RESUMEN
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
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.
Asunto(s)
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
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.
Asunto(s)
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
Rituximab (RTX) plus chemotherapy (R-CHOP) applied as a first-line therapy for lymphoma leads to a relapse in approximately 40% of the patients. Therefore, novel approaches to treat aggressive lymphomas are being intensively investigated. Several RTX-resistant (RR) cell lines have been established as surrogate models to study resistance to R-CHOP. Our study reveals that RR cells are characterized by a major downregulation of CD37, a molecule currently explored as a target for immunotherapy. Using CD20 knockout (KO) cell lines, we demonstrate that CD20 and CD37 form a complex, and hypothesize that the presence of CD20 stabilizes CD37 in the cell membrane. Consequently, we observe a diminished cytotoxicity of anti-CD37 monoclonal antibody (mAb) in complement-dependent cytotoxicity in both RR and CD20 KO cells that can be partially restored upon lysosome inhibition. On the other hand, the internalization rate of anti-CD37 mAb in CD20 KO cells is increased when compared to controls, suggesting unhampered efficacy of antibody drug conjugates (ADCs). Importantly, even a major downregulation in CD37 levels does not hamper the efficacy of CD37-directed chimeric antigen receptor (CAR) T cells. In summary, we present here a novel mechanism of CD37 regulation with further implications for the use of anti-CD37 immunotherapies.
Asunto(s)
Antígenos CD20 , Inmunoterapia , Linfoma de Células B , Rituximab , Tetraspaninas , Humanos , Antígenos CD20/inmunología , Antígenos CD20/metabolismo , Antígenos CD20/genética , Rituximab/farmacología , Rituximab/uso terapéutico , Tetraspaninas/genética , Tetraspaninas/metabolismo , Línea Celular Tumoral , Linfoma de Células B/inmunología , Linfoma de Células B/terapia , Linfoma de Células B/genética , Linfoma de Células B/tratamiento farmacológico , Inmunoterapia/métodos , Antígenos de Neoplasias/inmunología , Antígenos de Neoplasias/genética , Resistencia a Antineoplásicos/efectos de los fármacos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Doxorrubicina/farmacología , Doxorrubicina/administración & dosificación , Ciclofosfamida/farmacología , Ciclofosfamida/uso terapéutico , Vincristina/farmacología , Vincristina/uso terapéutico , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Receptores Quiméricos de Antígenos/inmunología , Receptores Quiméricos de Antígenos/genética , Receptores Quiméricos de Antígenos/metabolismo , Regulación Neoplásica de la Expresión GénicaRESUMEN
BACKGROUNDPredicting immune effector cell-associated neurotoxicity syndrome (ICANS) in patients infused with CAR T cells is still a conundrum. This complication, thought to be consequent to CAR T cell activation, arises a few days after infusion, when circulating CAR T cells are scarce and specific CAR T cell-derived biomarkers are lacking.METHODSCAR+ extracellular vesicle (CAR+EV) release was assessed in human CD19.CAR T cells cocultured with CD19+ target cells. A prospective cohort of 100 patients with B cell lymphoma infused with approved CD19.CAR T cell products was assessed for plasma CAR+EVs as biomarkers of in vivo CD19.CAR T cell activation. Human induced pluripotent stem cell-derived (iPSC-derived) neural cells were used as a model for CAR+EV-induced neurotoxicity.RESULTSIn vitro release of CAR+EVs occurs within 1 hour after target engagement. Plasma CAR+EVs are detectable 1 hour after infusion. A concentration greater than 132.8 CAR+EVs/µL at hour +1 or greater than 224.5 CAR+EVs/µL at day +1 predicted ICANS in advance of 4 days, with a sensitivity and a specificity outperforming other ICANS predictors. ENO2+ nanoparticles were released by iPSC-derived neural cells upon CAR+EV exposure and were increased in plasma of patients with ICANS.CONCLUSIONPlasma CAR+EVs are an immediate signal of CD19.CAR T cell activation, are suitable predictors of neurotoxicity, and may be involved in ICANS pathogenesis.TRIAL REGISTRATIONNCT04892433, NCT05807789.FUNDINGLife Science Hub-Advanced Therapies (financed by Health Ministry as part of the National Plan for Complementary Investments to the National Recovery and Resilience Plan [NRRP]: E.3 Innovative health ecosystem for APC fees and immunomonitoring).
