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1.
Med (N Y) ; 3(6): 353-354, 2022 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-35690053

RESUMO

Chimeric antigen receptor (CAR) T cell therapy has shown limited efficacy against solid tumors in clinical studies in contrast to hematological malignancies. In a paper recently published in Nature, Larson et al. report that CAR T cell activity against solid tumors depends on cell adhesion mediated by IFNγ signaling, opening the prospect of improving their clinical activity in the future.


Assuntos
Neoplasias Hematológicas , Neoplasias , Neoplasias Hematológicas/metabolismo , Humanos , Imunoterapia Adotiva/efeitos adversos , Neoplasias/terapia , Receptores de Antígenos de Linfócitos T/genética , Linfócitos T
2.
Front Immunol ; 13: 879983, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35669773

RESUMO

Patients with Burkitt lymphoma who are refractory to initial therapy or who relapse after undergoing intensive chemotherapy and autologous stem cell transplantation (ASCT) usually have a poor prognosis. While there has been considerable progress in the use of chimeric antigen receptor-modified (CAR) T cell immunotherapy for the treatment of relapsed and refractory (r/r) malignancies, explicit data on adult patients with r/r Burkitt lymphoma are limited. We conducted two single-arm clinical trials to evaluate the clinical efficacy and toxicity of CD19/CD22 CAR T cell immunotherapy both alone (trial A) and in combination with ASCT (trial B) in adult patients with r/r Burkitt lymphoma. In total, 28 adult patients with r/r Burkitt lymphoma were enrolled [trial A (n = 15) and trial B (n = 13)]. The median doses of CD22 and CD19 CAR T cell infusions were 4.1 × 106/kg and 4.0 × 106/kg, respectively. Subsequently, after CAR T cell infusion, overall and complete responses were observed in 19 (67.9%) and 16 (57.1%) patients, respectively. The cumulative incidence rates of grade 2-4 cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome were 39.3% (11/28) and 10.7% (3/28), respectively. After a median follow-up duration of 12.5 months, 16 patients (5 in trial A and 11 in trial B) survived. Both the estimated 1-year progression-free and overall survival rates were 55.6%. Our preliminary results indicated that salvage therapy with CD19/CD22 CAR T cell infusion alone and that in combination with ASCT are effective in treating some adult patients with r/r Burkitt lymphoma.


Assuntos
Linfoma de Burkitt , Transplante de Células-Tronco Hematopoéticas , Receptores de Antígenos Quiméricos , Adulto , Antígenos CD19 , Linfoma de Burkitt/terapia , Síndrome da Liberação de Citocina , Humanos , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Recidiva Local de Neoplasia , Linfócitos T , Transplante Autólogo
3.
Front Immunol ; 13: 887866, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35663947

RESUMO

Cellular therapies have transformed the treatment of relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL), which typically does not respond well to salvage chemotherapy. Recently, approximately 40% of r/r DLBCL patients across three different trials achieved a complete remission at 1 year after receiving treatment with autologous chimeric antigen receptor (CAR) T cells (auto-CARs). These successes have prompted studies of auto-CARs in second-line settings, in which axicabtagene ciloleucel and lisocabtagene maraleucel both showed improved event-free survival over autologous hematopoietic cell transplantation (AHCT). While encouraging, this data also highlights that 60% of patients relapse or progress following treatment with auto-CARs. Individual disease characteristics and logistical challenges of cell engineering also limit patients' eligibility for auto-CARs. Allogeneic CAR T cells (allo-CARs) may address some of these limitations as they may mitigate delays associated with auto-CARs, thereby reducing the need for bridging chemotherapies and increasing availability of cellular products for patients with aggressive lymphomas. By being sourced from healthy donors who have never been exposed to cytotoxic chemotherapy, allo-CARs can be created from T cells with better fitness. Allo-CARs made from specific cellular subsets (e.g., stem cell memory or naïve/early memory T cells) may also have increased efficacy and long-term persistence. Additionally, allo-CARs have been successfully created from other cell types, including natural killer cells, gamma-delta T-cells and induced pluripotent stem cells. These cell types can be engineered to target viral antigens, enabling precision targeting of virally driven DLBCL. As allogeneic donor cells can be banked and cryopreserved in batches, they can be made more readily available, potentially reducing logistical hurdles and costs compared to engineering auto-CARs. This may ultimately create a more sustainable platform for cell therapies. Challenges with allo-CARs that will need to be addressed include graft versus host disease, alloimmunization, potentially decreased persistence relative to auto-CARs, and antigen escape. In short, the adaptability of allo-CARs makes them ideal for treating patients with r/r DLBCL who have progressed through standard chemotherapy, AHCT, or auto-CARs. Here, we review the published literature on patients with r/r DLBCL treated with allogeneic CAR products manufactured from various cell types as well as forthcoming allogeneic CAR technologies.


