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1.
Biomaterials ; 313: 122773, 2025 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-39217794

RESUMO

The development of artificial Antigen Presenting Cells (aAPCs) has led to improvements in adoptive T cell therapy (ACT), an immunotherapy, for cancer treatment. aAPCs help to streamline the consistent production and expansion of T cells, thus reducing the time and costs associated with ACT. However, several issues still exist with ACT, such as insufficient T cell potency, which diminishes the translational potential for ACT. While aAPCs have been used primarily to increase production efficiency of T cells for ACT, the intrinsic properties of a biomaterial-based aAPC may affect T cell phenotype and function. In CD8+ T cells, reactive oxygen species (ROS) and oxidative stress accumulation can activate Forkhead box protein O1 (FOXO1) to transcribe antioxidants which reduce ROS and improve memory formation. Alginate, a biocompatible and antioxidant rich biomaterial, is promising for incorporation into an aAPC formulation to modulate T cell phenotype. To investigate its utility, a novel alginate-based aAPC platform was developed that preferentially expanded CD8+ T cells with memory related features. Alginate-based aAPCs allowed for greater control of CD8+ T cell qualities, including, significantly improved in vivo persistence and augmented in vivo anti-tumor T cell responses.


Assuntos
Alginatos , Células Apresentadoras de Antígenos , Linfócitos T CD8-Positivos , Memória Imunológica , Imunoterapia Adotiva , Alginatos/química , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Animais , Imunoterapia Adotiva/métodos , Células Apresentadoras de Antígenos/imunologia , Memória Imunológica/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos , Espécies Reativas de Oxigênio/metabolismo , Humanos , Proliferação de Células/efeitos dos fármacos
2.
Cell ; 187(18): 4826-4828, 2024 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-39241743

RESUMO

Early reports suggest that chimeric antigen receptor (CAR)-T therapy has remarkable potential for treating autoimmune disease. Current approaches rely on autologous CAR-T cells, creating a bottleneck to the broad deployment of this therapy. In this issue of Cell, Wang et al.1 report the first use of allogeneic CAR-T cells in three patients with systemic autoimmune disease.


Assuntos
Doenças Autoimunes , Receptores de Antígenos Quiméricos , Humanos , Doenças Autoimunes/terapia , Doenças Autoimunes/imunologia , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/metabolismo , Linfócitos T/imunologia , Imunoterapia Adotiva/métodos , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos de Linfócitos T/imunologia
3.
Medicine (Baltimore) ; 103(36): e38659, 2024 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-39252328

RESUMO

RATIONALE: Anti-CD19 chimeric antigen receptor T-cell (CAR-T) therapy is a successful treatment for B-cell malignancies associated with cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Cardiovascular toxicities have also been reported in this setting. However, there is scarce data regarding development of autonomic disorders after CAR-T cell therapy. PATIENT CONCERNS: We report a case with a patient with non-Hodgkin B-cell lymphoma, refractory to 2 prior lines of immunochemotherapy, treated with CAR-T therapy. DIAGNOSES: Orthostatic hypotension secondary to autonomic dysfunction was diagnosed as manifestation of ICANS. INTERVENTIONS: The patient received metilprednisolone 1000 mg IV daily for 3 days and anakinra 100 mg IV every 6h. OUTCOMES: The vast majority of autonomic symptoms ceased and 4 months after CAR-T therapy, autonomic dysfunction was resolved. LESSONS: New-onset autonomic dysfunction can occur as manifestation of ICANS in patients who experience persistent neurologic and cardiovascular symptoms after resolution of acute neurotoxicity and should be early recognized. Differences in differential diagnosis, mechanisms and treatment approaches are discussed.


Assuntos
Doenças do Sistema Nervoso Autônomo , Humanos , Doenças do Sistema Nervoso Autônomo/etiologia , Doenças do Sistema Nervoso Autônomo/diagnóstico , Imunoterapia Adotiva/efeitos adversos , Masculino , Síndrome da Liberação de Citocina/etiologia , Pessoa de Meia-Idade , Linfoma de Células B/complicações , Linfoma de Células B/tratamento farmacológico , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/diagnóstico , Hipotensão Ortostática/etiologia , Hipotensão Ortostática/diagnóstico , Metilprednisolona/uso terapêutico
6.
Front Immunol ; 15: 1457771, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39224603