Asunto(s)
Antígenos CD19 , Vesículas Extracelulares , Inmunoterapia Adoptiva , Linfoma de Células B , Humanos , Vesículas Extracelulares/inmunología , Vesículas Extracelulares/metabolismo , Masculino , Femenino , Persona de Mediana Edad , Antígenos CD19/inmunología , Linfoma de Células B/inmunología , Linfoma de Células B/terapia , Linfoma de Células B/sangre , Adulto , Anciano , Receptores Quiméricos de Antígenos/inmunología , Estudios ProspectivosRESUMEN
The introduction of immunotherapies has led to remarkable progress in the treatment of hematological malignancies, including B-cell malignancies such as B-cell lymphoma and multiple myeloma (MM). Although conventional therapeutic antibodies are effective as immunotherapy for newly diagnosed and relapsed/refractory B-cell lymphoma and MM, some cases are resistant. Chimeric antigen receptor (CAR) T-cell therapies targeting B-cell lymphoma and MM have progressed through several generations, and have improved treatment strategies for relapsed/refractory disease. In addition to conventional therapeutic antibodies, bispecific antibodies targeting both tumor cells and T cells have been developed for MM. Both CAR T-cell therapies and bispecific antibodies are effective for heavily treated patients with relapsed/refractory disease. However, most patients treated with these therapies relapse, and serious adverse events like cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are problematic. This Progress in Hematology, "Novel treatment strategies for hematological malignancies in the immunotherapy era," focuses on such limitations and the future outlook for CAR T-cell therapies and bispecific antibodies for B-cell malignancies. The role of NK cells in anti-tumor immunity for AML and various therapeutic strategies for NK-cell therapy in AML is also discussed.
Asunto(s)
Anticuerpos Biespecíficos , Neoplasias Hematológicas , Inmunoterapia Adoptiva , Humanos , Anticuerpos Biespecíficos/uso terapéutico , Neoplasias Hematológicas/terapia , Neoplasias Hematológicas/inmunología , Inmunoterapia Adoptiva/efectos adversos , Inmunoterapia Adoptiva/métodos , Inmunoterapia/métodos , Células Asesinas Naturales/inmunología , Receptores Quiméricos de Antígenos/inmunología , Linfoma de Células B/terapia , Linfoma de Células B/inmunología , Mieloma Múltiple/terapia , Mieloma Múltiple/inmunología , Síndrome de Liberación de Citoquinas/etiología , Síndrome de Liberación de Citoquinas/terapiaRESUMEN
Despite excellent cure rates among children, adolescents, and young adults (CAYAs) with mature B-cell non-Hodgkin lymphomas (B-NHLs) treated with chemoimmunotherapy, CAYAs with relapsed/refractory B-NHL remain difficult to treat, with a dismal prognosis. Reinduction and subsequent therapeutic management are not standardized. The armamentarium of active agents against B-NHL, including antibody-drug conjugates, monoclonal antibodies, checkpoint inhibitors, T-cell engagers, CAR T cells, CAR-natural killer (CAR-NK) cells, and cell signaling inhibitors, continues to expand. This article reviews current management practices and novel therapies in this difficult to treat population.
Asunto(s)
Linfoma de Células B , Humanos , Adolescente , Niño , Adulto Joven , Linfoma de Células B/terapia , Linfoma de Células B/tratamiento farmacológico , Linfoma de Células B/patología , Linfoma de Células B/diagnóstico , Recurrencia Local de Neoplasia/patología , Resistencia a Antineoplásicos , AdultoRESUMEN
Chimeric antigen receptor T (CAR-T) cell therapy is a rapidly developing new immunotherapy in recent years. Compared with other therapies, CAR-T has significant advantages for high-risk and relapsed/refractory B cell non-Hodgkin's lymphoma (B-NHL) patients. Currently, a variety of anti-CD19 CAR-T cells have been approved by the FDA for the treatment of B-NHL, such as axicabtagene ciloleucel, tisagenlecucel, lisocababtagene maraleucel and brexucabtagene autoleucel. In addition, many studies are actively exploring and developing different targeted CAR-T cells, which show great potential in B-NHL. This review briefly summarized the latest research progress on the application of CAR-T in common B-NHL.
