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1.
BMJ Open Sport Exerc Med ; 10(1): e001782, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38481557

RESUMO

This study explored professional wrestlers' experiences of the consequences of an anterior cruciate ligament (ACL) injury and their perception of whether the ACL injury could have been prevented. We interviewed 10 professional wrestlers (60% women, age range 21-34) treated with ACL reconstruction with semistructured interviews. Transcripts were analysed using qualitative content analysis: One major theme, 'Wrestling with a ghost: facing an opponent I can neither see nor clinch', supported by five main categories, emerged from the collected data. The five main categories were: My ACL injury: bad luck or bad planning?; The way back: a fight to return to sport; Only performance counts; The injury's impact on life: a wrestling with emotions; In hindsight, personal growth. Professional wrestlers who experienced an ACL injury expressed that not only the injury itself but also the subsequent recovery posed major challenges that they did not know how to deal with and that, in some cases, ended the athletes' wrestling careers. Professional wrestlers attributed their ACL injuries to bad luck or large training loads and wished that they had more support from the wrestling community when injured.

2.
Clin Cancer Res ; 24(24): 6185-6194, 2018 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-30097433

RESUMO

PURPOSE: The chimeric antigen receptor (CAR) T-cell therapy has been effective for patients with CD19+ B-cell malignancies. Most studies have investigated the second-generation CARs with either CD28 or 4-1BB costimulatory domains in the CAR receptor. Here, we describe the first clinical phase I/IIa trial using third-generation CAR T cells targeting CD19 to evaluate safety and efficacy. PATIENTS AND METHODS: Fifteen patients with B-cell lymphoma or leukemia were treated with CAR T cells. The patients with lymphoma received chemotherapy during CAR manufacture and 11 of 15 were given low-dose cyclophosphamide and fludarabine conditioning prior to CAR infusion. Peripheral blood was sampled before and at multiple time points after CAR infusion to evaluate the persistence of CAR T cells and for immune profiling, using quantitative PCR, flow cytometry, and a proteomic array. RESULTS: Treatment with third-generation CAR T cells was generally safe with 4 patients requiring hospitalization due to adverse reactions. Six of the 15 patients had initial complete responses [4/11 lymphoma and 2/4 acute lymphoblastic leukemia (ALL)], and 3 of the patients with lymphoma were in remission at 3 months. Two patients are still alive. Best predictor of response was a good immune status prior to CAR infusion with high IL12, DC-Lamp, Fas ligand, and TRAIL. Responding patients had low monocytic myeloid-derived suppressor cells (MDSCs; CD14+CD33+HLA-DR-) and low levels of IL6, IL8, NAP3, sPDL1, and sPDL2. CONCLUSIONS: Third-generation CARs may be efficient in patients with advanced B-cell lymphoproliferative malignancy with only modest toxicity. Immune profiling pre- and posttreatment can be used to find response biomarkers.


Assuntos
Antígenos CD19 , Imunoterapia Adotiva , Leucemia/imunologia , Leucemia/terapia , Linfoma/imunologia , Linfoma/terapia , Receptores de Antígenos de Linfócitos T , Linfócitos T , Adulto , Idoso , Antígenos CD19/imunologia , Antígenos CD19/metabolismo , Técnicas de Cultura Celular por Lotes , Separação Celular , Feminino , Humanos , Imunidade Celular , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Leucemia/diagnóstico , Leucemia/mortalidade , Contagem de Linfócitos , Linfoma/diagnóstico , Linfoma/mortalidade , Masculino , Pessoa de Meia-Idade , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Análise de Sobrevida , Linfócitos T/imunologia , Linfócitos T/metabolismo , Transgenes , Resultado do Tratamento , Adulto Jovem
3.
Biochem Soc Trans ; 44(2): 371-6, 2016 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-27068942