RESUMO

Invariant natural killer T (iNKT) cells are a small subset of T lymphocytes that release large amounts of cytokines such as IFN-γ and exhibit cytotoxic activity upon activation, inducing strong anti-tumor effects. Harnessing the anti-tumor properties of iNKT cells, iNKT cell-based immunotherapy has been developed to treat cancer patients. In one of the iNKT cell-based immunotherapies, two approaches are utilized, namely, active immunotherapy or adoptive immunotherapy, the latter involving the ex vivo expansion and subsequent administration of iNKT cells. There are two sources of iNKT cells for adoptive transfer, autologous and allogeneic, each with its own advantages and disadvantages. Here, we assess clinical trials conducted over the last decade that have utilized iNKT cell adoptive transfer as iNKT cell-based immunotherapy, categorizing them into two groups based on the use of autologous iNKT cells or allogeneic iNKT cells.


Assuntos
Imunoterapia Adotiva , Células T Matadoras Naturais , Neoplasias , Células T Matadoras Naturais/imunologia , Humanos , Imunoterapia Adotiva/métodos , Neoplasias/terapia , Neoplasias/imunologia , Animais , Ensaios Clínicos como Assunto , Células Alógenas/imunologia , Transplante Autólogo
7.
Oncol Res ; 32(9): 1479-1516, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39220130

RESUMO

Chimeric antigen receptor T-cesll therapy (CAR-T) has achieved groundbreaking advancements in clinical application, ushering in a new era for innovative cancer treatment. However, the challenges associated with implementing this novel targeted cell therapy are increasingly significant. Particularly in the clinical management of solid tumors, obstacles such as the immunosuppressive effects of the tumor microenvironment, limited local tumor infiltration capability of CAR-T cells, heterogeneity of tumor targeting antigens, uncertainties surrounding CAR-T quality, control, and clinical adverse reactions have contributed to increased drug resistance and decreased compliance in tumor therapy. These factors have significantly impeded the widespread adoption and utilization of this therapeutic approach. In this paper, we comprehensively analyze recent preclinical and clinical reports on CAR-T therapy while summarizing crucial factors influencing its efficacy. Furthermore, we aim to identify existing solution strategies and explore their current research status. Through this review article, our objective is to broaden perspectives for further exploration into CAR-T therapy strategies and their clinical applications.


Assuntos
Imunoterapia Adotiva , Neoplasias , Receptores de Antígenos Quiméricos , Microambiente Tumoral , Humanos , Imunoterapia Adotiva/métodos , Imunoterapia Adotiva/efeitos adversos , Neoplasias/terapia , Neoplasias/imunologia , Receptores de Antígenos Quiméricos/imunologia , Microambiente Tumoral/imunologia , Animais , Linfócitos T/imunologia , Antígenos de Neoplasias/imunologia , Receptores de Antígenos de Linfócitos T/imunologia
8.
WMJ ; 123(4): 304-306, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39284092

RESUMO

INTRODUCTION: COVID-19 can have severe consequences for immunocompromised individuals, including those with hematological malignancies. Prolonged infections causing pneumonia and lung injury are rare in patients with diffuse large B-cell lymphoma (DLBCL) treated with chimeric antigen receptor T-cell (CAR-T). CASE PRESENTATION: A 43-year-old male with a history of DLBCL, in remission for 2 years after CAR-T therapy, developed a persistent COVID infection, as confirmed via positive polymerase chain reaction. This slowly progressed to symptomatic hypoxemic pneumonitis and biopsy-proven diffuse alveolar damage, which responded to corticosteroid treatment. DISCUSSION: COVID-19 poses increased risks to patients with a history of hematologic malignancies and can lead to severe respiratory distress and mortality. Studies have shown prolonged pneumonitis may require corticosteroids for improvement. However, data on appropriate regimen for managing prolonged COVID-19 pneumonitis are lacking. CONCLUSIONS: This case highlights challenges of the treatment of COVID-19 infections in immunocompromised individuals with hematological malignancies. Corticosteroid treatment shows benefits, but dosing and duration should be based on individual patient response. Extended monitoring, individualized treatment plans, and research are crucial for optimizing outcomes in this vulnerable population.