Asunto(s)
Inmunoterapia Adoptiva , Receptores Quiméricos de Antígenos , Humanos , Inmunoterapia Adoptiva/métodos , Linfoma de Células B/terapia , Antígenos CD19/inmunología , Linfoma no Hodgkin/terapia , Receptores de Antígenos de Linfocitos T , Linfocitos T/inmunología , Inmunoterapia/métodos , Productos BiológicosRESUMEN
In this narrative medicine essay, a newly minted pediatric critical care physician learns firsthand what holistic medical care is from the love and attention she received during a hospitalization for mediastinal lymphoma.
Asunto(s)
Linfoma de Células B , Neoplasias del Mediastino , Atención al Paciente , Relaciones Médico-Paciente , Humanos , Femenino , Adulto , Embarazo , Neoplasias del Mediastino/complicaciones , Neoplasias del Mediastino/diagnóstico por imagen , Neoplasias del Mediastino/terapia , Linfoma de Células B/complicaciones , Linfoma de Células B/diagnóstico por imagen , Linfoma de Células B/terapia , Aborto Inducido/psicología , Antineoplásicos/efectos adversos , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Primer Trimestre del Embarazo/efectos de los fármacos , Pediatras/psicología , Emociones , Atención al Paciente/métodos , Atención al Paciente/psicología , Atención al Paciente/normasRESUMEN
Talicabtagene autoleucel (NexCAR19™) is a chimeric antigen receptor (CAR) T-cell therapy being developed by the Indian Institute of Technology, Bombay (IIT-B) and Immunoadoptive Cell Therapy (ImmunoACT) for the treatment of relapsed/refractory B-cell malignancies. Talicabtagene autoleucel contains autologous T cells from the patient, which have been modified to express a humanized anti-CD19 CAR that targets B cells. A single intravenous dose of talicabtagene autoleucel was associated with high response rates in pooled results from a phase I and phase II trial in patients with relapsed/refractory B-cell malignancies. Talicabtagene autoleucel was approved in India for the treatment of relapsed/refractory B-cell lymphomas and relapsed/refractory B-cell acute lymphoblastic leukaemia on 13 October 2023. This article summarizes the milestones in the development of talicabtagene autoleucel leading to this first approval for relapsed/refractory B-cell lymphomas and relapsed/refractory B-cell acute lymphoblastic leukaemia.
Asunto(s)
Antígenos CD19 , Inmunoterapia Adoptiva , Receptores Quiméricos de Antígenos , Humanos , Inmunoterapia Adoptiva/métodos , Antígenos CD19/inmunología , Antígenos CD19/uso terapéutico , Receptores Quiméricos de Antígenos/inmunología , Linfoma de Células B/terapia , Linfoma de Células B/tratamiento farmacológico , Linfoma de Células B/inmunología , Linfocitos T/inmunología , India , Resultado del Tratamiento , Ensayos Clínicos como AsuntoRESUMEN
Invariant natural killer T (iNKT) cells are a conserved population of innate T lymphocytes that are uniquely suitable as off-the-shelf cellular immunotherapies due to their lack of alloreactivity. Two major subpopulations of human iNKT cells have been delineated, a CD4- subset that has a TH1/cytolytic profile, and a CD4+ subset that appears polyfunctional and can produce both regulatory and immunostimulatory cytokines. Whether these two subsets differ in anti-tumour effects is not known. Using live cell imaging, we found that CD4- iNKT cells limited growth of CD1d+ Epstein-Barr virus (EBV)-infected B-lymphoblastoid spheroids in vitro, whereas CD4+ iNKT cells showed little or no direct anti-tumour activity. However, the effects of the two subsets were reversed when we tested them as adoptive immunotherapies in vivo using a xenograft model of EBV-driven human B cell lymphoma. We found that EBV-infected B cells down-regulated CD1d in vivo, and administering CD4- iNKT cells had no discernable impact on tumour mass. In contrast, xenotransplanted mice bearing lymphomas showed rapid reduction in tumour mass after administering CD4+ iNKT cells. Immunotherapeutic CD4+ iNKT cells trafficked to both spleen and tumour and were associated with subsequently enhanced responses of xenotransplanted human T cells against EBV. CD4+ iNKT cells also had adjuvant-like effects on monocyte-derived DCs and promoted antigen-dependent responses of human T cells in vitro. These results show that allogeneic CD4+ iNKT cellular immunotherapy leads to marked anti-tumour activity through indirect pathways that do not require tumour cell CD1d expression and that are associated with enhanced activity of antigen-specific T cells.
