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1.
Viruses ; 13(7)2021 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-34372571

RESUMO

Anti-cancer activity can be improved by engineering immune cells to express chimeric antigen receptors (CARs) that recognize tumor-associated antigens. Retroviral vector gene transfer strategies allow stable and durable transgene expression. Here, we used alpharetroviral vectors to modify NK-92 cells, a natural killer cell line, with a third-generation CAR designed to target the IL-3 receptor subunit alpha (CD123), which is strongly expressed on the surface of acute myeloid leukemia (AML) cells. Alpharetroviral vectors also contained a transgene cassette to allow constitutive expression of human IL-15 for increased NK cell persistence in vivo. The anti-AML activity of CAR-NK-92 cells was tested via in vitro cytotoxicity assays with the CD123+ AML cell line KG-1a and in vivo in a patient-derived xenotransplantation CD123+ AML model. Unmodified NK-92 cells or NK-92 cells modified with a truncated version of the CAR that lacked the signaling domain served as controls. Alpharetroviral vector-modified NK-92 cells stably expressed the transgenes and secreted IL-15. Anti-CD123-CAR-NK-92 cells exhibited enhanced anti-AML activity in vitro and in vivo as compared to control NK-92 cells. Our data (1) shows the importance of IL-15 expression for in vivo persistence of NK-92 cells, (2) supports continued investigation of anti-CD123-CAR-NK cells to target AML, and (3) points towards potential strategies to further improve CAR-NK anti-AML activity.


Assuntos
Imunoterapia Adotiva/métodos , Subunidade alfa de Receptor de Interleucina-3/imunologia , Leucemia Mieloide Aguda/tratamento farmacológico , Idoso , Alpharetrovirus/genética , Animais , Linhagem Celular Tumoral , Feminino , Terapia Genética , Vetores Genéticos/genética , Humanos , Subunidade alfa de Receptor de Interleucina-3/genética , Subunidade alfa de Receptor de Interleucina-3/metabolismo , Células Matadoras Naturais/imunologia , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/imunologia , Masculino , Camundongos , Camundongos Endogâmicos NOD , Cultura Primária de Células , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/imunologia , Transdução Genética , Transgenes , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Theranostics ; 11(16): 7700-7714, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34335959

RESUMO

CD4+ T helper cells are capable of mediating long-term antitumoral immune responses. We developed a combined immunotherapy (COMBO) using tumor antigen-specific T helper 1 cells (Tag-Th1), dual PD-L1/LAG-3 immune checkpoint blockade, and a low-dose total body irradiation (TBI) of 2 Gy, that was highly efficient in controlling the tumor burden of non-immunogenic RIP1-Tag2 mice with late-stage endogenous pancreatic islet carcinomas. In this study, we aimed to explore the impact of 2 Gy TBI on the treatment efficacy and the underlying mechanisms to boost CD4+ T cell-based immunotherapies. Methods: Heavily progressed RIP1-Tag2 mice underwent COMBO treatment and their survival was compared to a cohort without 2 Gy TBI. Positron emission tomography/computed tomography (PET/CT) with radiolabeled anti-CD3 monoclonal antibodies and flow cytometry were applied to investigate 2 Gy TBI-induced alterations in the biodistribution of endogenous T cells of healthy C3H mice. Migration and homing properties of Cy5-labeled adoptive Tag-Th1 cells were monitored by optical imaging and flow cytometric analyses in C3H and tumor-bearing RIP1-Tag2 mice. Splenectomy or sham-surgery of late-stage RIP1-Tag2 mice was performed before onset of COMBO treatment to elucidate the impact of the spleen on the therapy response. Results: First, we determined a significant longer survival of RIP1-Tag2 mice and an increased CD4+ T cell tumor infiltrate when 2 Gy TBI was applied in addition to Tag-Th1 cell PD-L1/LAG-3 treatment. In non-tumor-bearing C3H mice, TBI induced a moderate host lymphodepletion and a tumor antigen-independent accumulation of Tag-Th1 cells in lymphoid and non-lymphoid organs. In RIP1-Tag2, we found increased numbers of effector memory-like Tag-Th1 and endogenous CD4+ T cells in the pancreatic tumor tissue after TBI, accompanied by a tumor-specific Th1-driven immune response. Furthermore, the spleen negatively regulated T cell effector function by upregulation PD-1/LAG-3/TIM-3 immune checkpoints, providing a further rationale for this combined treatment approach. Conclusion: Low-dose TBI represents a powerful tool to foster CD4+ T cell-based cancer immunotherapies by favoring Th1-driven antitumoral immunity. As TBI is a clinically approved and well-established technique it might be an ideal addition for adoptive cell therapy with CD4+ T cells in the clinical setting.


Assuntos
Imunoterapia/métodos , Células Th1/metabolismo , Irradiação Corporal Total/métodos , Animais , Anticorpos Monoclonais/farmacologia , Antígenos CD/imunologia , Antígenos CD/metabolismo , Antígenos de Neoplasias , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Antígeno B7-H1/metabolismo , Feminino , Imunidade/efeitos dos fármacos , Imunoterapia Adotiva/métodos , Camundongos , Camundongos Endogâmicos C3H , Imagem Óptica , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/patologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Células Th1/imunologia , Distribuição Tecidual
3.
Front Immunol ; 12: 655122, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34408743

RESUMO

FOXP3+ regulatory T cells (Tregs) are central for maintaining peripheral tolerance and immune homeostasis. Because of their immunosuppressive characteristics, Tregs are a potential therapeutic target in various diseases such as autoimmunity, transplantation and infectious diseases like COVID-19. Numerous studies are currently exploring the potential of adoptive Treg therapy in different disease settings and novel genome editing techniques like CRISPR/Cas will likely widen possibilities to strengthen its efficacy. However, robust and expeditious protocols for genome editing of human Tregs are limited. Here, we describe a rapid and effective protocol for reaching high genome editing efficiencies in human Tregs without compromising cell integrity, suitable for potential therapeutic applications. By deletion of IL2RA encoding for IL-2 receptor α-chain (CD25) in Tregs, we demonstrated the applicability of the method for downstream functional assays and highlighted the importance for CD25 for in vitro suppressive function of human Tregs. Moreover, deletion of IL6RA (CD126) in human Tregs elicits cytokine unresponsiveness and thus may prevent IL-6-mediated instability of Tregs, making it an attractive target to potentially boost functionality in settings of adoptive Treg therapies to contain overreaching inflammation or autoimmunity. Thus, our rapid and efficient protocol for genome editing in human Tregs may advance possibilities for Treg-based cellular therapies.


Assuntos
Edição de Genes/métodos , Subunidade alfa de Receptor de Interleucina-2/genética , Receptores de Interleucina-6/genética , Linfócitos T Reguladores/metabolismo , Buffy Coat/citologia , Sistemas CRISPR-Cas/genética , Fatores de Transcrição Forkhead/metabolismo , Técnicas de Silenciamento de Genes , Células HEK293 , Voluntários Saudáveis , Humanos , Imunoterapia Adotiva/métodos , Cultura Primária de Células , RNA Guia/genética , Fatores de Tempo
4.
Anticancer Res ; 41(7): 3281-3285, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34230122

RESUMO

BACKGROUND/AIM: Recent studies have indicated that natural killer (NK) cells present in peripheral blood mononuclear cells (PBMCs) might be responsible for the somewhat poor outcome of clinical trials conducted with the NK cell line NK-92, as well as chimeric antigen receptor-modified NK-92 cells against leukemias and lymphomas. These NK cells and how their cytotoxic profiles can be altered by some common gamma chain receptor-dependent cytokines or by removal of CD4+ cells have been addressed herein. MATERIALS AND METHODS: A time-resolved fluorometric assay using 2.2':6'.2"-terpyridine-6.6"-dicarboxylic acid-labeled NK-92 or K562 as target cells was used for measuring the cytotoxic activity of cytokine-treated PBMCs and purified NK cells. RESULTS: Pre-incubation with 25 ng/ml interleukin 12 (IL-12), IL-15 or IL-21 for 72 h increased NK cell activity against K562 cells by more than 90% (1:25 target:effector ratio), whereas the corresponding NK cell activity against NK-92 cells was reduced by 15.9±0.1% by IL-12 and 50.6±2.9% by IL-15 compared to cells treated with medium alone. IL-7, on the other hand, increased NK activity against K562 to a much smaller extent (10.4±0.4%) and inhibited NK-92 cell lysis by 15.2±0.3%. Interestingly, similar amounts of IL-2 potentiated NK cell activity against both K562 and NK-92 cells by 50.9±0.5% and 14.3±0.9%, respectively. Purification of NK cells with magnetic beads demonstrated that NK cells indeed were responsible for the observed cytotoxic activity against both NK-92 cells (58.5±9.10%, 1:100 target:effector ratio) and K562 cells (81.6±9.57%, 1:100 target:effector ratio). Elimination of CD4+ cells from PBMCs did not alter the NK activity profile. CONCLUSION: This study highlights a problem that might arise with immune-based NK-92 and chimeric antigen receptor-transduced NK-92 cell therapies and pinpoints the need for evaluating new NK-like cell lines.


Assuntos
Interleucina-15/imunologia , Células Matadoras Naturais/imunologia , Leucemia/imunologia , Linfoma/imunologia , Linfócitos T CD4-Positivos/imunologia , Linhagem Celular , Linhagem Celular Tumoral , Citotoxicidade Imunológica/imunologia , Humanos , Imunoterapia Adotiva/métodos , Interleucina-2/imunologia , Interleucinas/imunologia , Células K562 , Leucócitos Mononucleares/imunologia , Receptores de Antígenos Quiméricos/imunologia
5.
Cells ; 10(6)2021 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-34205262