Assuntos
COVID-19 , Linfoma Difuso de Grandes Células B , SARS-CoV-2 , Humanos , Masculino , Linfoma Difuso de Grandes Células B/tratamento farmacológico , COVID-19/complicações , Adulto , Imunoterapia Adotiva/efeitos adversos , Corticosteroides/uso terapêutico , Lesão Pulmonar/etiologia , Hospedeiro Imunocomprometido
9.
J Hematol Oncol ; 17(1): 85, 2024 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-39285441

RESUMO

BACKGROUND: Relapsed and refractory acute myeloid leukemia (AML) carries a dismal prognosis. CAR T cells have shown limited efficacy in AML, partially due to dysfunctional autologous T cells and the extended time for generation of patient specific CAR T cells. Allogeneic NK cell therapy is a promising alternative, but strategies to enhance efficacy and persistence may be necessary. Proteasome inhibitors (PI) induce changes in the surface proteome which may render malignant cells more vulnerable to NK mediated cytotoxicity. Here, we investigated the potential benefit of combining PIs with CAR-expressing allogeneic NK cells against AML. METHODS: We established the IC50 concentrations for Bortezomib and Carfilzomib against several AML cell lines. Surface expression of class-I HLA molecules and stress-associated proteins upon treatment with proteasome inhibitors was determined by multiparameter flow cytometry. Using functional in vitro assays, we explored the therapeutic synergy between pre-treatment with PIs and the anti-leukemic efficacy of NK cells with or without expression of AML-specific CAR constructs against AML cell lines and primary patient samples. Also, we investigated the tolerability and efficacy of a single PI application strategy followed by (CAR-) NK cell infusion in two different murine xenograft models of AML. RESULTS: AML cell lines and primary AML patient samples were susceptible to Bortezomib and Carfilzomib mediated cytotoxicity. Conditioned resistance to Azacitidine/Venetoclax did not confer primary resistance to PIs. Treating AML cells with PIs reduced the surface expression of class-I HLA molecules on AML cells in a time-and-dose dependent manner. Stress-associated proteins were upregulated on the transcriptional level and on the cell surface. NK cell mediated killing of AML cells was enhanced in a synergistic manner. PI pre-treatment increased effector-target cell conjugate formation and Interferon-γ secretion, resulting in enhanced NK cell activity against AML cell lines and primary samples in vitro. Expression of CD33- and CD70-specific CARs further improved the antileukemic efficacy. In vivo, Bortezomib pre-treatment followed by CAR-NK cell infusion reduced AML growth, leading to prolonged overall survival. CONCLUSIONS: PIs enhance the anti-leukemic efficacy of CAR-expressing allogeneic NK cells against AML in vitro and in vivo, warranting further exploration of this combinatorial treatment within early phase clinical trials.


Assuntos
Bortezomib , Células Matadoras Naturais , Leucemia Mieloide Aguda , Inibidores de Proteassoma , Receptores de Antígenos Quiméricos , Humanos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/efeitos dos fármacos , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/imunologia , Leucemia Mieloide Aguda/tratamento farmacológico , Inibidores de Proteassoma/farmacologia , Inibidores de Proteassoma/uso terapêutico , Receptores de Antígenos Quiméricos/imunologia , Animais , Camundongos , Linhagem Celular Tumoral , Bortezomib/farmacologia , Bortezomib/uso terapêutico , Oligopeptídeos/farmacologia , Oligopeptídeos/uso terapêutico , Imunoterapia Adotiva/métodos , Ensaios Antitumorais Modelo de Xenoenxerto , Camundongos Endogâmicos NOD , Camundongos SCID , Feminino
10.
Front Immunol ; 15: 1424269, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39286245

RESUMO

Background: Chimeric antigen receptor (CAR) T-cell therapy has attracted considerable attention since its recent endorsement by the Food and Drug Administration, as it has emerged as a promising immunotherapeutic modality within the landscape of oncology. This study explores the prognostic utility of [18F]Fluorodeoxyglucose positron emission tomography ([18F]FDG PET) in lymphoma patients undergoing CAR T-cell therapy. Through meta-analysis, pooled hazard ratio (HR) values were calculated for specific PET metrics in this context. Methods: PubMed, Scopus, and Ovid databases were explored to search for relevant topics. Dataset retrieval from inception until March 12, 2024, was carried out. The primary endpoints were impact of specific PET metrics on overall survival (OS) and progression-free survival (PFS) before and after treatment. Data from the studies were extracted for a meta-analysis using Stata 17.0. Results: Out of 27 studies identified for systematic review, 15 met the criteria for meta-analysis. Baseline OS analysis showed that total metabolic tumor volume (TMTV) had the highest HR of 2.66 (95% CI: 1.52-4.66), followed by Total-body total lesion glycolysis (TTLG) at 2.45 (95% CI: 0.98-6.08), and maximum standardized uptake values (SUVmax) at 1.30 (95% CI: 0.77-2.19). TMTV and TTLG were statistically significant (p < 0.0001), whereas SUVmax was not (p = 0.33). For PFS, TMTV again showed the highest HR at 2.65 (95% CI: 1.63-4.30), with TTLG at 2.35 (95% CI: 1.40-3.93), and SUVmax at 1.48 (95% CI: 1.08-2.04), all statistically significant (p ≤ 0.01). The ΔSUVmax was a significant predictor for PFS with an HR of 2.05 (95% CI: 1.13-3.69, p = 0.015). Conclusion: [18F]FDG PET parameters are valuable prognostic tools for predicting outcome of lymphoma patients undergoing CAR T-cell therapy.