Asunto(s)
Antígenos CD1d , Infecciones por Virus de Epstein-Barr , Herpesvirus Humano 4 , Inmunoterapia Adoptiva , Linfoma de Células B , Células T Asesinas Naturales , Antígenos CD1d/metabolismo , Antígenos CD1d/inmunología , Humanos , Animales , Células T Asesinas Naturales/inmunología , Inmunoterapia Adoptiva/métodos , Herpesvirus Humano 4/inmunología , Linfoma de Células B/inmunología , Linfoma de Células B/terapia , Ratones , Infecciones por Virus de Epstein-Barr/inmunología , Infecciones por Virus de Epstein-Barr/terapia , Ensayos Antitumor por Modelo de Xenoinjerto , Línea Celular Tumoral , Ratones SCID , Ratones Endogámicos NODRESUMEN
The introduction of immunologically targeted therapies has represented a significant advancement in the treatment of B-cell lymphomas, particularly aggressive B-cell lymphoma. CD19 CAR-T cells such as Axicabtagen-Ciloleucel (Axi-cel) and Lisocabtagen Maraleucel (Liso-cel) have been approved since 2022 and 2023, respectively, for second-line therapy of Diffuse Large B-Cell Lymphomas (DLBCL), when there is primary refractory disease or relapse within 12 months after the end of first-line therapy. These therapies result in a significant improvement in progression-free survival compared to the previous standard therapy (salvage chemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation). Especially in elderly patients or patients with underlying medical conditions, CAR-T cell therapies like Axi-cel and Liso-cel demonstrate acceptable tolerability and high efficacy.Furthermore, bispecific T-cell-engaging antibodies ("bispecifics") such as Glofitamab, Epcoritamab, and Mosunetuzumab also represent promising treatment options for patients with relapsed disease after failure of second- or later line therapy and show efficacy even in a subset of patients relapsing after CD19 CAR-T cells. However, randomized study results for these substances are not yet available. They are expected to be used in earlier lines of therapy in the future, especially in combination with standard chemotherapy regimens. Common side effects of bispecific antibody therapies are cytokine release syndrome (CRS) and immune-mediated cytopenias, whereas immune-cell associated neurotoxicity syndrome (ICANS) is relatively rare compared to CD19 CAR T cells. In summary, bispecifics represent a novel, highly effective immunotherapy for the treatment of lymphomas with a very favourable toxicity profile.
Asunto(s)
Inmunoterapia Adoptiva , Humanos , Inmunoterapia Adoptiva/efectos adversos , Linfocitos T/inmunología , Inmunoterapia/métodos , Linfoma de Células B/terapia , Linfoma de Células B/inmunología , Anticuerpos Biespecíficos/uso terapéutico , Linfoma de Células B Grandes Difuso/terapia , Linfoma de Células B Grandes Difuso/inmunología , Antígenos CD19/inmunologíaRESUMEN
INTRODUCTION: At the 65th American Society of Hematology (ASH) 2023 Annual Meeting, the latest advancements in CD20×CD3 BsAbs for B-cell lymphoma (BCL) were highlighted, particularly in relapsed/refractory (R/R) follicular lymphoma (FL) and R/R diffuse large B-cell lymphoma (DLBCL). AREAS COVERED: This summary highlights some of the major studies on CD20×CD3 BsAbs for BCL. EXPERT OPINION/COMMENTARY: CD20×CD3 is the most widely studied BsAb, with promising results in patients with R/R DLBCL and R/R FL ≥ two prior lines of systemic therapy. Trials with the first line of B-cell lymphoma also revealed promising results. Hopefully, BsAb monotherapy or BsAb-containing regimens may become the standard therapy in patients with FL and DLBCL.
Asunto(s)
Anticuerpos Biespecíficos , Antígenos CD20 , Complejo CD3 , Inmunoterapia , Linfoma de Células B Grandes Difuso , Adulto , Humanos , Anticuerpos Biespecíficos/uso terapéutico , Antígenos CD20/inmunología , Antineoplásicos Inmunológicos/uso terapéutico , Complejo CD3/inmunología , Linfoma de Células B/inmunología , Linfoma de Células B/tratamiento farmacológico , Linfoma de Células B/terapia , Linfoma Folicular/inmunología , Linfoma Folicular/tratamiento farmacológico , Linfoma Folicular/terapia , Linfoma de Células B Grandes Difuso/inmunología , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/terapia , Congresos como AsuntoRESUMEN
Currently, many off-the-shelf chimeric antigen receptor (CAR)-T cell products are under investigation for the treatment of relapsed or refractory (R/R) B-cell neoplasms. Compared with autologous CAR-T cell therapy, off-the-shelf universal CAR-T cell therapies have many potential benefits, such as immediate accessibility for patients, stable quality due to industrialized manufacturing and additional infusions of CAR-T cells with different targets. However, critical challenges, including graft-versus-host disease and CAR-T cell elimination by the host immune system, still require extensive research. The most common technological approaches involve modifying healthy donor T cells via gene editing technology and altering different types of T cells. This article summarizes some of the latest data from preclinical and clinical studies of off-the-shelf CAR-T cell therapies in the treatment of R/R B-cell malignancies from the 2023 ASH Annual Meeting (ASH 2023).
