, 180, and 365 after CAR T-cell infusion from 10 patients with R/R NHL were collected for next-generation sequencing (NGS) of clonal variable-diversity-joining (VDJ) rearrangements (Adaptive biotechnologies [Seattle, WA]). Response was assessed by PET/CT on days 90 and 365 and graded according to the Lugano 2014 criteria. The primary endpoint was to determine the feasibility of detecting ctDNA to monitor disease response after anti-CD19 CAR T-cell therapy. The secondary endpoint was to compare the sensitivity/specificity of MRD assessment from ctDNA to PET/CT imaging. RESULTS: Nine out of 10 patients with a trackable sequence [median age 69 (range: 56-76); 55.6% male; median LDH 224], were included in this study. Each received tisagenlecleucel (tisa-cel) CAR T-cell therapy after median 2 prior treatments (range: 2-4). 7/9 patients had R/R diffuse large B-cell lymphoma (DLBCL), and 2/9 had transformed follicular lymphoma. At a median follow up of 12.7 months (range: 1.5-30 months), 4 patients were alive. By day 90, 3 patients (33.3%) achieved a radiographic complete response (CR) whilst 6 patients (66.6%) had progressive disease (PD). Detectable MRD on day 14 or day 28 had 83% sensitivity and 100% specificity for radiographic progression at any time before 1 year. For patients with PD, the median (interquartile range) MRD at day 0, 14, and 28 were 17.31 (1.01, 96.84), 9.12 (0.30, 18.8), and 23.77 (8.01, 137.53) copies per milliliter (mL), respectively. For patients with detectable MRD at day 28, mOS and mPFS were 6.7 and 1.3 months, respectively. CONCLUSION: Monitoring MRD was a sensitive and specific method to detect poor response to tisa-cel. Additional studies evaluating MRD more frequently and with different products are warranted.
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Inmunoterapia Adoptiva , Humanos , Masculino , Inmunoterapia Adoptiva/métodos , Femenino , Persona de Mediana Edad , Anciano , Estudios Retrospectivos , Linfoma de Células B/terapia , Linfoma de Células B/inmunología , Antígenos CD19/inmunología , Neoplasia Residual , Proyectos Piloto , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodosRESUMEN
Advances in understanding of the pathogenesis of B-cell lymphoma have led to development of various novel targeted therapies. Among them, CD19-targeted chimeric antigen receptor (CAR) T-cell therapies for relapsed and refractory B-cell lymphomas have shown remarkable efficacy in clinical trials, and three CAR T-cell products are now available in Japan. Real-world evidence (RWE) has shown that these products can provide comparable efficacy to clinical trials in clinical practice, where CAR T-cells were administered in patients with wider range of backgrounds. This finding will certainly broaden the role of CAR T-cell therapies in the treatment of B-cell lymphoma. However, since about half of the patients treated with CAR T-cell therapy progress thereafter, there is an urgent need for risk stratification and optimized management of refractory cases. Here, we review the results of clinical trials and RWE of CAR T-cell therapy in B-cell lymphoma.
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Inmunoterapia Adoptiva , Humanos , Linfoma/terapia , Linfoma/inmunología , Receptores Quiméricos de Antígenos/inmunología , Ensayos Clínicos como Asunto , Linfoma de Células B/terapia , Linfoma de Células B/inmunologíaRESUMEN
The Food and Drug Administration and the European Medicines Agency have recently approved chimeric antigen receptor-engineered (CAR) T cells to treat several refractory/relapsed B-cell lymphomas. This comprehensive review aims to demonstrate the pivotal role that [18F]-FDG PET/computed tomographic (CT) imaging can play to enhance the care of patients treated with CAR T-cell therapy. To this end, this review deciphers evidence showing the diagnostic, prognostic, predictive, and theragnostic value of [18F]-FDG PET/CT-derived parameters.
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Fluorodesoxiglucosa F18 , Inmunoterapia Adoptiva , Linfoma de Células B , Tomografía Computarizada por Tomografía de Emisión de Positrones , Radiofármacos , Receptores Quiméricos de Antígenos , Humanos , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Linfoma de Células B/diagnóstico por imagen , Linfoma de Células B/terapia , Receptores Quiméricos de Antígenos/uso terapéutico , Inmunoterapia Adoptiva/métodosRESUMEN
Chimeric antigen receptor T cell (CAR-T) therapy has shown remarkable efficacy in treating advanced B-cell malignancies by targeting CD19, but antigen-negative relapses and immune responses triggered by murine-derived antibodies remain significant challenges, necessitating the development of novel humanized multitarget CAR-T therapies. Here, we engineered a second-generation 4-1BB-CD3ζ-based CAR construct incorporating humanized CD19 single-chain variable fragments (scFvs) and BAFFR single-variable domains on heavy chains (VHHs), also known as nanobodies. The resultant CAR-T cells, with different constructs, were functionally compared both in vitro and in vivo. We found that the optimal tandem and bicistronic (BI) structures retained respective antigen-binding abilities, and both demonstrated specific activation when stimulated with target cells. At the same time, BI CAR-T cells (BI CARs) exhibited stronger tumour-killing ability and better secretion of interleukin-2 and tumour necrosis factor-alpha than single-target CAR-T cells. Additionally, BI CARs showed less exhaustion phenotype upon repeated antigen stimulation and demonstrated more potent and persistent antitumor effects in mouse xenograft models. Overall, we developed a novel humanized CD19/BAFFR bicistronic CAR (BI CAR) based on a combination of scFv and VHH, which showed potent and sustained antitumor ability both in vitro and in vivo, including against tumours with CD19 or BAFFR deficiencies.