RESUMO

COVID-19 is an acute infectious disease of the respiratory system caused by infection with the SARS-CoV-2 virus (Severe Acute Respiratory Syndrome Coronavirus 2). Transmission of SARS-CoV-2 infections occurs through droplets and contaminated objects. A rapid and well-coordinated immune system response is the first line of defense in a viral infection. However, a disturbed and over-activated immune response may be counterproductive, causing damage to the body. Severely ill patients hospitalised with COVID-19 exhibit increased levels of many cytokines, including Interleukin (IL)-1ß, IL-2, IL-6, IL-7, IL-8, IL-10, IL-17, granulocyte colony stimulating factor (G-CSF), monocyte chemoattractant protein 1 (MCP-1) and tumor necrosis factor (TNF). Increasing evidence suggests that Th17 cells play an important role in the pathogenesis of COVID-19, not only by activating cytokine cascade but also by inducing Th2 responses, inhibiting Th1 differentiation and suppressing Treg cells. This review focuses on a Th17 pathway in the course of the immune response in COVID-19, and explores plausible targets for therapeutic intervention.


Assuntos
COVID-19/imunologia , Imunidade Celular/fisiologia , Células Th17/fisiologia , COVID-19/patologia , COVID-19/terapia , Citocinas/metabolismo , Humanos , Imunoterapia Adotiva/métodos , SARS-CoV-2/imunologia , Células Th17/metabolismo
6.
Int J Mol Sci ; 22(13)2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34201529

RESUMO

The emergence of immune-based treatments for cancer has led to a growing field dedicated to understanding and managing iatrogenic immunotoxicities that arise from these agents. Immune-related adverse events (irAEs) can develop as isolated events or as toxicities affecting multiple body systems. In particular, this review details the neurological irAEs from immune checkpoint inhibitors (ICI) and chimeric antigen receptor (CAR) T cell immunotherapies. The recognition and treatment of neurological irAEs has variable success, depending on the severity and nature of the neurological involvement. Understanding the involved mechanisms, predicting those at higher risk for irAEs, and establishing safety parameters for resuming cancer immunotherapies after irAEs are all important fields of ongoing research.


Assuntos
Inibidores de Checkpoint Imunológico/efeitos adversos , Imunoterapia Adotiva/efeitos adversos , Imunoterapia/efeitos adversos , Neoplasias/terapia , Biomarcadores Farmacológicos/análise , Biomarcadores Tumorais/análise , Antígeno CTLA-4/antagonistas & inibidores , Encefalite/induzido quimicamente , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia Adotiva/métodos , Meningite Asséptica/induzido quimicamente , Meningite Asséptica/imunologia , Neoplasias/imunologia , Síndromes Paraneoplásicas/induzido quimicamente , Receptores de Antígenos Quiméricos/uso terapêutico , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia
7.
Nat Commun ; 12(1): 4077, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34210970

RESUMO

Emerging data demonstrate that the activity of immune cells can be modulated by microbial molecules. Here, we show that the short-chain fatty acids (SCFAs) pentanoate and butyrate enhance the anti-tumor activity of cytotoxic T lymphocytes (CTLs) and chimeric antigen receptor (CAR) T cells through metabolic and epigenetic reprograming. We show that in vitro treatment of CTLs and CAR T cells with pentanoate and butyrate increases the function of mTOR as a central cellular metabolic sensor, and inhibits class I histone deacetylase activity. This reprogramming results in elevated production of effector molecules such as CD25, IFN-γ and TNF-α, and significantly enhances the anti-tumor activity of antigen-specific CTLs and ROR1-targeting CAR T cells in syngeneic murine melanoma and pancreatic cancer models. Our data shed light onto microbial molecules that may be used for enhancing cellular anti-tumor immunity. Collectively, we identify pentanoate and butyrate as two SCFAs with therapeutic utility in the context of cellular cancer immunotherapy.


Assuntos
Linfócitos T CD8-Positivos/metabolismo , Ácidos Graxos Voláteis/metabolismo , Fatores Imunológicos/metabolismo , Imunoterapia Adotiva/métodos , Microbiota/fisiologia , Neoplasias/imunologia , Linfócitos T Citotóxicos/imunologia , Animais , Butiratos/metabolismo , Linhagem Celular Tumoral , Citocinas/metabolismo , Feminino , Imunoterapia , Interferon gama , Subunidade alfa de Receptor de Interleucina-2 , Megasphaera , Melanoma/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Fragmentos de Peptídeos , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase , Receptores Acoplados a Proteínas G/genética , Fator de Necrose Tumoral alfa
8.
Int J Mol Sci ; 22(12)2021 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-34204326

RESUMO

Immunotherapy is now considered an innovative and strong strategy to beat metastatic, drug-resistant, or relapsing tumours. It is based on the manipulation of several mechanisms involved in the complex interplay between cancer cells and immune system that culminates in a form of immune-tolerance of tumour cells, favouring their expansion. Current immunotherapies are devoted enforcing the immune response against cancer cells and are represented by approaches employing vaccines, monoclonal antibodies, interleukins, checkpoint inhibitors, and chimeric antigen receptor (CAR)-T cells. Despite the undoubted potency of these treatments in some malignancies, many issues are being investigated to amplify the potential of application and to avoid side effects. In this review, we discuss how sphingolipids are involved in interactions between cancer cells and the immune system and how knowledge in this topic could be employed to enhance the efficacy of different immunotherapy approaches. In particular, we explore the following aspects: how sphingolipids are pivotal components of plasma membranes and could modulate the functionality of surface receptors expressed also by immune cells and thus their functionality; how sphingolipids are related to the release of bioactive mediators, sphingosine 1-phosphate, and ceramide that could significantly affect lymphocyte egress and migration toward the tumour milieu, in addition regulating key pathways needed to activate immune cells; given the renowned capability of altering sphingolipid expression and metabolism shown by cancer cells, how it is possible to employ sphingolipids as antigen targets.


Assuntos
Imunomodulação , Neoplasias/imunologia , Neoplasias/metabolismo , Esfingolipídeos/metabolismo , Animais , Antígenos de Neoplasias/imunologia , Comunicação Celular , Gerenciamento Clínico , Suscetibilidade a Doenças , Humanos , Sistema Imunitário/imunologia , Sistema Imunitário/metabolismo , Imunoterapia/efeitos adversos , Imunoterapia/métodos , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Lisofosfolipídeos/metabolismo , Neoplasias/terapia , Transdução de Sinais , Esfingolipídeos/química , Esfingolipídeos/imunologia , Esfingosina/análogos & derivados , Esfingosina/metabolismo , Resultado do Tratamento
9.
Theranostics ; 11(14): 6800-6817, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093854

RESUMO

Chimeric antigen receptor T cell (CAR-T) therapy is a new and effective form of adoptive cell therapy that is rapidly entering the mainstream for the treatment of CD19-positive hematological cancers because of its impressive effect and durable responses. Huge challenges remain in achieving similar success in patients with solid tumors. The current methods of monitoring CAR-T, including morphological imaging (CT and MRI), blood tests, and biopsy, have limitations to assess whether CAR-T cells are homing to tumor sites and infiltrating into tumor bed, or to assess the survival, proliferation, and persistence of CAR-T cells in solid tumors associated with an immunosuppressive microenvironment. Radionuclide-based molecular imaging affords improved CAR-T cellular visualization and therapeutic monitoring through either a direct cellular radiolabeling approach or a reporter gene imaging strategy, and endogenous cell imaging is beneficial to reflect functional information and immune status of T cells. Focusing on the dynamic monitoring and precise assessment of CAR-T therapy, this review summarizes the current applications of radionuclide-based noninvasive imaging in CAR-T cells visualization and monitoring and presents current challenges and strategic choices.


Assuntos
Antígenos de Neoplasias/imunologia , Imunoterapia Adotiva/métodos , Imagem Molecular/métodos , Neoplasias/diagnóstico por imagem , Receptores de Antígenos Quiméricos/uso terapêutico , Linfócitos T/imunologia , Microambiente Tumoral , Animais , Genes Reporter , Humanos , Camundongos , Radioisótopos , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/imunologia , Tomografia Computadorizada por Raios X , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Lancet ; 398(10297): 314-324, 2021 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-34175021

RESUMO

BACKGROUND: CARTITUDE-1 aimed to assess the safety and clinical activity of ciltacabtagene autoleucel (cilta-cel), a chimeric antigen receptor T-cell therapy with two B-cell maturation antigen-targeting single-domain antibodies, in patients with relapsed or refractory multiple myeloma with poor prognosis. METHODS: This single-arm, open-label, phase 1b/2 study done at 16 centres in the USA enrolled patients aged 18 years or older with a diagnosis of multiple myeloma and an Eastern Cooperative Oncology Group performance status score of 0 or 1, who received 3 or more previous lines of therapy or were double-refractory to a proteasome inhibitor and an immunomodulatory drug, and had received a proteasome inhibitor, immunomodulatory drug, and anti-CD38 antibody. A single cilta-cel infusion (target dose 0·75 × 106 CAR-positive viable T cells per kg) was administered 5-7 days after start of lymphodepletion. The primary endpoints were safety and confirmation of the recommended phase 2 dose (phase 1b), and overall response rate (phase 2) in all patients who received treatment. Key secondary endpoints were duration of response and progression-free survival. This trial is registered with ClinicalTrials.gov, NCT03548207. FINDINGS: Between July 16, 2018, and Oct 7, 2019, 113 patients were enrolled. 97 patients (29 in phase 1b and 68 in phase 2) received a cilta-cel infusion at the recommended phase 2 dose of 0·75 × 106 CAR-positive viable T cells per kg. As of the Sept 1, 2020 clinical cutoff, median follow-up was 12·4 months (IQR 10·6-15·2). 97 patients with a median of six previous therapies received cilta-cel. Overall response rate was 97% (95% CI 91·2-99·4; 94 of 97 patients); 65 (67%) achieved stringent complete response; time to first response was 1 month (IQR 0·9-1·0). Responses deepened over time. Median duration of response was not reached (95% CI 15·9-not estimable), neither was progression-free survival (16·8-not estimable). The 12-month progression-free rate was 77% (95% CI 66·0-84·3) and overall survival rate was 89% (80·2-93·5). Haematological adverse events were common; grade 3-4 haematological adverse events were neutropenia (92 [95%] of 97 patients), anaemia (66 [68%]), leukopenia (59 [61%]), thrombocytopenia (58 [60%]), and lymphopenia (48 [50%]). Cytokine release syndrome occurred in 92 (95%) of 97 patients (4% were grade 3 or 4); with median time to onset of 7·0 days (IQR 5-8) and median duration of 4·0 days (IQR 3-6). Cytokine release syndrome resolved in all except one with grade 5 cytokine release syndrome and haemophagocytic lymphohistiocytosis. CAR T-cell neurotoxicity occurred in 20 (21%) patients (9% were grade 3 or 4). 14 deaths occurred in the study; six due to treatment-related adverse events, five due to progressive disease, and three due to treatment-unrelated adverse events. INTERPRETATION: A single cilta-cel infusion at the target dose of 0·75 × 106 CAR-positive viable T cells per kg led to early, deep, and durable responses in heavily pretreated patients with multiple myeloma with a manageable safety profile. The data from this study formed the basis for recent regulatory submissions. FUNDING: Janssen Research & Development and Legend Biotech.


Assuntos
Antígeno de Maturação de Linfócitos B/administração & dosagem , Imunoterapia Adotiva/métodos , Mieloma Múltiplo/tratamento farmacológico , Receptores de Antígenos Quiméricos/administração & dosagem , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Estados Unidos
11.
Lancet ; 398(10299): 491-502, 2021 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-34097852

RESUMO

BACKGROUND: Despite treatment with novel therapies and allogeneic stem-cell transplant (allo-SCT) consolidation, outcomes in adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia remain poor, underlining the need for more effective therapies. METHODS: We report the pivotal phase 2 results of ZUMA-3, an international, multicentre, single-arm, open-label study evaluating the efficacy and safety of the autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy KTE-X19 in adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia. Patients were enrolled at 25 sites in the USA, Canada, and Europe. Eligible patients were aged 18 years or older, with Eastern Cooperative Oncology Group performance status of 0-1, and morphological disease in the bone marrow (>5% blasts). After leukapheresis and conditioning chemotherapy, patients received a single KTE-X19 infusion (1 × 106 CAR T cells per kg bodyweight). The primary endpoint was the rate of overall complete remission or complete remission with incomplete haematological recovery by central assessment. Duration of remission and relapse-free survival, overall survival, minimal residual disease (MRD) negativity rate, and allo-SCT rate were assessed as secondary endpoints. Efficacy and safety analyses were done in the treated population (all patients who received a dose of KTE-X19). This study is registered with ClinicalTrials.gov, NCT02614066. FINDINGS: Between Oct 1, 2018, and Oct 9, 2019, 71 patients were enrolled and underwent leukapheresis. KTE-X19 was successfully manufactured for 65 (92%) patients and administered to 55 (77%). The median age of treated patients was 40 years (IQR 28-52). At the median follow-up of 16·4 months (13·8-19·6), 39 patients (71%; 95% CI 57-82, p<0·0001) had complete remission or complete remission with incomplete haematological recovery, with 31 (56%) patients reaching complete remission. Median duration of remission was 12·8 months (95% CI 8·7-not estimable), median relapse-free survival was 11·6 months (2·7-15·5), and median overall survival was 18·2 months (15·9-not estimable). Among responders, the median overall survival was not reached, and 38 (97%) patients had MRD negativity. Ten (18%) patients received allo-SCT consolidation after KTE-X19 infusion. The most common adverse events of grade 3 or higher were anaemia (27 [49%] patients) and pyrexia (20 [36%] patients). 14 (25%) patients had infections of grade 3 or higher. Two grade 5 KTE-X19-related events occurred (brain herniation and septic shock). Cytokine release syndrome of grade 3 or higher occurred in 13 (24%) patients and neurological events of grade 3 or higher occurred in 14 (25%) patients. INTERPRETATION: KTE-X19 showed a high rate of complete remission or complete remission with incomplete haematological recovery in adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia, with the median overall survival not reached in responding patients, and a manageable safety profile. These findings indicate that KTE-X19 has the potential to confer long-term clinical benefit to these patients. FUNDING: Kite, a Gilead Company.


Assuntos
Imunoterapia Adotiva/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Receptores de Antígenos Quiméricos/uso terapêutico , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidade , Recidiva , Análise de Sobrevida , Resultado do Tratamento
12.
Nat Commun ; 12(1): 3182, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-34075041

RESUMO

Interleukin 9 (IL-9)-producing helper T (Th9) cells are essential for inducing anti-tumor immunity and inflammation in allergic and autoimmune diseases. Although transcription factors that are essential for Th9 cell differentiation have been identified, other signaling pathways that are required for their generation and functions are yet to be explored. Here, we identify that Epidermal Growth Factor Receptor (EGFR) is essential for IL-9 induction in helper T (Th) cells. Moreover, amphiregulin (Areg), an EGFR ligand, is critical for the amplification of Th9 cells induced by TGF-ß1 and IL-4. Furthermore, our data show that Areg-EGFR signaling induces HIF1α, which binds and transactivates IL-9 and NOS2 promoters in Th9 cells. Loss of EGFR or HIF1α abrogates Th9 cell differentiation and suppresses their anti-tumor functions. Moreover, in line with its reliance on HIF1α expression, metabolomics profiling of Th9 cells revealed that Succinate, a TCA cycle metabolite, promotes Th9 cell differentiation and Th9 cell-mediated tumor regression.


