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Recent Results Cancer Res ; 214: 93-128, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31473850


As a specifically programmable, living immunotherapeutic drug, chimeric antigen receptor (CAR)-modified T cells are providing an alternative treatment option for a broad variety of diseases including so far refractory cancer. By recognizing a tumor-associated antigen, the CAR triggers an anti-tumor response of engineered patient's T cells achieving lasting remissions in the treatment of leukemia and lymphoma. During the last years, significant progress was made in optimizing the CAR design, in manufacturing CAR-engineered T cells, and in the clinical management of patients showing promise to establish adoptive CAR T cell therapy as an effective treatment option in the forefront.

Imunoterapia Adotiva , Neoplasias/terapia , Receptores de Antígenos Quiméricos , Antígenos de Neoplasias/imunologia , Ensaios Clínicos como Assunto , Humanos , Receptores de Antígenos de Linfócitos T , Linfócitos T/imunologia
Hum Gene Ther ; 29(5): 559-568, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29620951


The adoptive transfer of chimeric antigen receptor (CAR)-modified T cells is attracting growing interest for the treatment of malignant diseases. Early trials with anti-CD19 CAR T cells have achieved spectacular remissions in B-cell leukemia and lymphoma, so far refractory, very recently resulting in the Food and Drug Administration approval of CD19 CAR T cells for therapy. With further applications and increasing numbers of patients, the reproducible manufacture of high-quality clinical-grade CAR T cells is becoming an ever greater challenge. New processing techniques, quality-control mechanisms, and logistic developments are required to meet both medical needs and regulatory restrictions. This paper summarizes the state-of-the-art in manufacturing CAR T cells and the current challenges that need to be overcome to implement this type of cell therapy in the treatment of a variety of malignant diseases and in a greater number of patients.

Cancer Immunol Immunother ; 65(12): 1433-1450, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27613725


In recent years, cancer treatment involving adoptive cell therapy with chimeric antigen receptor (CAR)-modified patient's immune cells has attracted growing interest. Using gene transfer techniques, the patient's T cells are modified ex vivo with a CAR which redirects the T cells toward the cancer cells through an antibody-derived binding domain. The T cells are activated by the CAR primary signaling and costimulatory domains. Such "second generation" CAR T cells induced complete remission of B cell malignancies in the long-term. In this fast-moving field with a growing number of engineered T cell products, we list about 100 currently ongoing trials here that involve CAR T cells targeting hematopoietic malignancies and solid cancer. Major challenges in the further development of the therapy are briefly discussed.

Imunoterapia Adotiva/métodos , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T/imunologia , Humanos
Methods Mol Biol ; 969: 187-201, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23296935


Redirecting T cells with a chimeric antigen receptor (CAR) of predefined specificity showed remarkable efficacy in the adoptive therapy trials of malignant diseases. The CAR consists of a single chain fragment of variable region (scFv) antibody targeting domain covalently linked to the CD3ζ signalling domain of the T cell receptor complex to mediate T cell activation upon antigen engagement. By using an antibody-derived targeting domain a CAR can potentially redirect T cells towards any target expressed on the cell surface as long as a binding domain is available. Antibody-mediated targeting moreover circumvents MHC restriction of the targeted antigen, thereby broadening the potential of applicability of adoptive T cell therapy. While T cells were so far genetically modified by viral transduction, transient modification with a CAR by RNA transfection gained increasing interest during the last years. This chapter focuses on methods to modify human T cells from peripheral blood with a CAR by electroporation of in vitro transcribed RNA and to test modified T cells for function for use in adoptive immunotherapy.

Transferência Adotiva , Engenharia Celular/métodos , Receptores de Antígenos , Proteínas Recombinantes de Fusão , Linfócitos T , Transfecção/métodos , Animais , Complexo CD3/biossíntese , Complexo CD3/genética , Complexo CD3/imunologia , Expressão Gênica , Humanos , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Receptores de Antígenos/biossíntese , Receptores de Antígenos/genética , Receptores de Antígenos/imunologia , Proteínas Recombinantes de Fusão/biossíntese , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/imunologia , Linfócitos T/citologia , Linfócitos T/imunologia , Linfócitos T/metabolismo