Assuntos
Linfoma Difuso de Grandes Células B , Recidiva Local de Neoplasia , Antígenos CD19/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Humanos , Imunoterapia Adotiva/efeitos adversos , Linfoma Difuso de Grandes Células B/terapia , Recidiva Local de Neoplasia/terapia
4.
Drugs Today (Barc) ; 58(6): 283-298, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35670706

RESUMO

In July 2020, the U.S. Food and Drug Administration (FDA) approved brexucabtagene autoleucel (BA), the first anti-CD19 chimeric antigen receptor (CAR) T-cell therapy for the treatment of relapsed/refractory mantle cell lymphoma (MCL). The pivotal ZUMA-2 trial led to the approval of BA in patients who experienced relapsed disease on prior therapies (chemotherapy and/or Bruton tyrosine kinase [BTK] inhibitors). The FDA approval of BA was based on excellent responses with this therapy in highly refractory patients with MCL, who conventionally had poor outcomes. Longer follow-up data from the ZUMA-2 study have been presented at recent international meetings. As is common with other CAR T-cell therapies in lymphomas, the main toxicities of BA therapy included cytokine release syndrome (CRS), infections, cytopenias and CAR-associated neurotoxicity. In this review, we provide a summary of the data in the development of BA and its impact on MCL patient survival and future directions.


Assuntos
Linfoma de Célula do Manto , Adulto , Antígenos CD19 , Humanos , Imunoterapia Adotiva/efeitos adversos , Linfoma de Célula do Manto/tratamento farmacológico , Receptores de Antígenos Quiméricos
5.
Front Immunol ; 13: 901365, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35720352

RESUMO

Prognosis for patients with refractory/relapsed (R/R) diffuse large B-cell lymphoma (DLBCL) is poor. Immune-based therapeutic treatments such as CD19 Chimeric Antigen Receptor (CAR) T cell therapies have dramatically changed the treatment landscape for R/R DLBCL leading to durable remissions in ~ 50% of patients. However, there remains an unmet need for developing novel therapies to improve clinical outcomes of patients not responding or relapsing after CAR T cell therapies. Lack of suitable immunotherapeutic targets and disease heterogeneity represent the foremost challenges in this emerging field. In this review, we discuss the recently approved and emerging novel immunotherapies for patients with R/R DLBCL in the post-CAR T era and the cell surface targets currently used.


Assuntos
Linfoma Difuso de Grandes Células B , Linfócitos T , Antígenos CD19 , Humanos , Imunoterapia Adotiva/efeitos adversos , Linfoma Difuso de Grandes Células B/patologia , Recidiva Local de Neoplasia
6.
Front Immunol ; 13: 903562, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35720364

RESUMO

The present treatments for lung cancer include surgical resection, radiation, chemotherapy, targeted therapy, and immunotherapy. Despite advances in therapies, the prognosis of lung cancer has not been substantially improved in recent years. Chimeric antigen receptor (CAR)-T cell immunotherapy has attracted growing interest in the treatment of various malignancies. Despite CAR-T cell therapy emerging as a novel potential therapeutic option with promising results in refractory and relapsed leukemia, many challenges limit its therapeutic efficacy in solid tumors including lung cancer. In this landscape, studies have identified several obstacles to the effective use of CAR-T cell therapy including antigen heterogeneity, the immunosuppressive tumor microenvironment, and tumor penetration by CAR-T cells. Here, we review CAR-T cell design; present the results of CAR-T cell therapies in preclinical and clinical studies in lung cancer; describe existing challenges and toxicities; and discuss strategies to improve therapeutic efficacy of CAR-T cells.


