Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 4 de 4
Filtrar
1.
Blood ; 119(12): 2709-20, 2012 Mar 22.
Artículo en Inglés | MEDLINE | ID: mdl-22160384

RESUMEN

We conducted a clinical trial to assess adoptive transfer of T cells genetically modified to express an anti-CD19 chimeric Ag receptor (CAR). Our clinical protocol consisted of chemotherapy followed by an infusion of anti-CD19-CAR-transduced T cells and a course of IL-2. Six of the 8 patients treated on our protocol obtained remissions of their advanced, progressive B-cell malignancies. Four of the 8 patients treated on the protocol had long-term depletion of normal polyclonal CD19(+) B-lineage cells. Cells containing the anti-CD19 CAR gene were detected in the blood of all patients. Four of the 8 treated patients had prominent elevations in serum levels of the inflammatory cytokines IFNγ and TNF. The severity of acute toxicities experienced by the patients correlated with serum IFNγ and TNF levels. The infused anti-CD19-CAR-transduced T cells were a possible source of these inflammatory cytokines because we demonstrated peripheral blood T cells that produced TNF and IFNγ ex vivo in a CD19-specific manner after anti-CD19-CAR-transduced T-cell infusions. Anti-CD19-CAR-transduced T cells have great promise to improve the treatment of B-cell malignancies because of a potent ability to eradicate CD19(+) cells in vivo; however, reversible cytokine-associated toxicities occurred after CAR-transduced T-cell infusions.


Asunto(s)
Linfocitos B/inmunología , Citocinas/efectos adversos , Inmunoterapia Adoptiva/efectos adversos , Inmunoterapia Adoptiva/métodos , Leucemia Linfocítica Crónica de Células B/terapia , Linfoma de Células B/terapia , Linfocitos T/inmunología , Antígenos CD19/inmunología , Citocinas/inmunología , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Humanos , Inmunohistoquímica , Leucemia Linfocítica Crónica de Células B/inmunología , Linfoma de Células B/inmunología , Persona de Mediana Edad , Reacción en Cadena en Tiempo Real de la Polimerasa , Proteínas Recombinantes de Fusión/inmunología , Proteínas Recombinantes de Fusión/uso terapéutico , Inducción de Remisión , Linfocitos T/trasplante , Transducción Genética
2.
Blood ; 116(20): 4099-102, 2010 Nov 18.
Artículo en Inglés | MEDLINE | ID: mdl-20668228

RESUMEN

Adoptive transfer of genetically modified T cells is an attractive approach for generating antitumor immune responses. We treated a patient with advanced follicular lymphoma by administering a preparative chemotherapy regimen followed by autologous T cells genetically engineered to express a chimeric antigen receptor (CAR) that recognized the B-cell antigen CD19. The patient's lymphoma underwent a dramatic regression, and B-cell precursors were selectively eliminated from the patient's bone marrow after infusion of anti-CD19-CAR-transduced T cells. Blood B cells were absent for at least 39 weeks after anti-CD19-CAR-transduced T-cell infusion despite prompt recovery of other blood cell counts. Consistent with eradication of B-lineage cells, serum immunoglobulins decreased to very low levels after treatment. The prolonged and selective elimination of B-lineage cells could not be attributed to the chemotherapy that the patient received and indicated antigen-specific eradication of B-lineage cells. Adoptive transfer of anti-CD19-CAR-expressing T cells is a promising new approach for treating B-cell malignancies. This study is registered at www.clinicaltrials.gov as #NCT00924326.


