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2.
Mol Ther ; 28(12): 2577-2592, 2020 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-32755564

RESUMO

T cells engineered to express chimeric antigen receptors (CARs) targeting CD19 have produced impressive outcomes for the treatment of B cell malignancies, but different products vary in kinetics, persistence, and toxicity profiles based on the co-stimulatory domains included in the CAR. In this study, we performed transcriptional profiling of bulk CAR T cell populations and single cells to characterize the transcriptional states of human T cells transduced with CD3ζ, 4-1BB-CD3ζ (BBζ), or CD28-CD3ζ (28ζ) co-stimulatory domains at rest and after activation by triggering their CAR or their endogenous T cell receptor (TCR). We identified a transcriptional signature common across CARs with the CD3ζ signaling domain, as well as a distinct program associated with the 4-1BB co-stimulatory domain at rest and after activation. CAR T cells bearing BBζ had increased expression of human leukocyte antigen (HLA) class II genes, ENPP2, and interleukin (IL)-21 axis genes, and decreased PD1 compared to 28ζ CAR T cells. Similar to previous studies, we also found BBζ CAR CD8 T cells to be enriched in a central memory cell phenotype and fatty acid metabolism genes. Our data uncovered transcriptional signatures related to costimulatory domains and demonstrated that signaling domains included in CARs uniquely shape the transcriptional programs of T cells.


Assuntos
Ligante 4-1BB/química , Ligante 4-1BB/metabolismo , Engenharia Celular/métodos , Domínios Proteicos/genética , RNA Citoplasmático Pequeno/genética , Receptores de Antígenos Quiméricos/genética , Transdução de Sinais/genética , Linfócitos T/metabolismo , Transcriptoma , Células HEK293 , Humanos , Células K562 , RNA-Seq/métodos , Análise de Célula Única , Transdução Genética
3.
Blood Adv ; 3(21): 3248-3260, 2019 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-31698455

RESUMO

Chimeric antigen receptor (CAR) T cells (CARTs) have shown tremendous potential for the treatment of certain B-cell malignancies, including patients with relapsed/refractory multiple myeloma (MM). Targeting the B-cell maturation antigen (BCMA) has produced the most promising results for CART therapy of MM to date, but not all remissions are sustained. Emergence of BCMA escape variants has been reported under the selective pressure of monospecific anti-BCMA CART treatment. Thus, there is a clinical need for continuous improvement of CART therapies for MM. Here, we show that a novel trimeric APRIL (a proliferation-inducing ligand)-based CAR efficiently targets both BCMA+ and BCMA- MM. Modeled after the natural ligand-receptor pair, APRIL-based CARs allow for bispecific targeting of the MM-associated antigens BCMA and transmembrane activator and CAML interactor (TACI). However, natural ligands as CAR antigen-binding domains may require further engineering to promote optimal binding and multimerization to adequately trigger T-cell activation. We found that using a trimeric rather than a monomeric APRIL format as the antigen-binding domain enhanced binding to BCMA and TACI and CART activity against MM in vitro and in vivo. Dual-specific, trimeric APRIL-based CAR are a promising therapeutic approach for MM with potential for preventing and treating BCMA escape.


Assuntos
Antígenos de Neoplasias , Imunoterapia Adotiva , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/terapia , Receptores de Antígenos Quiméricos/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/antagonistas & inibidores , Animais , Antígenos de Neoplasias/imunologia , Citocinas/metabolismo , Citotoxicidade Imunológica , Modelos Animais de Doenças , Humanos , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Ativação Linfocitária/imunologia , Camundongos , Ligação Proteica/imunologia , Receptores de Antígenos Quiméricos/genética , Especificidade do Receptor de Antígeno de Linfócitos T , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Clin Cancer Res ; 25(23): 7046-7057, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31439577