Assuntos
Neoplasias Pulmonares , Receptores de Antígenos Quiméricos , Humanos , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Neoplasias Pulmonares/terapia , Receptores de Antígenos Quiméricos/genética , Linfócitos T , Microambiente Tumoral
8.
Front Immunol ; 13: 886429, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35720306

RESUMO

In recent years, immunotherapy for cancer has become mainstream with several products now authorized for therapeutic use in the clinic and are becoming the standard of care for some malignancies. Chimeric antigen receptor (CAR)-T cell therapies have demonstrated substantial efficacy for the treatment of hematological malignancies; however, they are complex and currently expensive to manufacture, and they can generate life-threatening adverse events such as cytokine release syndrome (CRS). The limitations of current CAR-T cells therapies have spurred an interest in alternative immunotherapy approaches with safer risk profiles and with less restrictive manufacturing constraints. Natural killer (NK) cells are a population of immune effector cells with potent anti-viral and anti-tumor activity; they have the capacity to swiftly recognize and kill cancer cells without the need of prior stimulation. Although NK cells are naturally equipped with cytotoxic potential, a growing body of evidence shows the added benefit of engineering them to better target tumor cells, persist longer in the host, and be fitter to resist the hostile tumor microenvironment (TME). NK-cell-based immunotherapies allow for the development of allogeneic off-the-shelf products, which have the potential to be less expensive and readily available for patients in need. In this review, we will focus on the advances in the development of engineering of NK cells for cancer immunotherapy. We will discuss the sourcing of NK cells, the technologies available to engineer NK cells, current clinical trials utilizing engineered NK cells, advances on the engineering of receptors adapted for NK cells, and stealth approaches to avoid recipient immune responses. We will conclude with comments regarding the next generation of NK cell products, i.e., armored NK cells with enhanced functionality, fitness, tumor-infiltration potential, and with the ability to overcome tumor heterogeneity and immune evasion.


Assuntos
Neoplasias Hematológicas , Neoplasias , Neoplasias Hematológicas/etiologia , Humanos , Imunoterapia , Imunoterapia Adotiva/efeitos adversos , Células Matadoras Naturais , Microambiente Tumoral
10.
J Immunother Cancer ; 10(5)2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35577500

RESUMO

Despite promising clinical results in a small subset of malignancies, therapies based on engineered chimeric antigen receptor and T-cell receptor T cells are associated with serious adverse events, including cytokine release syndrome and neurotoxicity. These toxicities are sometimes so severe that they significantly hinder the implementation of this therapeutic strategy. For a long time, existing preclinical models failed to predict severe toxicities seen in human clinical trials after engineered T-cell infusion. However, in recent years, there has been a concerted effort to develop models, including humanized mouse models, which can better recapitulate toxicities observed in patients. The Accelerating Development and Improving Access to CAR and TCR-engineered T cell therapy (T2EVOLVE) consortium is a public-private partnership directed at accelerating the preclinical development and increasing access to engineered T-cell therapy for patients with cancer. A key ambition in T2EVOLVE is to design new models and tools with higher predictive value for clinical safety and efficacy, in order to improve and accelerate the selection of lead T-cell products for clinical translation. Herein, we review existing preclinical models that are used to test the safety of engineered T cells. We will also highlight limitations of these models and propose potential measures to improve them.