Assuntos
Fluordesoxiglucose F18 , Imunoterapia Adotiva , Linfoma , Tomografia por Emissão de Pósitrons , Humanos , Imunoterapia Adotiva/métodos , Linfoma/terapia , Linfoma/diagnóstico por imagem , Linfoma/imunologia , Linfoma/mortalidade , Prognóstico , Compostos Radiofarmacêuticos
11.
Front Immunol ; 15: 1408892, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39234256

RESUMO

Introduction: Ciltacabtagene autoleucel (cilta-cel) is a chimeric antigen receptor T-cell therapy approved for patients with relapsed/refractory multiple myeloma (RRMM). In the phase 3 trial, CARTITUDE-4 (NCT04181827), cilta-cel demonstrated improved efficacy vs. standard of care (SOC; daratumumab plus pomalidomide and dexamethasone [DPd] or pomalidomide plus bortezomib and dexamethasone [PVd]) with a ≥ complete response (≥CR) rate of 73.1% vs. 21.8%. Methods: A cost-per-responder model was developed to assess the value of cilta-cel and SOC (87% DPd and 13% PVd) based on the CARTITUDE-4 trial data from a US mixed payer perspective (76.7% commercial, 23.3% Medicare). The model was developed using progression-free survival (PFS), overall survival (OS), and ≥CR endpoints from CARTITUDE-4 over a period of 25.4 months. Inpatient stays, outpatient visits, drug acquisition, administration, and monitoring costs were included. The base-case model assumed an inpatient setting for each cilta-cel infusion; another scenario included 30% outpatient and 70% inpatient infusions. Costs of managing grade 3-4 adverse events (AEs) and grade 1-4 cytokine release syndrome and neurotoxicity were included. Subsequent therapy costs were incurred after disease progression; terminal care costs were considered upon death events. Outcomes included total cost per treated patient, total cost per complete responder, and cost per month in PFS between cilta-cel and SOC. Costs were adjusted to 2024 US dollars. Results: Total cost per treated patient, total cost per complete responder, and total cost per month in PFS were estimated at $704,641, $963,941, and $30,978 for cilta-cel, respectively, and $840,730, $3,856,559, and $42,520 for SOC over the 25.4-month period. Cost drivers included treatment acquisition costs before progression and subsequent treatment costs ($451,318 and $111,637 for cilta-cel; $529,795 and $265,167 for SOC). A scenario analysis in which 30% of patients received an outpatient infusion (assuming the same payer mix) showed a lower cost per complete responder for cilta-cel ($956,523) than those with an infusion in the inpatient setting exclusively. Discussion: This analysis estimated that cost per treated patient, cost per complete responder, and cost per month in PFS for cilta-cel were remarkably lower than for DPd or PVd, highlighting the substantial clinical and economic benefit of cilta-cel for patients with RRMM.


Assuntos
Análise Custo-Benefício , Imunoterapia Adotiva , Lenalidomida , Mieloma Múltiplo , Talidomida , Humanos , Mieloma Múltiplo/terapia , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/tratamento farmacológico , Lenalidomida/uso terapêutico , Lenalidomida/administração & dosagem , Imunoterapia Adotiva/economia , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Talidomida/análogos & derivados , Talidomida/uso terapêutico , Talidomida/economia , Talidomida/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/economia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Dexametasona/uso terapêutico , Dexametasona/administração & dosagem , Receptores de Antígenos Quiméricos/uso terapêutico , Receptores de Antígenos Quiméricos/imunologia , Masculino , Feminino , Bortezomib/uso terapêutico , Bortezomib/administração & dosagem , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Resultado do Tratamento , Idoso , Resistencia a Medicamentos Antineoplásicos , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais/economia
12.
Front Immunol ; 15: 1408718, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39234257

