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1.
Mol Ther ; 31(11): 3193-3209, 2023 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-37735875

RESUMO

Claudin18.2 (CLDN18.2)-specific chimeric antigen receptor (CAR-T) cells displayed limited efficacy in CLDN18.2-positive pancreatic ductal adenocarcinoma (PDAC). Strategies are needed to improve the trafficking capacity of CLDN18.2-specific CAR-T cells. PDAC has a unique microenvironment that consists of abundant cancer-associated fibroblasts (CAFs), which could secrete stromal cell-derived factor 1α (SDF-1α), the ligand of CXCR4. Then, we constructed and explored CLDN18.2-targeted CAR-T cells with CXCR4 co-expression in treating immunocompetent mouse models of PDAC. The results indicated that CXCR4 could promote the infiltration of CAR-T cells and enhance their efficacy in vivo. Mechanistically, the activation of signal transducer and activator of transcription 3 (STAT3) signaling was impaired in CXCR4 CAR-T cells, which reduced the release of inflammatory factors, such as tumor necrosis factor-α, IL-6, and IL-17A. Then, the lower release of inflammatory factors suppressed SDF-1α secretion in CAFs via the nuclear factor κB (NF-κB) pathway. Therefore, the decreased secretion of SDF-1α in feedback decreased the migration of myeloid-derived suppressor cells (MDSCs) in tumor sites. Overall, our study demonstrated that CXCR4 CAR-T cells could traffic more into tumor sites and also suppress MDSC migration via the STAT3/NF-κB/SDF-1α axis to obtain better efficacy in treating CLDN18.2-positive pancreatic cancer. Our findings provide a theoretical rationale for CXCR4 CAR-T cell therapy in PDAC.


Assuntos
Células Supressoras Mieloides , Neoplasias Pancreáticas , Receptores de Antígenos Quiméricos , Camundongos , Animais , NF-kappa B/metabolismo , Quimiocina CXCL12/genética , Quimiocina CXCL12/metabolismo , Células Supressoras Mieloides/metabolismo , Receptores de Antígenos Quiméricos/metabolismo , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Movimento Celular/fisiologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/terapia , Linfócitos T/metabolismo , Receptores CXCR4/genética , Receptores CXCR4/metabolismo , Microambiente Tumoral
2.
Mol Ther ; 31(3): 701-714, 2023 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-36523165

RESUMO

Limited T cell persistence restrains chimeric antigen receptor (CAR)-T cell therapy in solid tumors. To improve persistence, T cells have been engineered to secrete proinflammatory cytokines, but other possible methods have been understudied. Runx3 has been considered a master regulator of T cell development, cytotoxic T lymphocyte differentiation, and tissue-resident memory T (Trm)-cell formation. A study using a transgenic mouse model revealed that overexpression of Runx3 promoted T cell persistence in solid tumors. Here, we generated CAR-T cells overexpressing Runx3 (Run-CAR-T cells) and found that Run-CAR-T cells had long-lasting antitumor activities and achieved better tumor control than conventional CAR-T cells. We observed that more Run-CAR-T cells circulated in the peripheral blood and accumulated in tumor tissue, indicating that Runx3 coexpression improved CAR-T cell persistence in vivo. Tumor-infiltrating Run-CAR-T cells showed less cell death with enhanced proliferative and effector activities. Consistently, in vitro studies indicated that AICD was also decreased in Run-CAR-T cells via downregulation of tumor necrosis factor (TNF) secretion. Further studies revealed that Runx3 could bind to the TNF promoter and suppress its gene transcription after T cell activation. In conclusion, Runx3-armored CAR-T cells showed increased antitumor activities and could be a new modality for the treatment of solid tumors.