Asunto(s)
Inmunoterapia Adoptiva , Receptores Quiméricos de Antígenos , Humanos , Inmunoterapia Adoptiva/métodos , Leucemia de Células B/terapia , Leucemia de Células B/inmunología , Linfoma de Células B/terapia , Linfoma de Células B/inmunología , Receptores Quiméricos de Antígenos/inmunología , Receptores Quiméricos de Antígenos/uso terapéutico , Linfocitos T/inmunología , Linfocitos T/trasplanteRESUMEN
ABSTRACT: Chimeric antigen receptor (CAR) natural killer (NK) cells can eliminate tumors not only through the ability of the CAR molecule to recognize antigen-expressed cancer cells but also through NK-cell receptors themselves. This overcomes some of the limitations of CAR T cells, paving the way for CAR NK cells for safer and more effective off-the-shelf cellular therapy. In this study, CD70-specific (a pan-target of lymphoma) fourth-generation CAR with 4-1BB costimulatory domain and interleukin-15 (IL-15) was constructed and transduced into cord blood-derived NK cells by Baboon envelope pseudotyped lentiviral vector. CD70-CAR NK cells displayed superior cytotoxic activity in vitro and in vivo against CD19-negative B-cell lymphoma when compared with nontransduced NK cells and CD19-specific CAR NK cells. Importantly, mice that received 2 doses of CD70-CAR NK cells showed effective eradication of tumors, accompanied by increased concentration of plasma IL-15 and enhanced CAR NK cell proliferation and persistence. Our study suggests that repetitive administration-based CAR NK-cell therapy has clinical advantage compared with a single dose of CAR NK cells for the treatment of B-cell lymphoma.
Asunto(s)
Antígenos CD19 , Ligando CD27 , Inmunoterapia Adoptiva , Interleucina-15 , Células Asesinas Naturales , Linfoma de Células B , Receptores Quiméricos de Antígenos , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Animales , Humanos , Ratones , Linfoma de Células B/terapia , Linfoma de Células B/inmunología , Receptores Quiméricos de Antígenos/inmunología , Receptores Quiméricos de Antígenos/metabolismo , Receptores Quiméricos de Antígenos/genética , Inmunoterapia Adoptiva/métodos , Antígenos CD19/inmunología , Ensayos Antitumor por Modelo de Xenoinjerto , Línea Celular Tumoral , Citotoxicidad InmunológicaRESUMEN
B-cell lymphomas occur with an incidence of 20 new cases per 100 000 people per year in high-income countries. They can affect any organ and are characterised by heterogeneous clinical presentations and courses, varying from asymptomatic, to indolent, to very aggressive cases. Since the topic of B-cell non-Hodgkin lymphomas was last reviewed in The Lancet in 2017, a deeper understanding of the biological background of this heterogeneous group of malignancies, the availability of new diagnostic methods, and the development and implementation of new targeted and immunotherapeutic approaches have improved our ability to treat patients. This Seminar provides an overview of the pathobiology, classification, and prognostication of B-cell non-Hodgkin lymphomas and summarises the current knowledge and standard of care regarding biology and clinical management of the most common subtypes of mature B-cell non-Hodgkin lymphomas. It also highlights new findings in deciphering the molecular background of disease development and the implementation of new therapeutic approaches, particularly those targeting the immune system.
