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1.
J Immunother ; 44(2): 63-70, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33443972

RESUMO

Adoptive cell transfer (ACT) with tumor-infiltrating lymphocytes (TILs) can generate durable clinical responses in patients with metastatic melanoma and ongoing trials are evaluating efficacy in other advanced solid tumors. The aim of this study was to develop methods for the expansion of tumor-reactive TIL from resected soft tissue sarcoma to a degree required for the ACT. From 2015 to 2018, 70 patients were consented to an institutional review board-approved protocol, and fresh surgical specimens were taken directly from the operating room to the laboratory. Fragments of the tumor (1 mm3) or fresh tumor digest were placed in culture for a period of 4 weeks. Successfully propagated TIL from these cultures were collected and analyzed by flow cytometry. TIL were cocultured with autologous tumor and function was assessed by measurement of interferon-γ in the supernatant by enzyme-linked immunosorbent assay. Initial TIL cultures were further expanded using a rapid expansion protocol. Nearly all specimens generated an initial TIL culture (91% fragment method, 100% digest method). The phenotype of the TIL indicated a predominant CD3+ population after culture (43% fragment, 52% digest) and TIL were responsive to the autologous tumor (56% fragment, 40% digest). The cultured TIL expanded to a degree required for clinical use following rapid expansion protocol (median: 490-fold fragment, 403-fold digest). The data demonstrate the feasibility of TIL culture from fresh soft tissue sarcoma. The derived TIL have tumor-specific reactivity and can be expanded to clinically relevant numbers. An active ACT clinical trial using the methods described in this report is now approved for patients with metastatic soft tissue sarcoma.


Assuntos
Linfócitos do Interstício Tumoral/imunologia , Sarcoma/imunologia , Sarcoma/patologia , Microambiente Tumoral , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Terapia Combinada/efeitos adversos , Terapia Combinada/métodos , Citotoxicidade Imunológica , Gerenciamento Clínico , Suscetibilidade a Doenças , Feminino , Humanos , Imunofenotipagem , Imunoterapia/efeitos adversos , Imunoterapia/métodos , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Sarcoma/terapia , Adulto Jovem
2.
PLoS One ; 11(4): e0153053, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27050669

RESUMO

Tumor-infiltrating lymphocytes (TIL) has been associated with improved survival in cancer patients. Within the tumor microenvironment, regulatory cells and expression of co-inhibitory immune checkpoint molecules can lead to the inactivation of TIL. Hence, there is a need to develop strategies that disrupt these negative regulators to achieve robust anti-tumor immune responses. We evaluated the blockade of immune checkpoints and their effect on T cell infiltration and function. We examined the ability of TIL to induce tumor-specific immune responses in vitro and in vivo. TIL isolated from tumor bearing mice were tumor-specific and expressed co-inhibitory immune checkpoint molecules. Administration of monoclonal antibodies against immune checkpoints led to a significant delay in tumor growth. However, anti-PD-L1 antibody treated mice had a significant increase in T cell infiltration and IFN-γ production compared to other groups. Adoptive transfer of in vitro expanded TIL from tumors of anti-PD-L1 antibody treated mice led to a significant delay in tumor growth. Blockade of co-inhibitory immune checkpoints could be an effective strategy to improve TIL infiltration and function.


Assuntos
Transferência Adotiva , Linfócitos do Interstício Tumoral/imunologia , Neoplasias Experimentais/terapia , Animais , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias Experimentais/imunologia
3.
Cancer Res ; 76(6): 1381-90, 2016 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-26719539

RESUMO

Cancer immunotherapies, such as immune checkpoint blockade or adoptive T-cell transfer, can lead to durable responses in the clinic, but response rates remain low due to undefined suppression mechanisms. Solid tumors are characterized by a highly acidic microenvironment that might blunt the effectiveness of antitumor immunity. In this study, we directly investigated the effects of tumor acidity on the efficacy of immunotherapy. An acidic pH environment blocked T-cell activation and limited glycolysis in vitro. IFNγ release blocked by acidic pH did not occur at the level of steady-state mRNA, implying that the effect of acidity was posttranslational. Acidification did not affect cytoplasmic pH, suggesting that signals transduced by external acidity were likely mediated by specific acid-sensing receptors, four of which are expressed by T cells. Notably, neutralizing tumor acidity with bicarbonate monotherapy impaired the growth of some cancer types in mice where it was associated with increased T-cell infiltration. Furthermore, combining bicarbonate therapy with anti-CTLA-4, anti-PD1, or adoptive T-cell transfer improved antitumor responses in multiple models, including cures in some subjects. Overall, our findings show how raising intratumoral pH through oral buffers therapy can improve responses to immunotherapy, with the potential for immediate clinical translation.


Assuntos
Antineoplásicos/imunologia , Microambiente Tumoral/imunologia , Animais , Anticorpos/imunologia , Bicarbonatos/farmacologia , Antígeno CTLA-4/imunologia , Linhagem Celular Tumoral , Feminino , Concentração de Íons de Hidrogênio , Imunoterapia/métodos , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Receptor de Morte Celular Programada 1/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Microambiente Tumoral/efeitos dos fármacos
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