RESUMO

Despite significant breakthroughs in the understanding of immunological and pathophysiological features for immune-mediated kidney diseases, a proportion of patients exhibit poor responses to current therapies or have been categorized as refractory renal disease. Engineered T cells have emerged as a focal point of interest as a potential treatment strategy for kidney diseases. By genetically modifying T cells and arming them with chimeric antigen receptors (CARs), effectively targeting autoreactive immune cells, such as B cells or antibody-secreting plasma cells, has become feasible. The emergence of CAR T-cell therapy has shown promising potential in directing effector and regulatory T cells (Tregs) to the site of autoimmunity, paving the way for effective migration, proliferation, and execution of suppressive functions. Genetically modified T-cells equipped with artificial receptors have become a novel approach for alleviating autoimmune manifestations and reducing autoinflammatory events in the context of kidney diseases. Here, we review the latest developments in basic, translational, and clinical studies of CAR-based therapies for immune-mediated kidney diseases, highlighting their potential as promising avenues for therapeutic intervention.


Assuntos
Imunoterapia Adotiva , Nefropatias , Receptores de Antígenos Quiméricos , Humanos , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/genética , Imunoterapia Adotiva/métodos , Nefropatias/terapia , Nefropatias/imunologia , Animais , Linfócitos T/imunologia
13.
Front Immunol ; 15: 1441410, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39234260

RESUMO

Mucosal melanoma (MM) poses a significant clinical challenge due to its aggressive nature and limited treatment options. In recent years, immunotherapy has emerged as a promising strategy for MM, with a particular focus on immune checkpoint inhibitors such as PD-1 and CTLA-4 inhibitors. These inhibitors have demonstrated substantial efficacy by harnessing the body's immune response against tumors. Moreover, adoptive cell transfer (ACT), anti-angiogenic therapy, and combination therapies have garnered attention for their potential in MM treatment. ACT involves modifying T cells to target melanoma cells, showing promising antitumor activity. Anti-angiogenic therapy aims to impede tumor growth by inhibiting angiogenesis, while combination therapies, including immune checkpoint inhibitors and targeted therapies, offer a multifaceted approach to overcome treatment resistance. This comprehensive review explores the advancements in immunotherapy for MM, highlighting the role of diverse therapeutic modalities in enhancing treatment outcomes and addressing the challenges posed by this aggressive malignancy.


Assuntos
Inibidores de Checkpoint Imunológico , Imunoterapia , Melanoma , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Melanoma/terapia , Melanoma/imunologia , Melanoma/tratamento farmacológico , Imunoterapia/métodos , Animais , Resultado do Tratamento , Mucosa/imunologia , Terapia Combinada , Imunoterapia Adotiva/métodos
14.
Bull World Health Organ ; 102(9): 628-629, 2024 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-39219764

RESUMO

Alka Dwivedi talks to Gary Humphreys about developing a new form of CAR T-cell therapy in collaboration with clinicians with a view to improving treatment outcomes and lowering costs.


Assuntos
Imunoterapia Adotiva , Humanos , Imunoterapia Adotiva/métodos , Receptores de Antígenos Quiméricos
15.
Sci Adv ; 10(36): eadj4632, 2024 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-39231214

RESUMO

Low antigen sensitivity and a gradual loss of effector functions limit the clinical applicability of chimeric antigen receptor (CAR)-modified T cells and call for alternative antigen receptor designs for effective T cell-based cancer immunotherapy. Here, we applied advanced microscopy to demonstrate that TCR/CD3-based synthetic constructs (TCC) outperform second-generation CAR formats with regard to conveyed antigen sensitivities by up to a thousandfold. TCC-based antigen recognition occurred without adverse nonspecific signaling, which is typically observed in CAR-T cells, and did not depend-unlike sensitized peptide/MHC detection by conventional T cells-on CD4 or CD8 coreceptor engagement. TCC-endowed signaling properties may prove critical when targeting antigens in low abundance and aiming for a durable anticancer response.


