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1.
Mol Ther ; 27(11): 1919-1929, 2019 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-31420241

RESUMO

This phase I study investigated the safety and activity of lentiviral-transduced chimeric antigen receptor (CAR)-modified autologous T cells redirected against mesothelin (CART-meso) in patients with malignant pleural mesothelioma, ovarian carcinoma, and pancreatic ductal adenocarcinoma. Fifteen patients with chemotherapy-refractory cancer (n = 5 per indication) were treated with a single CART-meso cell infusion. CART-meso cells were engineered by lentiviral transduction with a construct composed of the anti-mesothelin single-chain variable fragment derived from the mouse monoclonal antibody SS1 fused to intracellular signaling domains of 4-1BB and CD3zeta. Patients received 1-3 × 107 or 1-3 × 108 CART-meso cells/m2 with or without 1.5 g/m2 cyclophosphamide. Lentiviral-transduced CART-meso cells were well tolerated; one dose-limiting toxicity (grade 4, sepsis) occurred at 1-3 × 107/m2 CART-meso without cyclophosphamide. The best overall response was stable disease (11/15 patients). CART-meso cells expanded in the blood and reached peak levels by days 6-14 but persisted transiently. Cyclophosphamide pre-treatment enhanced CART-meso expansion but did not improve persistence beyond 28 days. CART-meso DNA was detected in 7/10 tumor biopsies. Human anti-chimeric antibodies (HACA) were detected in the blood of 8/14 patients. CART-meso cells were well tolerated and expanded in the blood of all patients but showed limited clinical activity. Studies evaluating a fully human anti-mesothelin CAR are ongoing.


Assuntos
Proteínas Ligadas por GPI/imunologia , Imunoterapia Adotiva , Neoplasias/imunologia , Neoplasias/terapia , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos Quiméricos/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Idoso , Biomarcadores , Feminino , Proteínas Ligadas por GPI/antagonistas & inibidores , Terapia Genética , Vetores Genéticos/genética , Humanos , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Lentivirus/genética , Masculino , Mesotelina , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias/diagnóstico , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos Quiméricos/genética , Tomografia Computadorizada por Raios X
2.
Gastroenterology ; 155(1): 29-32, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29567081

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is resistant to T-cell-mediated immunotherapy. We engineered T cells to transiently express a messenger RNA encoding a chimeric antigen receptor (CAR) specific for mesothelin, a protein that is overexpressed by PDAC cells. We performed a phase I study to evaluate the safety and efficacy of adoptive cell therapy with autologous mesothelin-specific CAR T cells (CARTmeso cells) in 6 patients with chemotherapy-refractory metastatic PDAC. Patients were given intravenous CARTmeso cells 3 times weekly for 3 weeks. None of the patients developed cytokine release syndrome or neurologic symptoms and there were no dose-limiting toxicities. Disease stabilized in 2 patients, with progression-free survival times of 3.8 and 5.4 months. We used 18F-2-fluoro-2-deoxy-D-glucose (FDG)-positron emission tomography/computed tomography imaging to monitor the metabolic active volume (MAV) of individual tumor lesions. The total MAV remained stable in 3 patients and decreased by 69.2% in 1 patient with biopsy-proven mesothelin expression; in this patient, all liver lesions had a complete reduction in FDG uptake at 1 month compared with baseline, although there was no effect on the primary PDAC. Transient CAR expression was detected in patients' blood after infusion and led to expansion of new immunoglobulin G proteins. Our results provide evidence for the potential antitumor activity of messenger RNA CARTmeso cells, as well as PDAC resistance to the immune response.


Assuntos
Carcinoma Ductal Pancreático/tratamento farmacológico , Proteínas Ligadas por GPI/imunologia , Imunoterapia Adotiva/métodos , Neoplasias Pancreáticas/tratamento farmacológico , RNA Mensageiro/genética , Receptores de Antígenos de Linfócitos T/genética , Linfócitos T/transplante , Idoso , Carcinoma Ductal Pancreático/secundário , Intervalo Livre de Doença , Feminino , Fluordesoxiglucose F18 , Humanos , Masculino , Mesotelina , Pessoa de Meia-Idade , Metástase Neoplásica , Neoplasias Pancreáticas/patologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Compostos Radiofarmacêuticos , Taxa de Sobrevida , Linfócitos T/imunologia , Transplante Autólogo
3.
Blood Cancer Discov ; 4(2): 118-133, 2023 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-36413381

RESUMO

We conducted a phase I clinical trial of anti-BCMA chimeric antigen receptor T cells (CART-BCMA) with or without anti-CD19 CAR T cells (huCART19) in multiple myeloma (MM) patients responding to third- or later-line therapy (phase A, N = 10) or high-risk patients responding to first-line therapy (phase B, N = 20), followed by early lenalidomide or pomalidomide maintenance. We observed no high-grade cytokine release syndrome (CRS) and only one instance of low-grade neurologic toxicity. Among 15 subjects with measurable disease, 10 exhibited partial response (PR) or better; among 26 subjects responding to prior therapy, 9 improved their response category and 4 converted to minimal residual disease (MRD)-negative complete response/stringent complete response. Early maintenance therapy was safe, feasible, and coincided in some patients with CAR T-cell reexpansion and late-onset, durable clinical response. Outcomes with CART-BCMA + huCART19 were similar to CART-BCMA alone. Collectively, our results demonstrate favorable safety, pharmacokinetics, and antimyeloma activity of dual-target CAR T-cell therapy in early lines of MM treatment. SIGNIFICANCE: CAR T cells in early lines of MM therapy could be safer and more effective than in the advanced setting, where prior studies have focused. We evaluated the safety, pharmacokinetics, and efficacy of CAR T cells in patients with low disease burden, responding to current therapy, combined with standard maintenance therapy. This article is highlighted in the In This Issue feature, p. 101.


Assuntos
Mieloma Múltiplo , Receptores de Antígenos Quiméricos , Humanos , Mieloma Múltiplo/terapia , Receptores de Antígenos Quiméricos/uso terapêutico , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Lenalidomida/uso terapêutico , Antígenos CD19/uso terapêutico , Linfócitos T
4.
Trop Doct ; 42(4): 206-7, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22875807

RESUMO

The cause of endomyocardial fibrosis in Uganda remains unknown in spite of studies dating back to 1948. Herbal decoctions have been used by traditional healers for countless generations to treat many complaints, especially fever. We present evidence - ethnic, geographical, tribal, pathological and distribution by age - that the toxic herbal decoctions taken as medicines in Uganda can cause endomyocardial fibrosis.


Assuntos
Argemone/efeitos adversos , Fibrose Endomiocárdica/induzido quimicamente , Medicinas Tradicionais Africanas/efeitos adversos , Fitoterapia/efeitos adversos , Adulto , Criança , Feminino , Humanos , Masculino , Uganda
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