Assuntos
Imunoterapia Adotiva , Neoplasias , Receptores de Antígenos Quiméricos , Animais , Síndrome da Liberação de Citocina , Humanos , Imunoterapia Adotiva/efeitos adversos , Camundongos , Neoplasias/terapia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/uso terapêutico , Linfócitos T
11.
J Med Econ ; 25(1): 730-740, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35611697

RESUMO

AIMS: The objective of this study is to estimate the cost-effectiveness of KTE-X19 versus standard of care (SoC) in the treatment of patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL) post-Bruton tyrosine kinase inhibitor (BTKi) treatment from a UK healthcare perspective. MATERIALS AND METHODS: A three-state partitioned survival model (pre-progression, post-progression and death) with a cycle length of one month was used to extrapolate progression-free and overall survival over a lifetime horizon. Population inputs along with KTE-X19 (brexucabtagene autoleucel) efficacy and safety data were derived from the single-arm trial ZUMA-2 (NCT02601313). The composition of SoC was informed by a literature-based meta-analysis, SoC efficacy data were obtained from the SCHOLAR-2 real-world study. Survival was modelled using standard parametric curves for SoC and a mixture-cure methodology for KTE-X19. It was assumed that patients whose disease had not progressed after five years experienced long-term remission. Costs, resource use and utility, and adverse event disutility inputs were obtained from published literature and publicly available data sources. An annual discount rate of 3.5% was applied to costs and health outcomes. Modelled outcomes for KTE-X19 and SoC included expected life years (LY), quality-adjusted life years (QALY) and total costs. Deterministic and probabilistic sensitivity analyses and scenario analyses were performed. RESULTS: Estimated median survival was 5.96 years for KTE-X19 and 1.38 for SoC. Discounted LYs, QALYs and lifetime costs were 8.27, 5.99 and £385,765 for KTE-X19 versus 1.98, 1.48 and £79,742 for SoC, respectively. The KTE-X19 versus SoC cost per QALY was £67,713 and the cost per LY was £48,645. Influential scenario analyses use alternative KTE-X19 survival curves and discount rates, and shorter time horizons. CONCLUSION: Considering the survival and quality of life benefits compared to SoC, KTE-X19 for R/R MCL appears as a cost-effective treatment in the real-world UK setting.


Assuntos
Imunoterapia Adotiva , Linfoma de Célula do Manto , Recidiva Local de Neoplasia , Receptores de Antígenos Quiméricos , Adulto , Ensaios Clínicos como Assunto , Análise Custo-Benefício , Humanos , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/economia , Linfoma de Célula do Manto/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Qualidade de Vida , Anos de Vida Ajustados por Qualidade de Vida , Receptores de Antígenos Quiméricos/uso terapêutico , Padrão de Cuidado
12.
Cytotherapy ; 24(7): 720-732, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35570170

RESUMO

BACKGROUND: Chimeric antigen receptor (CAR) T cell therapy has yielded impressive clinical results in hematological malignancies and is a promising approach for solid tumor treatment. However, toxicity, including cytokine-release syndrome (CRS) and neurotoxicity, is a concern hampering its broader use. METHODS: In selecting a lead CAR-T candidate against the oncofetal antigen glypican 3 (GPC3), we compared CARs bearing a low- and high-affinity single-chain variable fragment (scFv) binding to a similar epitope and cross-reactive with murine GPC3. RESULTS: Where the high-affinity CAR-T cells were toxic in vivo, the low-affinity CAR maintained cytotoxic function against antigen-positive tumor cells but did not show toxicity against normal tissues. High-affinity CAR-induced toxicity was caused by on-target, off-tumor binding, based on the observation that higher doses of the high-affinity CAR-T caused toxicity in non-tumor-bearing mice and accumulated in organs with low expression of GPC3. To explore another layer of controlling CAR-T toxicity, we developed a means to target and eliminate CAR-T cells using anti-TNF-α antibody therapy after CAR-T infusion. The antibody was shown to function by eliminating early antigen-activated, but not all, CAR-T cells, allowing a margin where the toxic response could be effectively decoupled from antitumor efficacy with only a minor loss in tumor control. By exploring additional traits of the CAR-T cells after activation, we identified a mechanism whereby we could use approved therapeutics and apply them as an exogenous kill switch that eliminated early activated CAR-T following antigen engagement in vivo. CONCLUSIONS: By combining the reduced-affinity CAR with this exogenous control mechanism, we provide evidence that we can modulate and control CAR-mediated toxicity.


