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2.
Adv Exp Med Biol ; 1168: 131-145, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31713169

RESUMO

Adoptive T cell transfer (ACT) is a new era for cancer treatment, involving infusion of autologous lymphocytes. Chimeric antigen receptors (CAR) on the surface of T cells are emerging as a novel therapeutic that is giving other direction to T-cell specificity and precision medicine. T cells are engineered modification to recognize specific target antigen and are co-stimulated with intracellular signal to increase the T cell response. CAR-T cells have impressive involvement in outcome on hematological malignancies; however severe toxicities as cytokine release syndrome or neurotoxicity are a challenge to face. Solid tumors have heterogeneous antigens and tumor microenvironment that hinder CAR-T cell efficacy and increase the risk of on-target/off-tumor. Novel strategies to increase CAR-Ts specificity, safety and efficacy are ongoing in clinical trials to improve clinical outcomes in hematological and solid malignances.


Assuntos
Neoplasias , Medicina de Precisão , Receptores de Antígenos Quiméricos , Linfócitos T , Antígenos de Neoplasias , Humanos , Imunoterapia Adotiva , Neoplasias/imunologia , Neoplasias/terapia , Medicina de Precisão/tendências , Receptores de Antígenos de Linfócitos T , Receptores de Antígenos Quiméricos/uso terapêutico , Linfócitos T/imunologia
3.
Medicine (Baltimore) ; 98(43): e17572, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31651858

RESUMO

RATIONALE: Rhabdomyosarcoma (RMS) is a common soft tissue sarcoma in children with high malignancy. The prognosis of refractory recurrent RMS is extremely poor, and the 5-year survival rate is less than 20%. PATIENT CONCERNS: We reported a 2-year-old male patient with RMS who underwent 3 operations and 2 recurrences while being treated with regular multidisciplinary therapy. DIAGNOSES: A diagnosis of embryonal rhabdomyosarcoma with primary bladder (IIIa, TNM stage 2, and medium risk group) was made. INTERVENTIONS: After repeated recurrence, the patient was treated with chimeric antigen receptor T (CAR-T) cells, which had a safety mechanism and specifically bound the CD56 antigen in the fourth generation. OUTCOMES: The process of CAR-T cell transfusion was smooth, and there were no significant cytokine release syndrome manifestations after reinfusion. The patient was in complete remission at last follow-up visit after 3.5 years. CONCLUSION: CD56-CAR-T cell therapy is a safe and effective approach and may be an option for children with solid tumors who are nonresponsive to conventional radiotherapy and chemotherapy, or are unsuitable for hematopoietic stem cell transplantation.


Assuntos
Antígeno CD56/imunologia , Imunoterapia Adotiva/métodos , Recidiva Local de Neoplasia/terapia , Receptores de Antígenos Quiméricos/uso terapêutico , Rabdomiossarcoma/terapia , Neoplasias da Bexiga Urinária/terapia , Pré-Escolar , Seguimentos , Humanos , Masculino , Indução de Remissão , Rabdomiossarcoma/patologia , Neoplasias da Bexiga Urinária/patologia
4.
Rinsho Ketsueki ; 60(9): 1351-1357, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31597863

RESUMO

The adoptive transfer of chimeric antigen receptor (CAR)-modified autologous T cells targeted at the B-cell antigen CD19 is highly effective in patients with relapsed or refractory B-cell malignancies. In Japan, tisagenlecleucel has been approved in March 2019, whereas axicabtagene ciloleucel, lisocabtagene maraleucel, and TBI-1501 have been tested in clinical trials. In addition, allogeneic CD19 CAR T cells from family or third-party donors have been developed for treating B-cell malignancies. Moreover, CAR T-cell therapies for acute myeloid leukemia (AML), T-cell leukemia, and multiple myeloma are still under development. Our group is currently preparing a phase I study on granulocyte macrophage colony-stimulating factor receptor-targeted CAR T cells in pediatric and adult patients with AML.