Assuntos
Neoplasias , Linfócitos T , Animais , Camundongos , Neoplasias/genética , Neoplasias/terapia , Imunoterapia Adotiva/métodos , Citocinas/metabolismo , Morte Celular/genética , Linhagem Celular Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Mol Ther ; 29(1): 60-74, 2021 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-33010818

RESUMO

A hostile tumor microenvironment is one of the major obstacles for the efficacy of chimeric antigen receptor modified T (CAR-T) cells, and combination treatment might be a potential way to overcome this obstacle. Poly(ADP-ribose) polymerase inhibitor (PARPi) has demonstrated tremendous potential in breast cancer. In this study, we explored the possible combination of the PAPRi olaparib with EGFRvIII-targeted CAR (806-28Z CAR) T cells in immunocompetent mouse models of breast cancer. The results indicated that the administration of olaparib could significantly enhance the efficacy of 806-28Z CAR-T cells in vivo. Interestingly, we observed that olaparib could suppress myeloid-derived suppressor cell (MDSC) migration and promote the survival of CD8+ T cells in tumor tissue. Mechanistically, olaparib was shown to reduce the expression of SDF1α released from cancer-associated fibroblasts (CAFs) and thereby decreased MDSC migration through CXCR4. Taken together, this study demonstrated that olaparib could increase the antitumor activities of CAR-T cell therapy at least partially through inhibiting MDSC migration via the SDF1α/CXCR4 axis. These findings uncover a novel mechanism of PARPi function and provide additional mechanistic rationale for combining PARPi with CAR-T cells for the treatment of breast cancer.


Assuntos
Quimiocina CXCL12/metabolismo , Imunoterapia Adotiva , Células Supressoras Mieloides/efeitos dos fármacos , Células Supressoras Mieloides/metabolismo , Ftalazinas/farmacologia , Piperazinas/farmacologia , Receptores CXCR4/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Animais , Neoplasias da Mama , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Camundongos , Células Supressoras Mieloides/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos Quiméricos/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
4.
J Natl Cancer Inst ; 111(4): 409-418, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30203099

RESUMO

BACKGROUND: Claudin18.2 (CLDN18.2), a gastric-specific membrane protein, has been regarded as a potential therapeutic target for gastric cancer and other cancer types. The aim of our study was to elucidate whether chimeric antigen receptor T (CAR T) cells redirected to CLDN18.2 have the potential to be used in the treatment of this deadly disease. METHODS: CLDN18.2-specific humanized antibodies were developed using hybridoma and humanization technology. CLDN18.2-specific CAR T cells were prepared by lentiviral vector transduction. In vitro antitumor activities and cytokine production of the CAR T cells to gastric cancer cell lines were examined by cytotoxicity and ELISA assay. In vivo antitumor activities of CAR T cells were evaluated in mice bearing gastric cancer cell line and patient-derived tumor xenograft (PDX) models (n ≥ 6 mice per group). All statistical tests were two-sided. RESULTS: Humanized CLDN18.2-specific hu8E5 and hu8E5-2I single-chain fragment variables (scFv) were successfully developed. CLDN18.2-specific CAR T cells were developed using hu8E5 or hu8E5-2I scFv as targeting moieties. Both hu8E5-28Z and hu8E5-2I-28Z CAR T cells comprising the CD28 costimulatory domain potently suppressed tumor growth in a cancer cell line xenograft mouse model (mean [SD] tumor volume: hu8E5-28Z = 118.0 [108.6] mm3 and hu8E5-2I-28Z group = 75.5 [118.7] mm3 vs untransduced T cell group = 731.8 [206.3] mm3 at day 29 after tumor inoculation, P < .001). Partial or complete tumor elimination was observed in CLDN18.2-positive gastric cancer PDX models treated with the hu8E5-2I-28Z CAR T cells (P < .001), which persist well in vivo and infiltrate efficiently into the tumor tissues. Although the CLDN18.2 CAR T cells could lyse target cells expressing murine CLDN18.2 (mCLDN18.2), no obvious deleterious effect on the normal organs including the gastric tissues was observed in the mice. CONCLUSIONS: CLDN18.2-specific CAR T cells could be a promising treatment strategy for gastric cancer and potentially other CLDN18.2-positive tumors.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Claudinas/imunologia , Imunoterapia Adotiva/métodos , Receptores de Antígenos Quiméricos/imunologia , Neoplasias Gástricas/terapia , Linfócitos T/transplante , Animais , Apoptose , Proliferação de Células , Claudinas/genética , Humanos , Camundongos , Receptores de Antígenos Quiméricos/genética , Neoplasias Gástricas/imunologia , Linfócitos T/imunologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Front Pharmacol ; 9: 1118, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30327605

RESUMO

Cancer immunotherapy has made unprecedented breakthrough in the fields of chimeric antigen receptor-redirected T (CAR T) cell therapy and immune modulation. Combination of CAR modification and the disruption of endogenous inhibitory immune checkpoints on T cells represent a promising immunotherapeutic modality for cancer treatment. However, the potential for the treatment of hepatocellular carcinoma (HCC) has not been explored. In this study, the gene expressing the programmed death 1 receptor (PD-1) on the Glypican-3 (GPC3)-targeted second-generation CAR T cells employing CD28 as the co-stimulatory domain was disrupted using the CRISPR/Cas9 gene-editing system. It was found that, in vitro, the CAR T cells with the deficient PD-1 showed the stronger CAR-dependent anti-tumor activity against native programmed death 1 ligand 1-expressing HCC cell PLC/PRF/5 compared with the wild-type CAR T cells, and meanwhile, the CD4 and CD8 subsets, and activation status of CAR T cells were stable with the disruption of endogenous PD-1. Additionally, the disruption of PD-1 could protect the GPC3-CAR T cells from exhaustion when combating with native PD-L1-expressing HCC, as the levels of Akt phosphorylation and anti-apoptotic protein Bcl-xL expression in PD-1 deficient GPC3-CAR T cells were significantly higher than those in wild-type GPC3-CAR T cells after coculturing with PLC/PRF/5. Furthermore, the in vivo anti-tumor activity of the CAR T cells with the deficient PD-1 was investigated using the subcutaneous xenograft tumor model established by the injection of PLC/PRF/5 into NOD-scid-IL-2Rγ-/- (NSG) mice. The results indicated that the disruption of PD-1 enhanced the in vivo anti-tumor activity of CAR T cells against HCC, improved the persistence and infiltration of CAR T cells in the NSG mice bearing the tumor, and strengthened the inhibition of tumor-related genes expression in the xenograft tumors caused by the GPC3-CAR T cells. This study indicates the enhanced anti-tumor efficacy of PD-1-deficient CAR T cells against HCC and suggests the potential of precision gene editing on the immune checkpoints to enhance the CAR T cell therapies against HCC.

6.
Biomed Pharmacother ; 84: 1783-1791, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27899251

RESUMO

Lack of satisfactory specificity towards tumor cells and poor intracellular delivery efficacy are the major drawbacks with conventional cancer chemotherapy. Conjugated anticancer drugs to targeting moieties e.g. to peptides with the ability to recognize cancer cells and to cell penetrating peptide can improve these characteristics, respectively. Combining a tumor homing peptide with an appropriate cell-penetrating peptide can enhance the tumor-selective internalization efficacy of the carrying cargo molecules. In the present study, the breast cancer homing ability of SP90 peptide and the synergistic effect of SP90 with a cell-penetrating peptide(C peptide) were evaluated. SP90 and chimeric peptide SP90-C specifically targeted cargo molecule into breast cancer cells, especially triple negative MDA-MB-231 cell, in a dose- and time-dependent manner, but not normal breast cells and other cancer cells, while C peptide alone had no cell-selectivity. SP90-C increased the intracellular delivery efficiency by 12-fold or 10-fold compared to SP90 or C peptide alone, respectively. SP90 and SP90-C conjugation increased the anti-proliferative and apoptosis-inducing activity of HIV-1 Vpr, a potential novel anticancer protein drug, to breast cancer cell but not normal breast cell by arresting cells in G2/M phase. With excellent breast cancer cell-selective penetrating efficacy, SP90-C appears as a promising candidate vector for targeted anti-cancer drug delivery. SP90-VPR-C is a potential novel breast cancer-targeted anticancer agent for its high anti-tumor activity and low toxicity.


Assuntos
Antineoplásicos/metabolismo , Neoplasias da Mama/metabolismo , Peptídeos Penetradores de Células/metabolismo , Portadores de Fármacos , Sistemas de Liberação de Medicamentos/métodos , Oligopeptídeos/metabolismo , Produtos do Gene vpr do Vírus da Imunodeficiência Humana/metabolismo , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Peptídeos Penetradores de Células/química , Relação Dose-Resposta a Droga , Composição de Medicamentos , Feminino , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Células MCF-7 , Oligopeptídeos/química , Proteínas Recombinantes de Fusão/metabolismo , Fatores de Tempo , Produtos do Gene vpr do Vírus da Imunodeficiência Humana/química , Produtos do Gene vpr do Vírus da Imunodeficiência Humana/farmacologia
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