Assuntos
Glipicanas , Receptores de Antígenos Quiméricos , Animais , Linhagem Celular Tumoral , Glipicanas/metabolismo , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Camundongos , Receptores de Antígenos de Linfócitos T , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/metabolismo , Linfócitos T , Inibidores do Fator de Necrose Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Nat Med ; 28(6): 1189-1198, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35534566

RESUMO

Despite success in hematologic malignancies, the treatment landscape of chimeric antigen receptor (CAR) T cell therapy for solid tumors remains limited. Claudin18.2 (CLDN18.2)-redirected CAR T cells showed promising efficacy against gastric cancer (GC) in a preclinical study. Here we report the interim analysis results of an ongoing, open-label, single-arm, phase 1 clinical trial of CLDN18.2-targeted CAR T cells (CT041) in patients with previously treated, CLDN18.2-positive digestive system cancers ( NCT03874897 ). The primary objective was safety after CT041 infusion; secondary objectives included CT041 efficacy, pharmacokinetics and immunogenicity. We treated 37 patients with one of three CT041 doses: 2.5 × 108, 3.75 × 108 or 5.0 × 108 cells. All patients experienced a grade 3 or higher hematologic toxicity. Grade 1 or 2 cytokine release syndrome (CRS) occurred in 94.6% of patients. No grade 3 or higher CRS or neurotoxicities, treatment-related deaths or dose-limiting toxicities were reported. The overall response rate (ORR) and disease control rate (DCR) reached 48.6% and 73.0%, respectively. The 6-month duration of response rate was 44.8%. In patients with GC, the ORR and DCR reached 57.1% and 75.0%, respectively, and the 6-month overall survival rate was 81.2%. These initial results suggest that CT041 has promising efficacy with an acceptable safety profile in patients with heavily pretreated, CLDN18.2-positive digestive system cancers, particularly in those with GC.


Assuntos
Imunoterapia Adotiva , Neoplasias Gástricas , Claudinas , Síndrome da Liberação de Citocina , Humanos , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Neoplasias Gástricas/terapia , Linfócitos T
14.
Front Immunol ; 13: 873789, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35572515

RESUMO

Despite impressive progress, a significant portion of patients still experience primary or secondary resistance to chimeric antigen receptor (CAR) T-cell immunotherapy for relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL). The mechanism of primary resistance involves T-cell extrinsic and intrinsic dysfunction. In the present study, a total of 135 patients of DLBCL treated with murine CD19/CD22 cocktail CAR T-therapy were assessed retrospectively. Based on four criteria (maximal expansion of the transgene/CAR-positive T-cell levels post-infusion [Cmax], initial persistence of the transgene by the CAR transgene level at +3 months [Tlast], CD19+ B-cell levels [B-cell recovery], and the initial response to CAR T-cell therapy), 48 patients were included in the research and divided into two groups (a T-normal group [n=22] and a T-defect [n=26] group). According to univariate and multivariate regression analyses, higher lactate dehydrogenase (LDH) levels before leukapheresis (hazard ratio (HR) = 1.922; p = 0.045) and lower cytokine release syndrome (CRS) grade after CAR T-cell infusion (HR = 0.150; p = 0.026) were independent risk factors of T-cell dysfunction. Moreover, using whole-exon sequencing, we found that germline variants in 47 genes were significantly enriched in the T-defect group compared to the T-normal group (96% vs. 41%; p<0.0001), these genes consisted of CAR structure genes (n=3), T-cell signal 1 to signal 3 genes (n=13), T cell immune regulation- and checkpoint-related genes (n=9), cytokine- and chemokine-related genes (n=13), and T-cell metabolism-related genes (n=9). Heterozygous germline UNC13D mutations had the highest intergroup differences (26.9% vs. 0%; p=0.008). Compound heterozygous CX3CR1 I249/M280 variants, referred to as pathogenic and risk factors according to the ClinVar database, were enriched in the T-defect group (3 of 26). In summary, the clinical characteristics and T-cell immunodeficiency genetic features may help explain the underlying mechanism of treatment primary resistance and provide novel insights into CAR T-cell immunotherapy.