Assuntos
Neoplasias Hematológicas/terapia , Imunoterapia Adotiva , Receptores de Antígenos de Linfócitos T/uso terapêutico , Receptores de Antígenos Quiméricos/uso terapêutico , Adulto , Criança , Ensaios Clínicos Fase I como Assunto , Humanos , Japão
5.
Nat Med ; 25(9): 1408-1414, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31477906

RESUMO

Chimeric antigen receptor (CAR)-modified T cells targeting CD19 demonstrate unparalleled responses in relapsed/refractory acute lymphoblastic leukemia (ALL)1-5, but toxicity, including cytokine-release syndrome (CRS) and neurotoxicity, limits broader application. Moreover, 40-60% of patients relapse owing to poor CAR T cell persistence or emergence of CD19- clones. Some factors, including the choice of single-chain spacer6 and extracellular7 and costimulatory domains8, have a profound effect on CAR T cell function and persistence. However, little is known about the impact of CAR binding affinity. There is evidence of a ceiling above which increased immunoreceptor affinity may adversely affect T cell responses9-11. We generated a novel CD19 CAR (CAT) with a lower affinity than FMC63, the high-affinity binder used in many clinical studies1-4. CAT CAR T cells showed increased proliferation and cytotoxicity in vitro and had enhanced proliferative and in vivo antitumor activity compared with FMC63 CAR T cells. In a clinical study (CARPALL, NCT02443831 ), 12/14 patients with relapsed/refractory pediatric B cell acute lymphoblastic leukemia treated with CAT CAR T cells achieved molecular remission. Persistence was demonstrated in 11 of 14 patients at last follow-up, with enhanced CAR T cell expansion compared with published data. Toxicity was low, with no severe CRS. One-year overall and event-free survival were 63% and 46%, respectively.


Assuntos
Antígenos CD19/administração & dosagem , Imunoterapia Adotiva , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Receptores de Antígenos de Linfócitos T/imunologia , Adolescente , Antígenos CD19/genética , Antígenos CD19/imunologia , Criança , Pré-Escolar , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/uso terapêutico , Recidiva , Linfócitos T/patologia , Sequenciamento Completo do Exoma , Adulto Jovem
6.
Zhonghua Nei Ke Za Zhi ; 58(9): 668-672, 2019 Sep 01.
Artigo em Chinês | MEDLINE | ID: mdl-31461818

RESUMO

Objective: To retrospectively analyze the efficacy and safety of modified cell infusion method in reducing the incidence of febrile non-hemolytic transfusion reaction (FNHTR). Methods: A total of 69 patients were enrolled in the clinical trial of CD(19) chimeric antigen receptor T (CAR-T) cell treatment from February 2017 to October 2018. Study group received the modified cell infusion method, that 1×10(6) CAR-T cells were re-suspended in 2 mg human serum albumin with total volume of 20 ml and injected intravenously. The control group was intravenously administrated with CAR-T cell in 100 ml normal saline. The incidence of FNHTR, cytokine releasing syndrome (CRS) grade, cytokine level and efficacy were compared. Results: (1)The incidence of FNHTR in the study group was 21.1%, significantly lower than that in the control group (71%)(P=0.000). (2)There was no statistical difference in cell proliferation between the study group and the control group on day 4, 7, 14 and 21 after CAR-T cell infusion (P=10.223, 3.254, 5.551, 7.605). (3)There was no statistical difference in CRS grading between the study group and the control group (P=0.767). There was no statistical difference in the levels of interleukin 2 receptor (IL-2R), IL-6, tumor necrosis factor (TNF)-α between the two groups. (4)The C-reaction protein (CRP) level of the study group was lower than that of the control group on day 4 and 7 (P=0.026, 0.007). (5)There was no statistical difference of response rates in acute lymphocytic leukemia (ALL) and non-Hodgkin lymphoma (NHL) patients between the two groups (P(ALL)=0.842; P(NHL)=0.866). Conclusion: The modified cell infusion method in CD(19) CAR-T cell treatment reduces the incidence of treatment-related FNHTR. It does not affect the proliferation of CAR-T cells in vivo, the grading of CRS and the response rates.


