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1.
Bull Cancer ; 108(10S): S92-S95, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34920812

RESUMO

Treatment of hematological malignancies by autologous T cells expressing a chimeric antigen receptor (CAR) is a breakthrough in the field of cancer immunotherapy. As CAR-T cells are entering advanced phases of clinical development, there is a need to develop universal, ready-to-use products using immune cells from healthy donors, to reduce time to treatment, improve response rate and finally reduce the cost of production. Mucosal-associated invariant T cells (MAIT) are unconventional T cells which recognize microbial-derived riboflavin derivatives presented by the conserved MR1 molecule and are endowed with potent effector functions. Because they are not selected by classical MHC/peptide complexes and express a semi-invariant T cell receptor, MAIT cells do not mediate alloreactivity, prompting their use as a new source of universal effector cells for allogeneic CAR-T cell therapy without the need to inactivate their endogenous TCR. We produced CD19-CAR MAIT cells as proof-of-concept allowing subsequent head-to-head comparison with currently used CD19-CAR T cells. We demonstrated their anti-tumor efficacy in vitro and their capacity to engraft without mediating GVHD in preclinical immunodeficient mouse models. Universal, off-the-shelf CAR-MAIT cells could provide a suitable alternative to current autologous CAR-T cells to treat patients regardless of HLA disparity, without production delay, enabling a cost-effective manufacturing model for large-scale clinical application.


Assuntos
Neoplasias Hematológicas/terapia , Imunoterapia Adotiva/métodos , Células T Invariantes Associadas à Mucosa/transplante , Receptores de Antígenos Quiméricos/imunologia , Animais , Antígenos CD19/imunologia , Análise Custo-Benefício , Neoplasias Hematológicas/imunologia , Camundongos , Camundongos SCID , Células T Invariantes Associadas à Mucosa/citologia , Células T Invariantes Associadas à Mucosa/imunologia , Estudo de Prova de Conceito
2.
Front Immunol ; 10: 206, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30853958

RESUMO

Mucosal associated invariant T (MAIT) cells are unconventional, semi-invariant T lymphocytes that recognize microbial-derived vitamin B2 (riboflavin) biosynthesis precursor derivatives presented by the monomorphic MHC class 1-related (MR1) molecule. Upon microbial infection, MAIT cells rapidly produce cytokines and cytotoxic effectors, and are thus important players in anti-microbial defense. MAIT cells are protective in experimental models of infection and are decreased in the blood of adult patients with bacterial infections, including Mycobacterium tuberculosis (Mtb). In children, the risk of rapid progression to active tuberculosis (TB) following Mtb infection is higher than in adults. Whether MAIT cells influence the outcome of Mtb infection in children is therefore, an important issue. We analyzed MAIT cell numbers and phenotype in 115 children investigated for pulmonary TB and determined their potential correlation with disease progression. MAIT cells were reduced in numbers and activated in the peripheral blood of children with active TB as compared to those with latent TB infection (LTBI) and healthy children. Moreover, MAIT cells did not accumulate and did not proliferate in the lung of children with active TB. These results suggest that MAIT cells may be important in preventing progression of Mtb infection to active TB in children.


Assuntos
Contagem de Linfócitos , Células T Invariantes Associadas à Mucosa/imunologia , Mycobacterium tuberculosis/imunologia , Tuberculose Pulmonar/imunologia , Adolescente , Fatores Etários , Biomarcadores , Criança , Pré-Escolar , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Imunidade Inata , Imunidade nas Mucosas , Imunofenotipagem , Lactente , Pulmão/imunologia , Pulmão/microbiologia , Pulmão/patologia , Células T Invariantes Associadas à Mucosa/metabolismo , Tuberculose Pulmonar/sangue , Tuberculose Pulmonar/diagnóstico , Tuberculose Pulmonar/metabolismo
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