Asunto(s)
Linfoma de Células B , Humanos , Linfoma de Células B/terapia , Linfoma de Células B/diagnóstico , Linfoma de Células B/patología , PronósticoRESUMEN
OBJECTIVES: Our aim was to describe the frequency and severity of infectious complications after chimeric antigen receptor (CAR) T-cell therapy in patients with large B-cell lymphoma (LBCL). METHODS: We retrospectively reviewed clinical records of LBCL patients treated with CD19-targeted CAR T-cell therapy from July/2018 to December/2021 at our institution, and identified all infectious episodes from CAR T-cell infusion until disease progression, death or last follow-up. RESULTS: Overall, 137 patients were included. Thirty six percent had received ≥3 previous lines of therapy and 26% an autologous hematopoietic cell transplantation (auto-HCT). Cytokine release syndrome occurred in 87 (64%) patients. Antibacterial prophylaxis was not used in any patient; only 38% received antifungal prophylaxis. Sixty three infectious events were observed in 41 (30%) patients. Fifty two (83%) of the infectious events had at least one pathogen identified (bacteria [n = 38], virus [n = 11], and fungi [n = 3]). Most of the infectious events occurred during hospitalization for CAR-T treatment. Infection-related mortality was observed in two patients. Independent risk factors for infection included male gender, previous auto-HCT, ≥3 lines of treatment and pre-lymphodepletion neutropenia. CONCLUSIONS: Infections after CAR T-cell therapy in patients with lymphoma are frequent but generally not severe. A conservative and tailored antimicrobial prophylaxis seems to be a safe approach.
Asunto(s)
Antifúngicos , Inmunoterapia Adoptiva , Humanos , Masculino , Femenino , Inmunoterapia Adoptiva/métodos , Inmunoterapia Adoptiva/efectos adversos , Persona de Mediana Edad , Anciano , Antifúngicos/uso terapéutico , Adulto , Estudios Retrospectivos , Profilaxis Antibiótica/métodos , Linfoma de Células B/terapia , Linfoma de Células B/inmunología , Estadificación de Neoplasias , Receptores Quiméricos de Antígenos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Linfoma de Células B Grandes Difuso/terapia , Antibacterianos/uso terapéutico , Micosis/prevención & control , Micosis/etiología , Factores de RiesgoRESUMEN
Chimeric antigen receptors (CARs) offer a promising new approach for targeting B cell malignancies through the immune system. Despite the proven effectiveness of CAR T cells targeting CD19 and CD22 in hematological malignancies, it is imperative to note that their production remains a highly complex process. Unlike T cells, NK cells eliminate targets in a non-antigen-specific manner while avoiding graft vs. host disease (GvHD). CAR-NK cells are considered safer than CAR-T cells because they have a shorter lifespan and produce less toxic cytokines. Due to their unlimited ability to proliferate in vitro, NK-92 cells can be used as a source for CAR-engineered NK cells. We found that CARs created from the m971 anti-CD22 mAb, which specifically targets a proximal CD22 epitope, were more effective at anti-leukemic activity compared to those made with other binding domains. To further enhance the anti-leukemic capacity of NK cells, we used lentiviral transduction to generate the m971-CD28-CD3ζ NK-92. CD22 is highly expressed in B cell lymphoma. To evaluate the potential of targeting CD22, Raji cells were selected as CD22-positive cells. Our study aimed to investigate CD22 as a potential target for CAR-NK-92 therapy in the treatment of B cell lymphoma. We first generated m971-CD28-CD3ζ NK-92 that expressed a CAR for binding CD22 in vitro. Flow cytometric analysis was used to evaluate the expression of CAR. The 7AAD determined the cytotoxicity of the m971-CD28-CD3ζ NK-92 towards target lymphoma cell lines by flow cytometry assay. The ELISA assay evaluated cytokine production in CAR NK-92 cells in response to target cells. The m971-CD28-CD3ζ NK-92 cells have successfully expressed the CD22-specific CAR. m971-CD28-CD3ζ NK-92 cells efficiently lysed CD22-expressing lymphoma cell lines and produced large amounts of cytokines such as IFN-γ and GM-CSF but a lower level of IL-6 after coculturing with target cells. Based on our results, it is evident that transferring m971-CD28-CD3ζ NK-92 cells could be a promising immunotherapy for B cell lymphoma.
