A Phase Ia/Ib, Open-label, Single-arm, Dose-escalation and Expansion Study of Specific Dual-targeting VEGFR1 and PD-L1 CAR-T in Cancer Patients With Pleural or Peritoneal Metastases

Serosal cavity metastases of malignant tumor seriously affects the quality of life and survival time of patients with cancers in advanced stage. VEGFR1 is frequently expressed in breast cancer, ovarian cancer, lung cancer, gastric cancer and other malignant tumors and their metastases. The VEGFR1/PD-L1 dual-targeting CAR-T will be investigated in cancer patients with serosal cavity metastases.

开始日期2023-11-28

申办/合作机构

四川大学

100 项与 Dual-targeting VEGFR1 and PD-L1 CAR-T cells(Sichuan University) 相关的临床结果

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100 项与 Dual-targeting VEGFR1 and PD-L1 CAR-T cells(Sichuan University) 相关的转化医学

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100 项与 Dual-targeting VEGFR1 and PD-L1 CAR-T cells(Sichuan University) 相关的专利（医药）

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项与 Dual-targeting VEGFR1 and PD-L1 CAR-T cells(Sichuan University) 相关的文献（医药）

2022-03-01·Molecular Therapy - Oncolytics2区 · 医学

A novel PD-L1-targeted shark VNAR single-domain-based CAR-T cell strategy for treating breast cancer and liver cancer

2区 · 医学

ArticleOA

作者: Ho, Mitchell ; Merlino, Glenn ; Day, Chi-Ping ; Hong, Jessica ; English, Hejiao ; Liang, Tianyuzhou ; Li, Dan

Chimeric antigen receptor (CAR)-T cell therapy shows excellent potency against hematological malignancies, but it remains challenging to treat solid tumors, mainly because of a lack of appropriate antigenic targets and an immunosuppressive tumor microenvironment (TME). The checkpoint molecule programmed death-ligand 1 (PD-L1) is widely overexpressed in multiple tumor types, and the programmed death-ligand 1 (PD-1)/PD-L1 interaction is a crucial mediator of immunosuppression in the TME. Here we constructed a semi-synthetic shark V_NAR phage library and isolated anti-PD-L1 single-domain antibodies. Among these V_NARs, B2 showed cross-reactivity to human, mouse, and canine PD-L1, and it partially blocked the interaction of human PD-1 with PD-L1. CAR (B2) T cells specifically lysed human breast cancer and liver cancer cells by targeting constitutive and inducible expression of PD-L1 and hindered tumor metastasis. Combination of PD-L1 CAR (B2) T cells with CAR T cells targeted by GPC3 (a liver cancer-specific antigen) regresses liver tumors in mice. We concluded that PD-L1-targeted shark V_NAR single-domain-based CAR-T therapy is a novel strategy to treat breast and liver cancer. This study provides a rationale for potential use of PD-L1 CAR-T cells as a monotherapy or in combination with a tumor-specific therapy in clinical studies.

2022-01-01·Journal for ImmunoTherapy of Cancer2区 · 医学

PD-L1 CAR effector cells induce self-amplifying cytotoxic effects against target cells

2区 · 医学

ArticleOA

作者: Goral, Agnieszka ; Soroczynska, Karolina ; Zagozdzon, Radoslaw ; Zhylko, Andriy ; Pilch, Zofia ; Krawczyk, Marta ; Marhelava, Katsiaryna ; Paczek, Leszek ; Wälchli, Sébastien ; Winiarska, Magdalena ; Graczyk-Jarzynka, Agnieszka ; Retecki, Kuba ; Bajor, Malgorzata ; Burdzinska, Anna ; Klopotowska, Marta ; Muchowicz, Angelika ; Malmberg, Karl-Johan

