抗CD73和抗PD-L1单克隆抗体联合细胞毒疗法的疗效和药效学效应:小鼠肿瘤模型观察。

IF 4.4 4区 医学 Q2 ONCOLOGY Cancer Biology & Therapy Pub Date : 2024-12-31 Epub Date: 2024-01-11 DOI:10.1080/15384047.2023.2296048
Brajesh P Kaistha, Gozde Kar, Andreas Dannhorn, Amanda Watkins, Grace Opoku-Ansah, Kristina Ilieva, Stefanie Mullins, Judith Anderton, Elena Galvani, Fabien Garcon, Jean-Martin Lapointe, Lee Brown, James Hair, Tim Slidel, Nadia Luheshi, Kelli Ryan, Elizabeth Hardaker, Simon Dovedi, Rakesh Kumar, Robert W Wilkinson, Scott A Hammond, Jim Eyles
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引用次数: 0

摘要

CD73 是一种细胞表面 5'nucleotidase (NT5E),是癌症中产生免疫抑制腺苷的分解过程中的关键节点。我们使用小鼠单克隆抗体奥利珠单抗(Oleclumab)替代物,研究了CD73抑制与细胞毒疗法(化疗和分次放疗)和PD-L1阻断的协同作用。我们的研究结果表明,结直肠癌(CT26 和 MC38)和肉瘤(MCA205)共生肿瘤模型的生存率得到了改善。这种治疗结果部分是由细胞毒性 CD8 T 细胞驱动的,这一点可以从 CD8 清除抗体对接受抗 CD73、抗 PD-L1 和 5-氟尿嘧啶+奥沙利铂(5FU+OHP)治疗的 MCA205 肿瘤小鼠的不利影响得到证明。我们推测,抗 CD73 对体外细胞系的细胞病理效应没有增强,这说明反应的改善是由肿瘤微环境(TME)驱动的。利用成像质谱和 RNA 序列进行的药效学分析显示,CT26 TME 中的特定细胞群(如细胞毒性 T 细胞、B 细胞和 NK 细胞)发生了显著变化。转录组分析强调了与免疫反应、NK 和 T 细胞活化、T 细胞受体信号转导和干扰素(1 型和 2 型)通路相关的基因谱的治疗相关调控。纳入代表联合疗法各种成分的比较组后,可以对单个治疗要素的贡献进行解构;突出了抗 CD73 抗体在免疫细胞代表性、趋化性和骨髓生物学方面介导的特定效应。这些临床前数据反映了腺苷阻断与细胞毒疗法和 T 细胞检查点抑制的互补性,并为支持联合疗法提供了新的机理见解。
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Efficacy and pharmacodynamic effect of anti-CD73 and anti-PD-L1 monoclonal antibodies in combination with cytotoxic therapy: observations from mouse tumor models.

CD73 is a cell surface 5'nucleotidase (NT5E) and key node in the catabolic process generating immunosuppressive adenosine in cancer. Using a murine monoclonal antibody surrogate of Oleclumab, we investigated the effect of CD73 inhibition in concert with cytotoxic therapies (chemotherapies as well as fractionated radiotherapy) and PD-L1 blockade. Our results highlight improved survival in syngeneic tumor models of colorectal cancer (CT26 and MC38) and sarcoma (MCA205). This therapeutic outcome was in part driven by cytotoxic CD8 T-cells, as evidenced by the detrimental effect of CD8 depleting antibody treatment of MCA205 tumor bearing mice treated with anti-CD73, anti-PD-L1 and 5-Fluorouracil+Oxaliplatin (5FU+OHP). We hypothesize that the improved responses are tumor microenvironment (TME)-driven, as suggested by the lack of anti-CD73 enhanced cytopathic effects mediated by 5FU+OHP on cell lines in vitro. Pharmacodynamic analysis, using imaging mass cytometry and RNA-sequencing, revealed noteworthy changes in specific cell populations like cytotoxic T cells, B cells and NK cells in the CT26 TME. Transcriptomic analysis highlighted treatment-related modulation of gene profiles associated with an immune response, NK and T-cell activation, T cell receptor signaling and interferon (types 1 & 2) pathways. Inclusion of comparator groups representing the various components of the combination allowed deconvolution of contribution of the individual therapeutic elements; highlighting specific effects mediated by the anti-CD73 antibody with respect to immune-cell representation, chemotaxis and myeloid biology. These pre-clinical data reflect complementarity of adenosine blockade with cytotoxic therapy, and T-cell checkpoint inhibition, and provides new mechanistic insights in support of combination therapy.

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来源期刊
Cancer Biology & Therapy
Cancer Biology & Therapy 医学-肿瘤学
CiteScore
7.00
自引率
0.00%
发文量
60
审稿时长
2.3 months
期刊介绍: Cancer, the second leading cause of death, is a heterogenous group of over 100 diseases. Cancer is characterized by disordered and deregulated cellular and stromal proliferation accompanied by reduced cell death with the ability to survive under stresses of nutrient and growth factor deprivation, hypoxia, and loss of cell-to-cell contacts. At the molecular level, cancer is a genetic disease that develops due to the accumulation of mutations over time in somatic cells. The phenotype includes genomic instability and chromosomal aneuploidy that allows for acceleration of genetic change. Malignant transformation and tumor progression of any cell requires immortalization, loss of checkpoint control, deregulation of growth, and survival. A tremendous amount has been learned about the numerous cellular and molecular genetic changes and the host-tumor interactions that accompany tumor development and progression. It is the goal of the field of Molecular Oncology to use this knowledge to understand cancer pathogenesis and drug action, as well as to develop more effective diagnostic and therapeutic strategies for cancer. This includes preventative strategies as well as approaches to treat metastases. With the availability of the human genome sequence and genomic and proteomic approaches, a wealth of tools and resources are generating even more information. The challenge will be to make biological sense out of the information, to develop appropriate models and hypotheses and to translate information for the clinicians and the benefit of their patients. Cancer Biology & Therapy aims to publish original research on the molecular basis of cancer, including articles with translational relevance to diagnosis or therapy. We will include timely reviews covering the broad scope of the journal. The journal will also publish op-ed pieces and meeting reports of interest. The goal is to foster communication and rapid exchange of information through timely publication of important results using traditional as well as electronic formats. The journal and the outstanding Editorial Board will strive to maintain the highest standards for excellence in all activities to generate a valuable resource.
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