Assuntos
Linfoma Difuso de Grandes Células B , Receptores de Antígenos Quiméricos , Animais , Antígenos CD19 , Humanos , Imunoterapia Adotiva/efeitos adversos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/terapia , Proteínas de Membrana , Camundongos , Fatores R , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/uso terapêutico , Estudos Retrospectivos , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico/genética , Linfócitos T
15.
Med (N Y) ; 3(5): 281-283, 2022 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-35584646

RESUMO

Chimeric Antigen Receptor (CAR) T-cells have revolutionized the treatment of hematologic malignancies, but limitations exist in poor predictability and in observable toxicity with response to treatment. Here, Smith et al. present the gut microbiome as an actionable (and potentially targetable) biomarker of response and toxicity with (CD19) CAR T-cell treatment.1.


Assuntos
Neoplasias Hematológicas , Imunoterapia Adotiva , Antígenos CD19 , Humanos , Imunoterapia Adotiva/efeitos adversos , Linfócitos T
16.
Clin Adv Hematol Oncol ; 20(5): 309-318, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35579590

RESUMO

Non-Hodgkin lymphoma (NHL) is the seventh most common type of malignancy worldwide, with approximately 544,000 cases diagnosed in 2020.[1-3] The vast majority of NHLs are derived from B cells. The more than 80 subtypes of B-cell NHL are categorized according to their typical clinical course: indolent or aggressive.[4] Aggressive B-cell NHLs that are refractory to first-line therapy or that relapse following initial treatment are historically associated with a poor prognosis, despite the use of salvage chemotherapy and autologous stem cell transplant.[5] The advent of chimeric antigen receptor (CAR) T-cell therapy has changed the treatment paradigm for patients who have relapsed/refractory aggressive B-cell NHL, with impressive response rates and the possibility for a durable remission in those whose disease has progressed despite multiple prior treatments.[6-8] This review outlines current indications for CAR T-cell therapy, major toxicities, novel CARs under investigation, and future directions.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Linfoma de Células B , Linfoma não Hodgkin , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Humanos , Imunoterapia Adotiva/efeitos adversos , Linfoma de Células B/tratamento farmacológico , Linfoma não Hodgkin/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Terapia de Salvação
17.
Int J Mol Sci ; 23(10)2022 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-35628334

RESUMO

Immunotherapy is a milestone in the treatment of poor-prognosis pediatric acute lymphoblastic leukemia (ALL) and is expected to improve treatment outcomes and reduce doses of conventional chemotherapy without compromising the effectiveness of the therapy. However, both chemotherapy and immunotherapy cause side effects, including neurological ones. Acute neurological complications occur in 3.6-11% of children treated for ALL. The most neurotoxical chemotherapeutics are L-asparaginase (L-ASP), methotrexate (MTX), vincristine (VCR), and nelarabine (Ara-G). Neurotoxicity associated with methotrexate (MTX-NT) occurs in 3-7% of children treated for ALL and is characterized by seizures, stroke-like symptoms, speech disturbances, and encephalopathy. Recent studies indicate that specific polymorphisms in genes related to neurogenesis may have a predisposition to MTX toxicity. One of the most common complications associated with CAR T-cell therapy is immune effector cell-associated neurotoxicity syndrome (ICANS). Mechanisms of neurotoxicity in CAR T-cell therapy are still unknown and may be due to disruption of the blood-brain barrier and the effects of elevated cytokine levels on the central nervous system (CNS). In this review, we present an analysis of the current knowledge on the mechanisms of neurotoxicity of standard chemotherapy and the targeted therapy in children with ALL.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Síndromes Neurotóxicas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Asparaginase , Criança , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/tratamento farmacológico , Humanos , Fatores Imunológicos/uso terapêutico , Imunoterapia Adotiva/efeitos adversos , Metotrexato/efeitos adversos , Síndromes Neurotóxicas/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico
18.
Expert Rev Hematol ; 15(4): 305-320, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35385358