BackgroundImmune checkpoint inhibitors and chimeric antigen receptor (CAR)-based therapies have transformed cancer treatment. Recently, combining these approaches into a strategy of PD-L1-targeted CAR has been proposed to target PD-L1high tumors. Our study provides new information on the efficacy of such an approach against PD-L1low targets.MethodsNew atezolizumab-based PD-L1-targeted CAR was generated and introduced into T, NK, or NK-92 cells. Breast cancer MDA-MB-231 and MCF-7 cell lines or non-malignant cells (HEK293T, HMEC, MCF-10A, or BM-MSC) were used as targets to assess the reactivity or cytotoxic activity of the PD-L1–CAR-bearing immune effector cells. Stimulation with IFNγ or with supernatants from activated CAR T cells were used to induce upregulation of PD-L1 molecule expression on the target cells. HER2–CAR T cells were used for combination with PD-L1–CAR T cells against MCF-7 cells.ResultsPD-L1–CAR effector cells responded vigorously with degranulation and cytokine production to PD-L1high MDA-MB-231 cells, but not to PD-L1low MCF-7 cells. However, in long-term killing assays, both MDA-MB-231 and MCF-7 cells were eliminated by the PD-L1–CAR cells, although with a delay in the case of PD-L1low MCF-7 cells. Notably, the coculture of MCF-7 cells with activated PD-L1–CAR cells led to bystander induction of PD-L1 expression on MCF-7 cells and to the unique self-amplifying effect of the PD-L1–CAR cells. Accordingly, PD-L1–CAR T cells were active not only against MDA-MD-231 and MCF-7-PD-L1 but also against MCF-7-pLVX cells in tumor xenograft models. Importantly, we have also observed potent cytotoxic effects of PD-L1–CAR cells against non-malignant MCF-10A, HMEC, and BM-MSC cells, but not against HEK293T cells that initially did not express PD-L1 and were unresponsive to the stimulation . Finally, we have observed that HER-2–CAR T cells stimulate PD-L1 expression on MCF-7 cells and therefore accelerate the functionality of PD-L1–CAR T cells when used in combination.ConclusionsIn summary, our studies show that CAR-effector cells trigger the expression of PD-L1 on target cells, which in case of PD-L1–CAR results in the unique self-amplification phenomenon. This self-amplifying effect could be responsible for the enhanced cytotoxicity of PD-L1–CAR T cells against both malignant and non-malignant cells and implies extensive caution in introducing PD-L1–CAR strategy into clinical studies.

2021-01-01·Journal of Cancer3区 · 医学

Synergistic killing effects of PD-L1-CAR T cells and colorectal cancer stem cell-dendritic cell vaccine-sensitized T cells in ALDH1-positive colorectal cancer stem cells

3区 · 医学

ArticleOA

作者: Xia, Yang ; Liu, Liu ; Yuan, Yuan ; Liu, Shangquan ; Liu, Yuanyuan ; Wang, Yi ; Wang, Guanlong ; Zhang, Huan ; Zhang, Xiushan ; Xu, Yang

Cancer stem cells (CSCs) are characterized by self-renewal and unlimited proliferation, providing a basis for tumor occurrence, metastasis, and recurrence. Because CSCs are highly resistant to conventional chemotherapy and radiotherapy, various immunotherapies, particularly chimeric antigen receptor T cell (CAR-T) therapy and dendritic cell (DC)-based vaccine therapy, are currently being developed. Accordingly, in this study, we evaluated programmed cell death ligand-1 (PD-L1) expression in colorectal CSCs (CCSCs) and non-CCSCs and designed a combination immunotherapy synchronously utilizing PD-L1-CAR-T cells together with CCSC-DC vaccine-sensitized T cells for the treatment of colorectal cancer. PD-L1-CAR-T cells specifically recognized the PD-L1 molecule on CCSCs by binding to the extracellular domain of programmed cell death-1. The CCSC-DC vaccine was prepared using CCSC lysates. We found that aldehyde dehydrogenase 1 (ALDH1)-positive CCSCs were abundant in samples from patient tumor tissues and cancer cell lines. Moreover, PD-L1 was highly expressed in ALDH1-positive CCSCs compared with that in non-CCSCs. Monotherapy with PD-L1-CAR-T cells or CCSC-DC vaccine only elicited moderate tumor remission both in vitro and in vivo. However, combination therapy markedly killed cancer cells and relieved the tumor burden in mice. Our findings may provide a novel strategy for the clinical treatment of colorectal malignancy.

100 项与 Dual-targeting VEGFR1 and PD-L1 CAR-T cells(Sichuan University) 相关的药物交易

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