Assuntos
Receptores ErbB/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Interleucina-9/genética , Melanoma Experimental/terapia , Neoplasias Cutâneas/terapia , Linfócitos T Auxiliares-Indutores/imunologia , Anfirregulina/metabolismo , Animais , Diferenciação Celular/imunologia , Feminino , Células HEK293 , Voluntários Saudáveis , Humanos , Imunoterapia Adotiva/métodos , Melanoma Experimental/imunologia , Camundongos , Camundongos Knockout , Óxido Nítrico Sintase Tipo II/genética , Cultura Primária de Células , RNA-Seq , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Neoplasias Cutâneas/imunologia , Ácido Succínico/metabolismo , Linfócitos T Auxiliares-Indutores/transplante , Ativação Transcricional/imunologia
13.
Int J Mol Sci ; 22(11)2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34071550

RESUMO

Liver cancer has the fourth highest mortality rate of all cancers worldwide, with hepatocellular carcinoma (HCC) being the most prevalent subtype. Despite great advances in systemic therapy, such as molecular-targeted agents, HCC has one of the worst prognoses due to drug resistance and frequent recurrence and metastasis. Recently, new therapeutic strategies such as cancer immunosuppressive therapy have prolonged patients' lives, and the combination of an immune checkpoint inhibitor (ICI) and VEGF inhibitor is now positioned as the first-line therapy for advanced HCC. Since the efficacy of ICIs depends on the tumor immune microenvironment, it is necessary to elucidate the immune environment of HCC to select appropriate ICIs. In this review, we summarize the findings on the immune microenvironment and immunosuppressive approaches focused on monoclonal antibodies against cytotoxic T lymphocyte-associated protein 4 and programmed cell death protein 1 for HCC. We also describe ongoing treatment modalities, including adoptive cell transfer-based therapies and future areas of exploration based on recent literature. The results of pre-clinical studies using immunological classification and animal models will contribute to the development of biomarkers that predict the efficacy of immunosuppressive therapy and aid in the selection of appropriate strategies for HCC treatment.


Assuntos
Carcinoma Hepatocelular/terapia , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia Adotiva/métodos , Neoplasias Hepáticas/terapia , Fígado/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Animais , Carcinoma Hepatocelular/imunologia , Humanos , Fígado/imunologia , Fígado/patologia , Neoplasias Hepáticas/imunologia , Recidiva Local de Neoplasia , Linfócitos T/imunologia , Microambiente Tumoral/imunologia
14.
JCO Clin Cancer Inform ; 5: 668-678, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34110929

RESUMO

Chimeric antigen receptor T-cell (CAR-T) therapy is a paradigm-shifting immunotherapy modality in oncology; however, unique toxicities such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome limit its ability to be implemented more widely in the outpatient setting or at smaller-volume centers. Three operational challenges with CAR-T therapy include the following: (1) the logistics of toxicity monitoring, ie, with frequent vital sign checks and neurologic assessments; (2) the specialized knowledge required for toxicity management, particularly with regard to CRS and immune effector cell-associated neurotoxicity syndrome; and (3) the need for high-quality symptomatic and supportive care during this intensive period. In this review, we explore potential niches for digital innovations that can improve the implementation of CAR-T therapy in each of these domains. These tools include patient-facing technologies and provider-facing platforms: for example, wearable devices and mobile health apps to screen for fevers and encephalopathy, electronic patient-reported outcome assessments-based workflows to assist with symptom management, machine learning algorithms to predict emerging CRS in real time, clinical decision support systems to assist with toxicity management, and digital coaching to help maintain wellness. Televisits, which have grown in prominence since the novel coronavirus pandemic, will continue to play a key role in the monitoring and management of CAR-T-related toxicities as well. Limitations of these strategies include the need to ensure care equity and stakeholder buy-in, both operationally and financially. Nevertheless, once developed and validated, the next-generation implementation of CAR-T therapy using these digital tools may improve both its safety and accessibility.