Asunto(s)
Antígenos CD19/inmunología , Linfocitos B/citología , Linaje de la Célula/inmunología , Ingeniería Genética , Depleción Linfocítica , Linfoma/terapia , Linfocitos T/trasplante , Humanos , Linfoma/inmunología , Masculino , Receptores de Antígenos/inmunología , Inducción de Remisión , Linfocitos T/inmunología , Transducción Genética , Trasplante Autólogo
3.
Mol Ther ; 19(3): 620-6, 2011 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-21157437

RESUMEN

Autologous T lymphocytes genetically engineered to express a murine T cell receptor (TCR) against human carcinoembryonic antigen (CEA) were administered to three patients with metastatic colorectal cancer refractory to standard treatments. All patients experienced profound decreases in serum CEA levels (74-99%), and one patient had an objective regression of cancer metastatic to the lung and liver. However, a severe transient inflammatory colitis that represented a dose limiting toxicity was induced in all three patients. This report represents the first example of objective regression of metastatic colorectal cancer mediated by adoptive T cell transfer and illustrates the successful use of a TCR, raised in human leukocyte antigen (HLA) transgenic mice, against a human tumor associated antigen. It also emphasizes the destructive power of small numbers of highly avid T cells and the limitations of using CEA as a target for cancer immunotherapy.


Asunto(s)
Antígeno Carcinoembrionario/inmunología , Colitis/inmunología , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/secundario , Receptores de Antígenos de Linfocitos T/inmunología , Linfocitos T/inmunología , Adulto , Animales , Antígeno Carcinoembrionario/sangre , Colitis/inducido químicamente , Colitis/patología , Neoplasias Colorrectales/diagnóstico por imagen , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/terapia , Técnicas de Transferencia de Gen , Vectores Genéticos/genética , Vectores Genéticos/metabolismo , Humanos , Inmunoterapia Adoptiva , Masculino , Ratones , Persona de Mediana Edad , Radiografía , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/metabolismo , Retroviridae/genética , Retroviridae/metabolismo , Linfocitos T/metabolismo , Resultado del Tratamiento
4.
J Clin Oncol ; 33(6): 540-9, 2015 Feb 20.
Artículo en Inglés | MEDLINE | ID: mdl-25154820

RESUMEN

PURPOSE: T cells can be genetically modified to express an anti-CD19 chimeric antigen receptor (CAR). We assessed the safety and efficacy of administering autologous anti-CD19 CAR T cells to patients with advanced CD19(+) B-cell malignancies. PATIENTS AND METHODS: We treated 15 patients with advanced B-cell malignancies. Nine patients had diffuse large B-cell lymphoma (DLBCL), two had indolent lymphomas, and four had chronic lymphocytic leukemia. Patients received a conditioning chemotherapy regimen of cyclophosphamide and fludarabine followed by a single infusion of anti-CD19 CAR T cells. RESULTS: Of 15 patients, eight achieved complete remissions (CRs), four achieved partial remissions, one had stable lymphoma, and two were not evaluable for response. CRs were obtained by four of seven evaluable patients with chemotherapy-refractory DLBCL; three of these four CRs are ongoing, with durations ranging from 9 to 22 months. Acute toxicities including fever, hypotension, delirium, and other neurologic toxicities occurred in some patients after infusion of anti-CD19 CAR T cells; these toxicities resolved within 3 weeks after cell infusion. One patient died suddenly as a result of an unknown cause 16 days after cell infusion. CAR T cells were detected in the blood of patients at peak levels, ranging from nine to 777 CAR-positive T cells/µL. CONCLUSION: This is the first report to our knowledge of successful treatment of DLBCL with anti-CD19 CAR T cells. These results demonstrate the feasibility and effectiveness of treating chemotherapy-refractory B-cell malignancies with anti-CD19 CAR T cells. The numerous remissions obtained provide strong support for further development of this approach.


Asunto(s)
Antígenos CD19/inmunología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Inmunoterapia Adoptiva/métodos , Linfoma de Células B/terapia , Linfoma de Células B Grandes Difuso/terapia , Receptores de Antígenos de Linfocitos T/inmunología , Linfocitos T/trasplante , Adulto , Anciano , Terapia Combinada , Ciclofosfamida/administración & dosificación , Femenino , Humanos , Linfoma de Células B/tratamiento farmacológico , Linfoma de Células B/inmunología , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/inmunología , Masculino , Persona de Mediana Edad , Linfocitos T/inmunología , Acondicionamiento Pretrasplante/métodos , Vidarabina/administración & dosificación , Vidarabina/análogos & derivados
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA