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1.
Bioorg Med Chem ; 24(8): 1819-39, 2016 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-26988803

RESUMO

A novel set of GAC (kidney glutaminase isoform C) inhibitors able to inhibit the enzymatic activity of GAC and the growth of the triple negative MDA-MB-231 breast cancer cells with low nanomolar potency is described. Compounds in this series have a reduced number of rotatable bonds, improved ClogPs, microsomal stability and ligand efficiency when compared to the leading GAC inhibitors BPTES and CB-839. Property improvements were achieved by the replacement of the flexible n-diethylthio or the n-butyl moiety present in the leading inhibitors by heteroatom substituted heterocycloalkanes.


Assuntos
Benzenoacetamidas/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Glutaminase/antagonistas & inibidores , Sulfetos/farmacologia , Tiadiazóis/farmacologia , Benzenoacetamidas/química , Benzenoacetamidas/metabolismo , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Glutaminase/metabolismo , Humanos , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Sulfetos/química , Sulfetos/metabolismo , Tiadiazóis/química , Tiadiazóis/metabolismo
2.
Cancer Immunol Res ; 12(2): 214-231, 2024 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-38270373

RESUMO

T-cell receptor (TCR)-modified T-cell therapies have shown promise against solid tumors, but overall therapeutic benefits have been modest due in part to suboptimal T-cell persistence and activation in vivo, alongside potential tumor antigen escape. In this study, we demonstrate an approach to enhance the in vivo persistence and function of TCR T cells through combination with Amphiphile (AMP) vaccination including cognate TCR T peptides. AMP modification improves lymph node targeting of conjugated tumor immunogens and adjuvants, thereby coordinating a robust T cell-activating endogenous immune response. AMP vaccine combination with TCR T-cell therapy led to complete eradication and durable responses against established murine solid tumors refractory to TCR T-cell monotherapy. Enhanced antitumor efficacy was correlated with simultaneous in vivo invigoration of adoptively transferred TCR T cells and in situ expansion of the endogenous antitumor T-cell repertoire. Long-term protection against tumor recurrence in AMP-vaccinated mice was associated with antigen spreading to additional tumor-associated antigens not targeted by vaccination. AMP vaccination further correlated with pro-inflammatory lymph node transcriptional reprogramming and increased antigen presenting-cell maturation, resulting in TCR T-cell expansion and functional enhancement in lymph nodes and solid tumor parenchyma without lymphodepletion. In vitro evaluation of AMP peptides with matched human TCR T cells targeting NY-ESO-1, mutant KRAS, and HPV16 E7 illustrated the clinical potential of AMP vaccination to enhance human TCR T-cell proliferation, activation, and antitumor activity. Taken together, these studies provide rationale and evidence to support clinical evaluation of combining AMP vaccination with TCR T-cell therapies to augment antitumor activity.


Assuntos
Neoplasias , Vacinas , Camundongos , Humanos , Animais , Receptores de Antígenos de Linfócitos T/genética , Antígenos de Neoplasias , Linfonodos , Peptídeos , Terapia Baseada em Transplante de Células e Tecidos
3.
Cancer Immunol Res ; 8(6): 743-755, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32209638

RESUMO

T-cell receptor (TCR)-modified T-cell gene therapy can target a variety of extracellular and intracellular tumor-associated antigens, yet has had little clinical success. A potential explanation for limited antitumor efficacy is a lack of T-cell activation in vivo We postulated that expression of proinflammatory cytokines in TCR-modified T cells would activate T cells and enhance antitumor efficacy. We demonstrate that expression of interleukin 18 (IL18) in tumor-directed TCR-modified T cells provides a superior proinflammatory signal than expression of interleukin 12 (IL12). Tumor-targeted T cells secreting IL18 promote persistent and functional effector T cells and a proinflammatory tumor microenvironment. Together, these effects augmented overall survival of mice in the pmel-1 syngeneic tumor model. When combined with sublethal irradiation, IL18-secreting pmel-1 T cells were able to eradicate tumors, whereas IL12-secreting pmel-1 T cells caused toxicity in mice through excessive cytokine secretion. In another xenograft tumor model, IL18 secretion enhanced the persistence and antitumor efficacy of NY-ESO-1-reactive TCR-modified human T cells as well as overall survival of tumor-bearing mice. These results demonstrate a rationale for optimizing the efficacy of TCR-modified T-cell cancer therapy through expression of IL18.See related commentary by Wijewarnasuriya et al., p. 732.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Imunoterapia Adotiva/normas , Interleucina-12/metabolismo , Interleucina-18/metabolismo , Ativação Linfocitária/imunologia , Melanoma/terapia , Receptores de Antígenos de Linfócitos T/imunologia , Animais , Antígenos de Neoplasias/imunologia , Apoptose , Linfócitos T CD8-Positivos/metabolismo , Proliferação de Células , Humanos , Imunoterapia Adotiva/métodos , Melanoma/imunologia , Melanoma/metabolismo , Melanoma/patologia , Melanoma Experimental/imunologia , Melanoma Experimental/metabolismo , Melanoma Experimental/patologia , Melanoma Experimental/terapia , Camundongos , Camundongos Knockout , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Nat Biotechnol ; 36(9): 847-856, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30102295

RESUMO

The efficacy of chimeric antigen receptor (CAR) T cell therapy against poorly responding tumors can be enhanced by administering the cells in combination with immune checkpoint blockade inhibitors. Alternatively, the CAR construct has been engineered to coexpress factors that boost CAR-T cell function in the tumor microenvironment. We modified CAR-T cells to secrete PD-1-blocking single-chain variable fragments (scFv). These scFv-secreting CAR-T cells acted in both a paracrine and autocrine manner to improve the anti-tumor activity of CAR-T cells and bystander tumor-specific T cells in clinically relevant syngeneic and xenogeneic mouse models of PD-L1+ hematologic and solid tumors. The efficacy was similar to or better than that achieved by combination therapy with CAR-T cells and a checkpoint inhibitor. This approach may improve safety, as the secreted scFvs remained localized to the tumor, protecting CAR-T cells from PD-1 inhibition, which could potentially avoid toxicities associated with systemic checkpoint inhibition.


Assuntos
Receptor de Morte Celular Programada 1/imunologia , Receptores de Antígenos Quiméricos/imunologia , Anticorpos de Cadeia Única/imunologia , Linfócitos T/imunologia , Animais , Humanos , Camundongos , Microambiente Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto
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