Assuntos
Síndrome da Liberação de Citocina/etiologia , Imunoterapia Adotiva/efeitos adversos , Telemedicina/métodos , COVID-19 , Terapia Baseada em Transplante de Células e Tecidos/efeitos adversos , Humanos , Imunoterapia Adotiva/métodos , Aprendizado de Máquina , Síndromes Neurotóxicas/etiologia , Medicina de Precisão , Receptores de Antígenos de Linfócitos T , Receptores de Antígenos Quiméricos
15.
Int J Mol Sci ; 22(11)2021 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-34070747

RESUMO

Colorectal cancer (CRC) is one of the main causes of cancer death in the world. Post-translational modifications (PTMs) have been extensively studied in malignancies due to its relevance in tumor pathogenesis and therapy. This review is focused on the dysregulation of glycosyltransferase expression in CRC and its impact in cell function and in several biological pathways associated with CRC pathogenesis, prognosis and therapeutic approaches. Glycan structures act as interface molecules between cells and their environment and in several cases facilitate molecule function. CRC tissue shows alterations in glycan structures decorating molecules, such as annexin-1, mucins, heat shock protein 90 (Hsp90), ß1 integrin, carcinoembryonic antigen (CEA), epidermal growth factor receptor (EGFR), insulin-like growth factor-binding protein 3 (IGFBP3), transforming growth factor beta (TGF-ß) receptors, Fas (CD95), PD-L1, decorin, sorbin and SH3 domain-containing protein 1 (SORBS1), CD147 and glycosphingolipids. All of these are described as key molecules in oncogenesis and metastasis. Therefore, glycosylation in CRC can affect cell migration, cell-cell adhesion, actin polymerization, mitosis, cell membrane repair, apoptosis, cell differentiation, stemness regulation, intestinal mucosal barrier integrity, immune system regulation, T cell polarization and gut microbiota composition; all such functions are associated with the prognosis and evolution of the disease. According to these findings, multiple strategies have been evaluated to alter oligosaccharide processing and to modify glycoconjugate structures in order to control CRC progression and prevent metastasis. Additionally, immunotherapy approaches have contemplated the use of neo-antigens, generated by altered glycosylation, as targets for tumor-specific T cells or engineered CAR (Chimeric antigen receptors) T cells.


Assuntos
Neoplasias Colorretais/genética , Glicoesfingolipídeos/imunologia , Glicosiltransferases/genética , Mucinas/genética , Proteínas de Neoplasias/genética , Processamento de Proteína Pós-Traducional , Anexina A1/genética , Anexina A1/imunologia , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/patologia , Neoplasias Colorretais/terapia , Decorina/genética , Decorina/imunologia , Receptores ErbB/genética , Receptores ErbB/imunologia , Regulação Neoplásica da Expressão Gênica , Glicoesfingolipídeos/metabolismo , Glicosilação , Glicosiltransferases/imunologia , Humanos , Imunoterapia Adotiva/métodos , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/imunologia , Integrina beta1/genética , Integrina beta1/imunologia , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/imunologia , Mucinas/imunologia , Proteínas de Neoplasias/imunologia , Receptor fas/genética , Receptor fas/imunologia
16.
Medicine (Baltimore) ; 100(19): e25786, 2021 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-34106613

RESUMO

RATIONALE: Significant concerns about the adverse effects following chimeric antigen receptor T cell (CAR-T) therapy are still remained including cytokine release syndrome (CRS). In rare circumstances, CRS may be refractory to tocilizumab and/or corticosteroids, a new treatment is needed for the management of CRS. PATIENT CONCERNS: We present a case of a 20-year-old male patient with acute lymphoblastic leukemia developed CRS after CD19/CD22 bispecific CAR-T treatment. DIAGNOSIS: The patient was diagnosed with BCR-ABL(P210) positive B-ALL and developed CRS after CD19/CD22 bispecific CAR-T treatment. INTERVENTIONS: Tocilizumab and methylprednisolone were administered, unfortunately the patient's symptoms of CRS were still not resolved. Another methylprednisolone and ruxolitinib were administered. OUTCOMES: The persistent fever and hypotension of this patient achieved a rapid clinical remission within hours after ruxolitinib administration. LESSONS: Ruxolitinib can be used as an alternative therapeutic approach for severe and refractory CRS without impairing CAR-T amplification and anti-tumor effect.


Assuntos
Síndrome da Liberação de Citocina/tratamento farmacológico , Imunoterapia Adotiva/efeitos adversos , Inibidores de Janus Quinases/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Pirazóis/uso terapêutico , Receptores de Antígenos Quiméricos/uso terapêutico , Síndrome da Liberação de Citocina/etiologia , Humanos , Imunoterapia Adotiva/métodos , Masculino , Adulto Jovem
17.
Int J Mol Sci ; 22(11)2021 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-34073911

RESUMO

Chimeric antigen receptor (CAR) T-cell therapy has already achieved remarkable remissions in some difficult-to-treat patients with B-cell malignancies. Although the clinical experience in chronic lymphocytic leukemia (CLL) patients is limited, the proportion of remissions reached in this disease is clearly the lowest from the spectrum of B-cell tumors. In this review, we discuss the antigenic targets exploited in CLL CAR-T therapy, the determinants of favorable responses, as well as the mechanisms of treatment failure specific to this disease.


Assuntos
Antígenos CD19/imunologia , Imunoterapia Adotiva/métodos , Leucemia Linfocítica Crônica de Células B/imunologia , Leucemia Linfocítica Crônica de Células B/terapia , Receptores de Antígenos Quiméricos/imunologia , Linfócitos B/imunologia , Humanos , Indução de Remissão , Linfócitos T/imunologia
18.
Cancer Sci ; 112(9): 3427-3436, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34050690

RESUMO

Chimeric antigen receptors (CARs) have a unique facet of synthetic biology and offer a paradigm shift in personalized medicine as they can use and redirect the patient's immune cells to attack cancer cells. CAR-natural killer (NK) cells combine the targeted specificity of antigens with the subsequent intracellular signaling ability of the receptors to increase their anti-cancer functions. Importantly, CAR-NK cells can be utilized as universal cell-based therapy without requiring human leukocyte antigen (HLA) matching or earlier contact with tumor-associated antigens (TAAs). Indeed, CAR-NK cells can be adapted to recognize various antigens, hold higher proliferation capacity, and in vivo persistence, show improved infiltration into the tumors, and the ability to overcome the resistant tumor microenvironment leading to sustained cytotoxicity against tumors. Accumulating evidence from recent in vivo studies rendering CAR-NK cell anti-cancer competencies renewed the attention in the context of cancer immunotherapy, as these redirected effector cells can be used in the development of the "off-the-shelf" anti-cancer immunotherapeutic products. In the current review, we focus on the therapeutic efficacy of CAR-NK cell therapies for treating various human malignancies, including hematological malignancies and solid tumors, and will discuss the recent findings in this regard, with a special focus on animal studies.


Assuntos
Terapia Baseada em Transplante de Células e Tecidos/métodos , Neoplasias Hematológicas/terapia , Imunoterapia Adotiva/métodos , Células Matadoras Naturais/imunologia , Receptores de Antígenos Quiméricos/imunologia , Animais , Antígenos de Neoplasias/imunologia , Engenharia Genética/métodos , Vetores Genéticos , Humanos , Camundongos , Receptores de Antígenos Quiméricos/genética , Resultado do Tratamento , Microambiente Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Diabetes ; 70(6): 1211-1219, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34016597

RESUMO

Critical insights into the etiology of type 1 diabetes (T1D) came from genome-wide association studies that unequivocally connected genetic susceptibility to immune cell function. At the top of the susceptibility are genes involved in regulatory T-cell (Treg) function and development. The advances in epigenetic and transcriptional analyses have provided increasing evidence for Treg dysfunction in T1D. These are well supported by functional studies in mouse models and analysis of peripheral blood during T1D. For these reasons, Treg-based therapies are at the forefront of research and development and have a tangible probability to deliver a long-sought-after successful immune-targeted treatment for T1D. The current challenge in the field is whether we can directly assess Treg function at the tissue site or make informative interpretations based on peripheral data. Future studies focused on Treg function in pancreatic lymph nodes and pancreas could provide key insight into the ultimate mechanisms underlying Treg failure in T1D. In this Perspective we will provide an overview of current literature regarding Treg development and function in T1D and how this knowledge has been applied to Treg therapies.


Assuntos
Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/terapia , Linfócitos T Reguladores/fisiologia , Animais , Autoimunidade/fisiologia , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/patologia , Endocrinologia/métodos , Endocrinologia/tendências , Humanos , Tolerância Imunológica/fisiologia , Imunoterapia Adotiva/métodos , Imunoterapia Adotiva/tendências , Camundongos , Terapia de Alvo Molecular/métodos , Terapia de Alvo Molecular/tendências , Pâncreas/imunologia , Pâncreas/metabolismo , Pâncreas/patologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/transplante
20.
Curr Hematol Malig Rep ; 16(2): 218-233, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33939108

RESUMO

PURPOSE OF REVIEW: Both chimeric antigen receptor (CAR) T cells and T cell-engaging antibodies (BiAb) have been approved for the treatment of hematological malignancies. However, despite targeting the same antigen, they represent very different classes of therapeutics, each with its distinct advantages and drawbacks. In this review, we compare BiAb and CAR T cells with regard to their mechanism of action, manufacturing, and clinical application. In addition, we present novel strategies to overcome limitations of either approach and to combine the best of both worlds. RECENT FINDINGS: By now there are multiple approaches combining the advantages of BiAb and CAR T cells. A major area of research is the application of both formats for solid tumor entities. This includes improving the infiltration of T cells into the tumor, counteracting immunosuppression in the tumor microenvironment, targeting antigen heterogeneity, and limiting off-tumor on-target effects. BiAb come with the major advantage of being an off-the-shelf product and are more controllable because of their half-life. They have also been reported to induce less frequent and less severe adverse events. CAR T cells in turn demonstrate superior response rates, have the potential for long-term persistence, and can be additionally genetically modified to overcome some of their limitations, e.g., to make them more controllable.


Assuntos
Anticorpos Biespecíficos/imunologia , Imunoterapia Adotiva/métodos , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Animais , Anticorpos Biespecíficos/genética , Antígenos de Neoplasias/imunologia , Engenharia Genética , Humanos , Imunoterapia Adotiva/efeitos adversos , Ativação Linfocitária/imunologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Neoplasias/etiologia , Neoplasias/terapia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos Quiméricos/genética , Transdução de Sinais , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
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