Asunto(s)
Células Asesinas Naturales , Receptores Quiméricos de Antígenos , Lectina 2 Similar a Ig de Unión al Ácido Siálico , Humanos , Lectina 2 Similar a Ig de Unión al Ácido Siálico/inmunología , Células Asesinas Naturales/inmunología , Receptores Quiméricos de Antígenos/inmunología , Receptores Quiméricos de Antígenos/metabolismo , Línea Celular Tumoral , Inmunoterapia Adoptiva/métodos , Linfoma/terapia , Linfoma/inmunología , Linfoma/patología , Linfoma de Células B/terapia , Linfoma de Células B/inmunología , Linfoma de Células B/patología , Citotoxicidad InmunológicaRESUMEN
INTRODUCTION: Chimeric antigen receptor (CAR)-T cells obtained long-term durability in about 30% to 40% of relapsed/refractory (r/r) B-cell non-Hodgkin lymphoma (B-NHL). Maintenance therapy after CAR-T is necessary, and PD1 inhibitor is one of the important maintenance therapy options. METHODS: A total of 173 r/r B-NHL patients treated with PD1 inhibitor maintenance following CD19/22 CAR-T therapy alone or combined with autologous hematopoietic stem cell transplantation (ASCT) from March 2019 to July 2022 were assessed for eligibility for two trials. There were 81 patients on PD1 inhibitor maintenance therapy. RESULTS: In the CD19/22 CAR-T therapy trial, the PD1 inhibitor maintenance group indicated superior objective response rate (ORR) (82.9% vs 60%; P = 0.04) and 2-year progression-free survival (PFS) (59.8% vs 21.3%; P = 0.001) than the non-maintenance group. The estimated 2-year overall survival (OS) was comparable in the two groups (60.1% vs 45.1%; P = 0.112). No difference was observed in the peak expansion levels of CD19 CAR-T and CD22 CAR-T between the two groups. The persistence time of CD19 and CD22 CAR-T in the PD1 inhibitor maintenance group was longer than that in the non-maintenance group. In the CD19/22 CAR-T therapy combined with ASCT trial, no significant differences in ORR (81.4% vs 84.8%; P = 0.67), 2-year PFS (72.3% vs 74.9%; P = 0.73), and 2-year OS (84.1% vs 80.7%; P = 0.79) were observed between non-maintenance and PD1 inhibitor maintenance therapy groups. The peak expansion levels and duration of CD19 and CD22 CAR-T were not statistically different between the two groups. During maintenance treatment with PD1 inhibitor, all adverse events were manageable. In the multivariable analyses, type and R3m were independent predictive factors influencing the OS of r/r B-NHL with PD1 inhibitor maintenance after CAR-T therapy. CONCLUSION: PD1 inhibitor maintenance following CD19/22 CAR-T therapy obtained superior response and survival in r/r B-NHL, but not in the trial of CD19/22 CAR-T cell therapy combined with ASCT.
Asunto(s)
Inmunoterapia Adoptiva , Receptor de Muerte Celular Programada 1 , Receptores Quiméricos de Antígenos , Humanos , Masculino , Femenino , Persona de Mediana Edad , Adulto , Anciano , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Inmunoterapia Adoptiva/métodos , Receptores Quiméricos de Antígenos/inmunología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Adulto Joven , Linfoma de Células B/terapia , Linfoma de Células B/inmunología , Recurrencia Local de Neoplasia , Trasplante de Células Madre Hematopoyéticas , Resultado del TratamientoRESUMEN
The role of consolidative radiotherapy (RT) for patients with aggressive B-cell lymphoma has not been fully elucidated. The R-MegaCHOEP trial investigated the use of high-dose chemotherapy and rituximab with subsequent autologous stem cell transplantations compared to conventional immunochemotherapy (R-CHOEP) for high-risk patients up to 60 years. The study protocol included RT for patients with bulky (maximum diameter ≥7.5 cm) or extranodal disease. Two-hundred sixty-one patients were analyzed, 120 of whom underwent RT. The most frequently irradiated regions were mediastinum (n = 50) and paraaortic (n = 27). Median RT dose was 36 Gray in median fractions of 1.8 Gray. Acute toxicities were mostly mild to moderate, with only 24 and 8 grade 3 and 4 toxicities reported during RT. Patients with bulky disease who received RT showed significantly better 10-year EFS, PFS and OS (EFS: 64% vs. 35%; p < 0.001; PFS 68% vs. 47%; p = 0.003; OS: 72% vs. 59%; p = 0.011). There was no significant increase in secondary malignancies with the use of RT. RT administered for consolidation of bulky disease after immunochemotherapy improved the prognosis of young high-risk patients with aggressive B-cell lymphoma and should be considered part of first-line therapy. The trial was registered with ClinicalTrials.gov, number NCT00129090.