RESUMO

PURPOSE: T cells engineered to express a chimeric antigen receptor (CAR) against CD19 have recently been FDA approved for the treatment of relapsed or refractory large B-cell lymphoma. Despite the success and curative potential of CD19 CAR T cells, several reports describing disease relapse due to antigen loss are now emerging. EXPERIMENTAL DESIGN: We developed a novel CAR construct directed against CD79b, a critical receptor for successful B-cell development that remains highly expressed in several subtypes of B-cell lymphoma, including mantle cell lymphoma (MCL). We tested CAR T cells directed against CD79b alone or in combination with CD19 targeting in a single construct, against cell line- and patient-derived xenograft models. RESULTS: We demonstrate CAR79b antigen-specific recognition and cytotoxicity against a panel of cell lines and patient-derived xenograft models of MCL. Importantly, we show that downregulation of CD19 does not influence surface expression of CD79b and that anti-CD79b CAR T cells alone or arranged in a dual-targeting format with a CD19 single-chain variable fragment (scFv) are able to recognize and eliminate CD19+, CD19-, and mixed CD19+/CD19-B-cell lymphoma. CONCLUSIONS: Our findings demonstrate that CAR T cells targeting CD79b alone or in combination have promise for treating and preventing CD19 antigen escape in B-cell lymphomas.


Assuntos
Antígenos CD19/imunologia , Antígenos CD79/imunologia , Imunoterapia Adotiva/métodos , Linfoma de Célula do Manto/terapia , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/imunologia , Animais , Apoptose , Proliferação de Células , Humanos , Ativação Linfocitária , Linfoma de Célula do Manto/imunologia , Linfoma de Célula do Manto/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Prognóstico , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Blood ; 134(11): 860-866, 2019 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-31320380

RESUMO

Chimeric antigen receptor (CAR) T cells targeting CD19 have emerged as a leading engineered T-cell therapy for relapsed/refractory B-cell non-Hodgkin lymphoma. The phase 1/2 clinical trials that led to US Food and Drug Administration approval excluded patients with central nervous system (CNS) involvement, due to strict eligibility criteria. Here, we report on our institutional experience with 8 secondary CNS lymphoma patients treated with commercial tisagenlecleucel. No patient experienced greater than grade 1 neurotoxicity, and no patient required tocilizumab or steroids for CAR T-cell-mediated toxicities. Biomarker analysis suggested CAR T-cell expansion, despite the absence of systemic disease, and early response assessments demonstrated activity of IV infused CAR T cells within the CNS space.


Assuntos
Neoplasias do Sistema Nervoso Central/secundário , Neoplasias do Sistema Nervoso Central/terapia , Imunoterapia Adotiva/métodos , Linfoma/terapia , Receptores de Antígenos de Linfócitos T/uso terapêutico , Adolescente , Adulto , Idoso , Neoplasias do Sistema Nervoso Central/imunologia , Feminino , Humanos , Linfoma/imunologia , Linfoma/patologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Linfócitos T/imunologia , Linfócitos T/transplante , Resultado do Tratamento , Adulto Jovem
6.
JCI Insight ; 52019 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-30869654

RESUMO

Regulatory T cells (Tregs) are key modulators of inflammation and are important for the maintenance of peripheral tolerance. Adoptive immunotherapy with polyclonal Tregs holds promise in organ transplantation, graft-versus-host disease, and autoimmune diseases, but may be enhanced by antigen-specific, long-lived Treg cells. We modified primary human Tregs with chimeric antigen-receptors (CARs) bearing different costimulatory domains and performed in vitro analyses of their phenotype and function. While neither the presence of a CAR nor the type of costimulation domain influenced Foxp3 expression in Tregs, the costimulation domain of the CARs affected CAR Treg surface phenotype and functions such as cytokine production. Furthermore, signaling from the CD28 costimulation domain maintained CAR Treg suppressor function, whereas 4-1B costimulation did not. In vivo, CAR Tregs accumulated at sites expressing target antigen, and suppressed antigen specific effector T cell responses; however, only CAR Tregs with CD28 signaling domains were potent inhibitors of effector T cell mediated graft rejection in vivo. Our findings support the use of CD28 based CAR-Tregs for tissue specific immune suppression in the clinic.


Assuntos
Receptores de Antígenos Quiméricos/química , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Animais , Doenças Autoimunes , Autoimunidade , Antígenos CD28 , Linhagem Celular , Feminino , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Doença Enxerto-Hospedeiro , Granzimas , Xenoenxertos , Humanos , Terapia de Imunossupressão , Masculino , Camundongos , Camundongos Endogâmicos NOD , Transplante de Órgãos , Fenótipo , Pele/patologia
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