Assuntos
Antígenos CD19/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Receptores de Antígenos de Linfócitos T/uso terapêutico , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T , Reação Transfusional/prevenção & controle , Humanos , Receptores de Antígenos Quiméricos/uso terapêutico , Estudos Retrospectivos
7.
Medicine (Baltimore) ; 98(29): e16498, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31335716

RESUMO

RATIONALE: Relapse is the main cause of death after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Unfortunately, there are no efficient methods to prevent relapse after allo-HSCT. Chimeric antigen receptor T (CAR-T) cells have achieved favorable outcomes in the treatment of refractory/relapsed acute lymphoblastic leukemia (ALL) because of their strong anti-leukemia activity. However, it is unclear whether the CAR-T cells constructed using viral systems can be used as preventive infusions to prevent relapse after haploidentical HSCT. PATIENT CONCERNS: Two patients with ALL with high risk received haploidentical HSCT. DIAGNOSES: Two patients were diagnosed with ALL with high risk. INTERVENTIONS: Patients received preventive infusion of donor-derived CAR-T cells constructed using viral systems on day 60 after haploidentical HSCT. OUTCOMES: The CAR-T cells were continually detected, and no graft versus host disease developed. The two patients survived with disease-free for 1 year and 6 months, respectively. LESSONS: Preventive infusion of donor-derived CAR-T cells after haploidentical HSCT may be safe and that immunosuppressors may not affect the proliferation of CAR-T cells.


Assuntos
Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/métodos , Imunoterapia Adotiva/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Receptores de Antígenos Quiméricos/uso terapêutico , Transplante Haploidêntico , Adulto , Pré-Escolar , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Imunossupressores/uso terapêutico , Masculino , Doadores de Tecidos
8.
Nat Commun ; 10(1): 3137, 2019 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-31316055

RESUMO

Immunotherapy with chimeric antigen receptor-engineered T-cells (CAR-T) is under investigation in multiple myeloma. There are reports of myeloma remission after CD19 CAR-T therapy, although CD19 is hardly detectable on myeloma cells by flow cytometry (FC). We apply single molecule-sensitive direct stochastic optical reconstruction microscopy (dSTORM), and demonstrate CD19 expression on a fraction of myeloma cells (10.3-80%) in 10 out of 14 patients (density: 13-5,000 molecules per cell). In contrast, FC detects CD19 in only 2 of these 10 patients, on a smaller fraction of cells. Treatment with CD19 CAR-T in vitro results in elimination of CD19-positive myeloma cells, including those with <100 CD19 molecules per cell. Similar data are obtained by dSTORM analyses of CD20 expression on myeloma cells and CD20 CAR-T. These data establish a sensitivity threshold for CAR-T and illustrate how super-resolution microscopy can guide patient selection in immunotherapy to exploit ultra-low density antigens.


Assuntos
Antígenos CD19/metabolismo , Mieloma Múltiplo/terapia , Biomarcadores/metabolismo , Estudos de Coortes , Citometria de Fluxo , Humanos , Imunoterapia Adotiva , Interferon gama/metabolismo , Mieloma Múltiplo/metabolismo , Receptores de Antígenos Quiméricos/uso terapêutico
9.
Mol Med Rep ; 20(3): 2355-2364, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31322180

RESUMO

Colon cancer is a common malignancy worldwide and there is an urgent requirement to develop effective treatment strategies. In recent years, tumor immunotherapy has become a new method of effectively treating tumors. Chimeric antigen receptor (CAR) T cell technology combines the precise targeting specificity of monoclonal antibodies with the strong toxicity and persistence of cytotoxic T cells to specifically recognize tumor­associated antigens and promote tumor cell death efficiently and permanently, without depending on major histocompatibility complex restriction. In the present study, epithelial cell adhesion molecule (EpCAM)­targeting CAR T cells (EpCAM­CAR­T) were developed, and their ability to kill cancer cells in vitro was assessed. Firstly, an EpCAM­CAR plasmid was constructed using molecular biology techniques, and transfected into T cells to obtain EpCAM­CAR­T cells. Transfection efficiency was assessed using reverse transcription­quantitative PCR and flow cytometry. Next, the expression levels of EpCAM in five colon cancer cell lines were examined by western blotting and flow cytometry. Finally, the effect of EpCAM­CAR­T cells on cancer cell death was examined in vitro via co­culture experiments. T cells stably expressing EpCAM­CAR were successfully obtained, and the transduction efficiency according to flow cytometry was 50.4%. In vitro experiments showed that EpCAM­CAR­T cells exhibited a significantly higher apoptotic effect on cancer cells compared with untransfected T cells. Analyses also demonstrated that this effect was dependent on the ratio of EpCAM­CAR­T cells to tumor cells, and the expression of surface EpCAM. Similarly, the ELISA results showed that interleukin (IL)­2 IL­6 and interferon­Î³ levels were significantly elevated following exposure to EpCAM­CAR­T cells compared to exposure to untransfected T cells, and were dependent on the number of EpCAM­CAR­T cells and the amount of EpCAM expressed on the surface of tumor cells. The present study provided a basis for the clinical application of CAR­T cell therapy against solid tumors, and a provided a new strategy for the treatment of colon cancer.


Assuntos
Molécula de Adesão da Célula Epitelial/uso terapêutico , Imunoterapia Adotiva/métodos , Neoplasias/terapia , Receptores de Antígenos Quiméricos/uso terapêutico , Adulto , Apoptose , Linhagem Celular Tumoral , Células Cultivadas , Feminino , Humanos , Masculino , Adulto Jovem
11.
EMBO J ; 38(12)2019 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-31036555

RESUMO

Immunotherapy using chimeric antigen receptor (CAR)-engineered lymphocytes has shown impressive results in leukemia. However, for solid tumors such as colorectal cancer (CRC), new preclinical models are needed that allow to test CAR-mediated cytotoxicity in a tissue-like environment. Here, we developed a platform to study CAR cell cytotoxicity against 3-dimensional (3D) patient-derived colon organoids. Luciferase-based measurement served as a quantitative read-out for target cell viability. Additionally, we set up a confocal live imaging protocol to monitor effector cell recruitment and cytolytic activity at a single organoid level. As proof of principle, we demonstrated efficient targeting in diverse organoid models using CAR-engineered NK-92 cells directed toward a ubiquitous epithelial antigen (EPCAM). Tumor antigen-specific cytotoxicity was studied with CAR-NK-92 cells targeting organoids expressing EGFRvIII, a neoantigen found in several cancers. Finally, we tested a novel CAR strategy targeting FRIZZLED receptors that show increased expression in a subgroup of CRC tumors. Here, comparative killing assays with normal organoids failed to show tumor-specific activity. Taken together, we report a sensitive in vitro platform to evaluate CAR efficacy and tumor specificity in a personalized manner.


Assuntos
Neoplasias Colorretais/patologia , Neoplasias Colorretais/terapia , Citotoxicidade Imunológica , Modelos Biológicos , Organoides/patologia , Receptores de Antígenos Quiméricos/uso terapêutico , Técnicas de Cultura de Tecidos/métodos , Células Cultivadas , Neoplasias Colorretais/genética , Neoplasias Colorretais/imunologia , Citotoxicidade Imunológica/efeitos dos fármacos , Citotoxicidade Imunológica/genética , Terapia Genética/métodos , Células HEK293 , Humanos , Imunoterapia Adotiva/métodos , Cultura Primária de Células/métodos , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos de Linfócitos T/uso terapêutico , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/metabolismo , Tecidos Suporte/química
12.
N Engl J Med ; 380(18): 1726-1737, 2019 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-31042825

RESUMO

BACKGROUND: Preclinical studies suggest that bb2121, a chimeric antigen receptor (CAR) T-cell therapy that targets B-cell maturation antigen (BCMA), has potential for the treatment of multiple myeloma. METHODS: In this phase 1 study involving patients with relapsed or refractory multiple myeloma, we administered bb2121 as a single infusion at doses of 50×106, 150×106, 450×106, or 800×106 CAR-positive (CAR+) T cells in the dose-escalation phase and 150×106 to 450×106 CAR+ T cells in the expansion phase. Patients had received at least three previous lines of therapy, including a proteasome inhibitor and an immunomodulatory agent, or were refractory to both drug classes. The primary end point was safety. RESULTS: Results for the first 33 consecutive patients who received a bb2121 infusion are reported. The data-cutoff date was 6.2 months after the last infusion date. Hematologic toxic effects were the most common events of grade 3 or higher, including neutropenia (in 85% of the patients), leukopenia (in 58%), anemia (in 45%), and thrombocytopenia (in 45%). A total of 25 patients (76%) had cytokine release syndrome, which was of grade 1 or 2 in 23 patients (70%) and grade 3 in 2 patients (6%). Neurologic toxic effects occurred in 14 patients (42%) and were of grade 1 or 2 in 13 patients (39%). One patient (3%) had a reversible grade 4 neurologic toxic effect. The objective response rate was 85%, including 15 patients (45%) with complete responses. Six of the 15 patients who had a complete response have had a relapse. The median progression-free survival was 11.8 months (95% confidence interval, 6.2 to 17.8). All 16 patients who had a response (partial response or better) and who could be evaluated for minimal residual disease (MRD) had MRD-negative status (≤10-4 nucleated cells). CAR T-cell expansion was associated with responses, and CAR T cells persisted up to 1 year after the infusion. CONCLUSIONS: We report the initial toxicity profile of a BCMA-directed cellular immunotherapy for patients with relapsed or refractory multiple myeloma. Antitumor activity was documented. (Funded by Bluebird Bio and Celgene; CRB-401 ClinicalTrials.gov number, NCT02658929.).


Assuntos
Antígeno de Maturação de Linfócitos B/antagonistas & inibidores , Imunoterapia Adotiva , Mieloma Múltiplo/terapia , Receptores de Antígenos Quiméricos/uso terapêutico , Adulto , Idoso , Relação CD4-CD8 , Feminino , Humanos , Imunoterapia Adotiva/efeitos adversos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/imunologia , Intervalo Livre de Progressão , Linfócitos T/metabolismo
13.
Int J Mol Sci ; 20(8)2019 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-30999624

RESUMO

Artificial receptors designed for adoptive immune therapies need to absolve dual functions: antigen recognition and abilities to trigger the lytic machinery of reprogrammed effector T lymphocytes. In this way, CAR-T cells deliver their cytotoxic hit to cancer cells expressing targeted tumor antigens, bypassing the limitation of HLA-restricted antigen recognition. Expanding technologies have proposed a wide repertoire of soluble and cellular "immunological weapons" to kill tumor cells; they include monoclonal antibodies recognizing tumor associated antigens on tumor cells and immune cell checkpoint inhibition receptors expressed on tumor specific T cells. Moreover, a wide range of formidable chimeric antigen receptors diversely conceived to sustain quality, strength and duration of signals delivered by engineered T cells have been designed to specifically target tumor cells while minimize off-target toxicities. The latter immunological weapons have shown distinct efficacy and outstanding palmarès in curing leukemia, but limited and durable effects for solid tumors. General experience with checkpoint inhibitors and CAR-T cell immunotherapy has identified a series of variables, weaknesses and strengths, influencing the clinical outcome of the oncologic illness. These aspects will be shortly outlined with the intent of identifying the still "missing strategy" to combat epithelial cancers.