Assuntos
Receptores de Antígenos de Linfócitos T , Receptores de Antígenos Quiméricos , Humanos , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/metabolismo , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos de Linfócitos T/imunologia , Complexo CD3/metabolismo , Complexo CD3/imunologia , Ativação Linfocitária/imunologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Imunoterapia Adotiva/métodos , Transdução de Sinais , Linhagem Celular Tumoral
16.
Clin Exp Med ; 24(1): 210, 2024 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-39230837

RESUMO

The influence of chimeric antigen receptor T (CAR-T) cell therapy on platelet function in relapsed/refractory (R/R) multiple myeloma (MM) has not been thoroughly investigated. Our cohort comprised fifty MM patients treated with CAR-T cells. The mean platelet closure time (PCT) induced by collagen/adenosine diphosphate (CADP) in peripheral blood was significantly prolonged before lymphodepletion (195.24 ± 11.740 s) and notably reduced post-CAR-T cell therapy (128.02 ± 5.60 s), with a statistically significant improvement (67.22, 95% CI 46.91-87.53, P < 0.001). This post-treatment PCT was not significantly different from that of healthy controls (10.64, 95% CI 1.11-22.40, P > 0.05). Furthermore, a pronounced enhancement in PCT was observed in patients with a response greater than partial remission (PR) following CAR-T cell infusion compared to pre-treatment values (P < 0.001). An extended PCT was also associated with a less favorable remission status. In patients with cytokine release syndrome (CRS) grades 0-2, those with a PCT over 240.5 s exhibited a shorter progression-free survival (PFS), with median PFS times of 10.2 months for the PCT > 240.5 s group versus 22.0 months for the PCT ≤ 240.5 s group. Multivariate analysis revealed that a PCT value exceeding 240.5 s is an independent prognostic factor for overall survival (OS) in R/R MM patients after CAR-T cell therapy. The study demonstrates that CAR-T cell therapy enhances platelet function in R/R MM patients, and PCT emerges as a potential prognostic biomarker for the efficacy of CAR-T cell therapy.


Assuntos
Plaquetas , Imunoterapia Adotiva , Mieloma Múltiplo , Humanos , Mieloma Múltiplo/terapia , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/patologia , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Adulto , Resultado do Tratamento , Receptores de Antígenos Quiméricos , Síndrome da Liberação de Citocina/terapia , Testes de Função Plaquetária
17.
Artigo em Inglês | MEDLINE | ID: mdl-39277881

RESUMO

Endothelial Activation and Stress Index (EASIX) has been proposed as a prognostic factor of adverse events or survival in hematological malignancies. Endothelial dysfunction has been associated with complications following stem cell transplantation and chimeric antigen receptor (CAR)-T therapy. This retrospective cohort study evaluated the utility of the EASIX score as a prognostic factor of cytokine release syndrome (CRS) in multiple myeloma/light-chain amyloidosis (MM/AL amyloidosis; N = 69) and large B-cell lymphoma (LBCL) cohorts (N = 65). Occurrence of CRS grade ≥3 was the primary endpoint. For both cohorts, the EASIX and simplified EASIX (s-EASIX) scores were calculated at four different time points before CAR-T infusion to assess its prognostic value. In the MM/AL amyloidosis cohort, neither EASIX nor s-EASIX scores calculated at any time point were associated with the occurrence of CRS grade ≥3. In the LBCL cohort, EASIX and s-EASIX scores measured before lymphodepletion (EASIX-pre and s-EASIX-pre) showed a significant relationship with CRS grade ≥3 (odds ratio [OR] = 1.06 and OR = 1.05, respectively). The cutoff value of 1.835 for EASIX-pre was associated with 4.59-fold increased OR of CRS grade ≥3 (95% confidence interval [CI]: 1.13-21.84), whereas s-EASIX-pre cutoff equaled 2.134 and was associated with 4.13-fold increased OR of CRS grade ≥3 (95% CI: 1.01-17.93). However, after internal validation with bootstrapping, the significance was lost both for the EASIX-pre and s-EASIX-pre cutoff. The presented findings indicate that the EASIX scores fail to predict CRS in MM/amyloidosis CAR-T patients, whereas they can be implemented as CRS grade ≥3 predictors in LBCL CAR-T patients.