RESUMO

Chimaeric antigen receptor (CAR) T-cells have shown impressive results in patients with B-cell leukaemia. Yet, in patients with lymphoma durable responses are still rare and heavy preconditioning required. Apoptosis resistance is considered a hallmark of cancer, often conveyed by a halted apoptosis signalling. Tumours regularly skew the balance of the components of the apoptotic machinery either through up-regulating anti-apoptotic proteins or silencing pro-apoptotic ones. Malignant B-cells frequently up-regulate anti-apoptotic B-cell lymphoma 2 (Bcl-2) family proteins leading to therapy resistance. CAR T-cells kill tumour cells via apoptosis induction and their efficacy may be affected by the level of Bcl-2 family proteins. Hence, there is an interesting possibility to increase the effect of CAR T-cell therapy by combining it with apoptosis inhibitor blockade agents. Compounds that inhibit Bcl-2, B-cell lymphoma extra large (Bcl-xL) and Bcl-2-like protein 2 (Bcl-w), can restore execution of apoptosis in tumour cells or sensitize them to other apoptosis-dependent treatments. Hence, there is a great interest to combine such agents with CAR T-cell therapy to potentiate the effect of CAR T-cell killing. This review will focus on the potential of targeting the apoptotic machinery to sensitize tumour cells to CAR T-cell killing.


Assuntos
Apoptose , Imunoterapia , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T/imunologia , Humanos , Linfoma/imunologia , Linfoma/patologia , Linfoma/terapia
4.
PLoS One ; 10(12): e0144787, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26700307

RESUMO

CD19-targeting CAR T cells have shown potency in clinical trials targeting B cell leukemia. Although mainly second generation (2G) CARs carrying CD28 or 4-1BB have been investigated in patients, preclinical studies suggest that third generation (3G) CARs with both CD28 and 4-1BB have enhanced capacity. However, little is known about the intracellular signaling pathways downstream of CARs. In the present work, we have analyzed the signaling capacity post antigen stimulation in both 2G and 3G CARs. 3G CAR T cells expanded better than 2G CAR T cells upon repeated stimulation with IL-2 and autologous B cells. An antigen-driven accumulation of CAR+ cells was evident post antigen stimulation. The cytotoxicity of both 2G and 3G CAR T cells was maintained by repeated stimulation. The phosphorylation status of intracellular signaling proteins post antigen stimulation showed that 3G CAR T cells had a higher activation status than 2G. Several proteins involved in signaling downstream the TCR were activated, as were proteins involved in the cell cycle, cell adhesion and exocytosis. In conclusion, 3G CAR T cells had a higher degree of intracellular signaling activity than 2G CARs which may explain the increased proliferative capacity seen in 3G CAR T cells. The study also indicates that there may be other signaling pathways to consider when designing or evaluating new generations of CARs.


Assuntos
Antígenos CD28/imunologia , Imunoterapia , Leucemia Linfocítica Crônica de Células B/imunologia , Receptores de Antígenos/imunologia , Linfócitos T Citotóxicos/imunologia , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/imunologia , Animais , Estudos de Casos e Controles , Citometria de Fluxo , Voluntários Saudáveis , Humanos , Leucemia Linfocítica Crônica de Células B/patologia , Leucemia Linfocítica Crônica de Células B/terapia , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Transdução de Sinais
5.
Hum Gene Ther ; 26(8): 498-505, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26230974

RESUMO

Chimeric antigen receptor (CAR) T-cells have shown remarkable results in patients with B-cell leukemia and lymphoma. However, while CAR T-cells have shown complete responses in a majority of patients with acute lymphoblastic leukemia (ALL), lymphomas are more difficult to treat. Different CAR designs and conditioning protocols seem to affect the persistence of patient responses. However, factors that determine if patients receiving the same CARs will respond or not remain obscure. In Sweden, a phase I/IIa trial using third-generation CAR T-cells is ongoing in which we intend to compare tumor biology and immunology, in each patient, to treatment response. CAR T-cell therapy is a powerful tool to add to the treatment options for this patient group but we need to perform the necessary basic research on the multifactorial mechanisms of action to give patients the best possible option of survival. Such studies are also crucial to expand the success of CAR T-cells beyond CD19+ B-cell malignancy. This review will focus on possible barriers of treating lymphoma to define factors that need to be investigated to develop the next generation of CAR T-cell therapy.


Assuntos
Linfoma/terapia , Linfócitos T/transplante , Animais , Humanos , Terapia de Imunossupressão , Imunoterapia , Linfócitos do Interstício Tumoral/imunologia , Linfoma/imunologia , Proteínas Mutantes Quiméricas/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Microambiente Tumoral
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