Assuntos
Imunoterapia Adotiva/métodos , Neoplasias/terapia , Receptores de Antígenos Quiméricos/uso terapêutico , Animais , Antígenos de Neoplasias/imunologia , Antineoplásicos Imunológicos/imunologia , Antineoplásicos Imunológicos/uso terapêutico , Humanos , Imunidade Celular , Imunidade Humoral , Neoplasias/imunologia , Neoplasias/patologia , Medicina de Precisão/métodos , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/imunologia , Evasão Tumoral
14.
Drugs ; 79(4): 401-415, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30796733

RESUMO

While impressive clinical responses have been observed using chimeric antigen receptor (CAR) T cells targeting CD19+ hematologic malignancies, limited clinical benefit has been observed using CAR T cells for a variety of solid tumors. Results of clinical studies have highlighted several obstacles which CAR T cells face in the context of solid tumors, including insufficient homing to tumor sites, lack of expansion and persistence, encountering a highly immunosuppressive tumor microenvironment, and heterogeneous antigen expression. In this review, we review clinical outcomes and discuss strategies to improve the antitumor activity of CAR T cells for solid tumors.


Assuntos
Antineoplásicos/uso terapêutico , Imunoterapia Adotiva/métodos , Neoplasias/tratamento farmacológico , Receptores de Antígenos Quiméricos/uso terapêutico , Linfócitos T/imunologia , Antígenos CD19 , Genes Transgênicos Suicidas , Terapia Genética , Neoplasias Hematológicas/tratamento farmacológico , Humanos , Imunossupressores/uso terapêutico , Resultado do Tratamento , Microambiente Tumoral
15.
Int J Mol Sci ; 20(2)2019 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-30646574

RESUMO

Natural killer (NK) cells are innate immune cells that can be activated rapidly to target abnormal and virus-infected cells without prior sensitization. With significant advancements in cell biology technologies, many NK cell lines have been established. Among these cell lines, NK-92 cells are not only the most widely used but have also been approved for clinical applications. Additionally, chimeric antigen receptor-modified NK-92 cells (CAR-NK-92 cells) have shown strong antitumor effects. In this review, we summarize established human NK cell lines and their biological characteristics, and highlight the applications of NK-92 cells and CAR-NK-92 cells in tumor immunotherapy.


Assuntos
Imunoterapia , Células Matadoras Naturais/imunologia , Neoplasias/terapia , Receptores de Antígenos Quiméricos/imunologia , Linhagem Celular Tumoral , Citotoxicidade Imunológica/imunologia , Vetores Genéticos/imunologia , Vetores Genéticos/uso terapêutico , Humanos , Neoplasias/imunologia , Receptores de Antígenos Quiméricos/uso terapêutico
16.
N Engl J Med ; 380(1): 45-56, 2019 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-30501490

RESUMO

BACKGROUND: Patients with diffuse large B-cell lymphoma that is refractory to primary and second-line therapies or that has relapsed after stem-cell transplantation have a poor prognosis. The chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel targets and eliminates CD19-expressing B cells and showed efficacy against B-cell lymphomas in a single-center, phase 2a study. METHODS: We conducted an international, phase 2, pivotal study of centrally manufactured tisagenlecleucel involving adult patients with relapsed or refractory diffuse large B-cell lymphoma who were ineligible for or had disease progression after autologous hematopoietic stem-cell transplantation. The primary end point was the best overall response rate (i.e., the percentage of patients who had a complete or partial response), as judged by an independent review committee. RESULTS: A total of 93 patients received an infusion and were included in the evaluation of efficacy. The median time from infusion to data cutoff was 14 months (range, 0.1 to 26). The best overall response rate was 52% (95% confidence interval, 41 to 62); 40% of the patients had complete responses, and 12% had partial responses. Response rates were consistent across prognostic subgroups. At 12 months after the initial response, the rate of relapse-free survival was estimated to be 65% (79% among patients with a complete response). The most common grade 3 or 4 adverse events of special interest included cytokine release syndrome (22%), neurologic events (12%), cytopenias lasting more than 28 days (32%), infections (20%), and febrile neutropenia (14%). Three patients died from disease progression within 30 days after infusion. No deaths were attributed to tisagenlecleucel, cytokine release syndrome, or cerebral edema. No differences between response groups in tumor expression of CD19 or immune checkpoint-related proteins were found. CONCLUSIONS: In this international study of CAR T-cell therapy in relapsed or refractory diffuse large B-cell lymphoma in adults, high rates of durable responses were produced with the use of tisagenlecleucel. (Funded by Novartis; JULIET ClinicalTrials.gov number, NCT02445248 .).


Assuntos
Imunoterapia Adotiva , Linfoma Difuso de Grandes Células B/terapia , Receptores de Antígenos de Linfócitos T/uso terapêutico , Receptores de Antígenos Quiméricos/uso terapêutico , Adulto , Idoso , Feminino , Humanos , Linfoma Difuso de Grandes Células B/mortalidade , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Intervalo Livre de Progressão , Recidiva , Análise de Sobrevida , Adulto Jovem
17.
Br J Cancer ; 120(1): 54-56, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30478409

RESUMO

EGFRvIII targeted chimeric antigen receptor T (CAR-T) cell therapy has recently been reported for treating glioblastomas (GBMs); however, physiology-based MRI parameters have not been evaluated in this setting. Ten patients underwent multiparametric MRI at baseline, 1, 2 and 3 months after CAR-T therapy. Logistic regression model derived progression probabilities (PP) using imaging parameters were used to assess treatment response. Four lesions from "early surgery" group demonstrated high PP at baseline suggestive of progression, which was confirmed histologically. Out of eight lesions from remaining six patients, three lesions with low PP at baseline remained stable. Two lesions with high PP at baseline were associated with large decreases in PP reflecting treatment response, whereas other two lesions with high PP at baseline continued to demonstrate progression. One patient didn't have baseline data but demonstrated progression on follow-up. Our findings indicate that multiparametric MRI may be helpful in monitoring CAR-T related early therapeutic changes in GBM patients.


Assuntos
Receptores ErbB/imunologia , Glioblastoma/terapia , Imunoterapia Adotiva , Recidiva Local de Neoplasia/terapia , Linhagem Celular Tumoral , Receptores ErbB/antagonistas & inibidores , Feminino , Glioblastoma/diagnóstico por imagem , Glioblastoma/imunologia , Glioblastoma/patologia , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/diagnóstico por imagem , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/patologia , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/uso terapêutico
18.
Hematol Oncol ; 37(3): 233-239, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30427551

RESUMO

Recent advances in diffuse large B-cell lymphomas have included both identification of high-risk subtypes characterized by multiply relapsed and/or refractory disease as well as novel treatment in the form of cellular therapy. Chimeric antigen receptor (CAR)-T cell therapy is a recently developed approach to address the poor outcomes in this patient population. The CAR-T cell construct has evolved although several iterations as it transitioned from the lab to the clinic. Three major studies have evaluated the efficacy of CD19-directed CAR-T cell therapy in aggressive B-cell non-Hodgkin lymphoma; each demonstrating durable complete remissions in heavily pretreated patients. The cost of this remarkable therapy, however, includes cytokine release syndrome and neurotoxicity shortly after administration as well as delayed infectious complications due to B-cell aplasia. Future investigations are focused on the optimizing both safety and efficacy of CAR-T cell therapy.


Assuntos
Imunoterapia Adotiva/métodos , Linfoma Difuso de Grandes Células B/terapia , Linfoma não Hodgkin/terapia , Receptores de Antígenos Quiméricos/uso terapêutico , Animais , Antígenos CD19/metabolismo , Antígenos CD19/uso terapêutico , Linfócitos B/patologia , Citocinas/metabolismo , Humanos , Imunoterapia Adotiva/efeitos adversos , Linfoma Difuso de Grandes Células B/metabolismo , Camundongos , Receptores de Antígenos de Linfócitos T/uso terapêutico , Indução de Remissão , Linfócitos T/imunologia , Resultado do Tratamento
19.
Br J Cancer ; 120(1): 79-87, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30429531

RESUMO

BACKGROUND: CD16-chimeric antigen receptors (CAR) T cells recognise the Fc-portion of therapeutic antibodies, which can enable the selective targeting of different antigens. Limited evidence exists as to which CD16-CAR design and antibody partner might be most effective. We have hypothesised that the use of high-affinity CD16 variants, with increased Fc-terminus antibody affinity, combined with Fc-engineered antibodies, would provide superior CD16-CAR T cell efficacy. METHODS: CD16-CAR T (wild-type or variants) cells were co-cultured with Panc-1 pancreatic cancer, Raji lymphoma or A375 melanoma cells in the presence or absence of anti-CD20, anti-MCSP, wild-type or the glycoengineered antibody variants. The endpoints were proliferation, activation, and cytotoxicity in vitro. RESULTS: The CD16 158 V variant of CD16-CAR T cells showed increased cytotoxic activity against all the tested cancer cells in the presence of the wild-type antibody directed against MCSP or CD20. Glycoengineered antibodies enhanced CD16-CAR T cell activity irrespective of CD16 polymorphisms as compared with the wild-type antibody. The combination of the glycoengineered antibodies with the CD16-CAR 158 V variant synergised as seen by the increase in all endpoints. CONCLUSION: These results indicate that CD16-CAR with the high-affinity CD16 variant 158 V, combined with Fc-engineered antibodies, have high anti-tumour efficacy.


Assuntos
Imunoterapia Adotiva , Imunoterapia , Neoplasias/terapia , Receptores de Antígenos Quiméricos/imunologia , Animais , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacologia , Citotoxicidade Celular Dependente de Anticorpos/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Receptores ErbB/genética , Humanos , Fragmentos Fc das Imunoglobulinas/genética , Fragmentos Fc das Imunoglobulinas/farmacologia , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Camundongos , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/patologia , Polimorfismo Genético , Receptores de Antígenos Quiméricos/uso terapêutico , Receptores de IgG/imunologia , Rituximab/farmacologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia
20.
Br J Cancer ; 120(1): 26-37, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30413825

RESUMO

Adoptive T cell therapy (ACT) refers to the therapeutic use of T cells. T cells genetically engineered to express chimeric antigen receptors (CAR) constitute the most clinically advanced form of ACT approved to date for the treatment of CD19-positive leukaemias and lymphomas. CARs are synthetic receptors that are able to confer antigen-binding and activating functions on T cells with the aim of therapeutically targeting cancer cells. Several factors are essential for CAR T cell therapy to be effective, such as recruitment, activation, expansion and persistence of bioengineered T cells at the tumour site. Despite the advances made in CAR T cell therapy, however, most tumour entities still escape immune detection and elimination. A number of strategies counteracting these problems will need to be addressed in order to render T cell therapy effective in more situations than currently possible. Non-haematological tumours are also the subject of active investigation, but ACT has so far shown only marginal success rates in these cases. New approaches are needed to enhance the ability of ACT to target solid tumours without increasing toxicity, by improving recognition, infiltration, and persistence within tumours, as well as an enhanced resistance to the suppressive tumour microenvironment.


Assuntos
Imunoterapia Adotiva/tendências , Leucemia/terapia , Receptores de Antígenos Quiméricos/uso terapêutico , Linfócitos T/imunologia , Antígenos CD19/genética , Antígenos de Neoplasias/imunologia , Humanos , Leucemia/imunologia , Receptores de Antígenos Quiméricos/imunologia , Microambiente Tumoral/imunologia
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