Assuntos
Síndrome da Liberação de Citocina , Imunoterapia Adotiva , Linfoma Difuso de Grandes Células B , Mieloma Múltiplo , Receptores de Antígenos Quiméricos , Humanos , Estudos Retrospectivos , Masculino , Pessoa de Meia-Idade , Feminino , Mieloma Múltiplo/terapia , Mieloma Múltiplo/imunologia , Imunoterapia Adotiva/métodos , Imunoterapia Adotiva/efeitos adversos , Prognóstico , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/diagnóstico , Idoso , Linfoma Difuso de Grandes Células B/terapia , Linfoma Difuso de Grandes Células B/imunologia , Receptores de Antígenos Quiméricos/imunologia , Adulto , Estudos de Coortes
18.
Sci Rep ; 14(1): 21331, 2024 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-39266656

RESUMO

Programming cell signaling during T-cell activation represents a simple strategy for improving the potency of therapeutic T-cell products. Stim-R technology (Lyell Immunopharma) is a customizable, degradable synthetic cell biomimetic that emulates physiologic, cell-like presentation of signal molecules to control T-cell activation. A breadth of Stim-R formulations with different anti-CD3/anti-CD28 (αCD3/αCD28) antibody densities and stoichiometries were screened for their effects on multiple metrics of T-cell function. We identified an optimized formulation that produced receptor tyrosine kinase-like orphan receptor 1 (ROR1)-targeted chimeric antigen receptor (CAR) T cells with enhanced persistence and polyfunctionality in vitro, as assessed in repeat-stimulation assays, compared with a benchmark product generated using a conventional T-cell-activating reagent. In transcriptomic analyses, CAR T cells activated with Stim-R technology showed downregulation of exhaustion-associated gene sets and retained a unique subset of stem-like cells with effector-associated gene signatures following repeated exposure to tumor cells. Compared with the benchmark product, CAR T cells activated using the optimized Stim-R technology formulation exhibited higher peak expansion, prolonged persistence, and improved tumor control in a solid tumor xenograft model. Enhancing T-cell products with Stim-R technology during T-cell activation may help improve therapeutic efficacy against solid tumors.


Assuntos
Ativação Linfocitária , Receptores de Antígenos Quiméricos , Transdução de Sinais , Linfócitos T , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/metabolismo , Receptores de Antígenos Quiméricos/genética , Humanos , Animais , Ativação Linfocitária/imunologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Camundongos , Imunoterapia Adotiva/métodos , Ensaios Antitumorais Modelo de Xenoenxerto , Linhagem Celular Tumoral , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos de Linfócitos T/imunologia , Antígenos CD28/imunologia , Antígenos CD28/metabolismo
20.
Front Immunol ; 15: 1433012, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39267739

RESUMO

Background: Chimeric antigen receptor T cell (CAR-T) is a promising treatment for aggressive Non-Hodgkin lymphoma (NHL). The aim of the meta-analysis was to determine the association between metabolic tumor volumes (MTV) derived on positron emission tomography before CAR-T infusion and the survival of patients with NHL. Methods: Relevant observational studies pertaining to the purpose of the meta-analysis were obtained through a search of PubMed, Web of Science, and Embase from inception of the databases to April 1, 2024. The data was combined using a random-effects model that accounted for the potential influence of between-study heterogeneity. Results: Fifteen observational studies were included. Pooled results showed that compared to those with a lower MTV, the NHL patients with a higher MTV before CAR-T infusion were associated with a poor progression-free survival (hazard ratio [HR]: 1.73, 95% confidence interval [CI]: 1.48 to 2.02, p < 0.001; I2 = 20%) and overall survival (HR: 2.11, 95% CI: 1.54 to 2.89, p < 0.001; I2 = 58%). Subgroup analysis showed that the association between MTV and survival of NHL patients after CAR-T was not significantly impacted by study design, methods for determination of MTV cutoff, or analytic models (univariate or multivariate, p for each subgroup all < 0.05). Subgroup analysis suggested a stronger association between MTV and poor survival outcomes in patients with median of lines of previous treatment of 2 or 3 as compared to those of 4 (p for subgroup difference < 0.05). Further meta-regression analyses suggested that the association between MTV and survival was not significantly affected by sample size, age, proportion of men, cutoff value of MTV, follow-up duration, or study quality scores (p all > 0.05). Conclusion: A high MTV at baseline is associated with a poor survival of NHL patients after CAR-T. Systematic Review Registration: https://inplasy.com/, identifier INPLASY (INPLASY202450069).


Assuntos
Imunoterapia Adotiva , Linfoma não Hodgkin , Humanos , Imunoterapia Adotiva/métodos , Linfoma não Hodgkin/terapia , Linfoma não Hodgkin/mortalidade , Linfoma não Hodgkin/imunologia , Linfoma não Hodgkin/patologia , Carga Tumoral , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/metabolismo
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