RESUMO

INTRODUCTION: The unprecedented success of chimeric antigen receptor (CAR)-T-cell therapy in the management of B-cell malignancies comes with a price of specific side effects. Healthy B-cell depletion is an anticipated 'on-target' 'off-tumor' side effect and can contribute to severe and prolonged hypogammaglobulinemia. Evidence-based guidelines for the use of immunoglobulin replacement therapy (IGRT) for infection prevention are lacking in this population. AREAS COVERED: This article reviews the mechanisms and epidemiology of hypogammaglobulinemia and antibody deficiency, association with infections, and strategies to address these issues in CD19- and BCMA-CAR-T-cell recipients. EXPERT OPINION: CD19 and BCMA CAR-T-cell therapy result in unique immune deficits due to depletion of specific B-lineage cells and may require different infection prevention strategies. Hypogammaglobulinemia before and after CAR-T-cell therapy is frequent, but data on the efficacy and cost-effectiveness of IGRT are lacking. Monthly IGRT should be prioritized for patients with severe or recurrent bacterial infections. IGRT may be more broadly necessary to prevent infections in BCMA-CAR-T-cell recipients and children with severe hypogammaglobulinemia irrespective of infection history. Vaccinations are indicated to augment humoral immunity and can be immunogenic despite cytopenias; re-vaccination(s) may be required. Controlled trials are needed to better understand the role of IGRT and vaccines in this population.


Assuntos
Agamaglobulinemia , Neoplasias , Receptores de Antígenos Quiméricos , Agamaglobulinemia/etiologia , Agamaglobulinemia/terapia , Antígeno de Maturação de Linfócitos B , Terapia Baseada em Transplante de Células e Tecidos , Criança , Humanos , Imunoterapia Adotiva/efeitos adversos , Receptores de Antígenos Quiméricos/uso terapêutico
19.
Am J Hematol ; 97(7): 933-941, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35488407

RESUMO

In this open-label, single-arm, phase I/II clinical trial, we evaluated the efficacy of anti-B cell maturation antigen (BCMA) chimeric antigen receptor (CAR)-T cell (HDS269B) therapy in 49 relapsed/refractory multiple myeloma (RRMM) patients, including 20 with Eastern Cooperative Oncology Group (ECOG) grade 3-4. After HDS269B infusion (9 × 106 CAR+ cells/kg), 17 patients (34.69%, 11 ECOG 0-2, 6 ECOG 3-4) developed cytokine release syndrome [grade 1-2: 14 patients (28.57%); grade 3: 3 patients (6.12%)]. The objective response rate (ORR) was 77%, with a complete response (CR) achieved in 47%. Ongoing response >12 months occurred in 15 patients, and was extended beyond 38 months in one patient. The median progression-free survival (PFS) and overall survival (OS) were 10 months (95% CI 5.3-14.7) and 29 months (95% CI 10.0-48.0), respectively. The PFS (12 months) and OS (18 months) rates were 41.64% and 62.76%, respectively. In patients with ECOG 0-2 and 3-4, ORR was 79.31% (23/29) and 75.0% (15/20) and PFS were 15 months (95% CI 5.4-24.6) and 4 months (95% CI 0-11.7), respectively. OS was not reached in ECOG 0-2 patients, but was 10.5 months (95% CI 0-22) in ECOG 3-4 patients. Single-cell sequencing indicated that treatment efficacy might be related to mTORC1 signaling. Thus, HDS269B therapy is safe and effective for RRMM patients, even those with ECOG 3-4.


Assuntos
Linfoma Folicular , Mieloma Múltiplo , Receptores de Antígenos Quiméricos , Antígeno de Maturação de Linfócitos B , Terapia Baseada em Transplante de Células e Tecidos , Humanos , Imunoterapia Adotiva/efeitos adversos , Mieloma Múltiplo/tratamento farmacológico , Receptores de Antígenos Quiméricos/uso terapêutico
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