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Development of T-cell costimulatory antibodies for skin cancer immunotherapy

开发用于皮肤癌免疫治疗的 T 细胞共刺激抗体

基本信息

批准号：
MR/W03039X/1
负责人：
Chester Lai
金额：
$ 36.67万
依托单位：
University of Southampton
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2022
资助国家：
英国
起止时间：
2022 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FW03039X%2F1
关键词：
Development cell costimulatory antibodies skin

项目摘要

Despite advances in cancer treatment, current therapies are still not sufficiently effective in most patients with cancer. Immunostimulatory antibodies (ISAs), which bind to 'costimulatory receptors' on immune cells to activate these cells to attack the tumour, are a promising method for treating cancer in the future. However, more research is needed to determine whether ISAs can work as perfectly in human cancers as has been shown in mice, and to optimise ISAs so that they boost the human immune system's ability to destroy cancers without causing side effects elsewhere in the body. Some ISAs cause side effects by binding to receptors called Fc gamma receptors (FcgRs) found on cells throughout the body. Using a novel approach, we can improve the ability of ISAs to be directed to and retained in cancers, by creating 'bispecific' ISAs (bs-ISAs) which stick to molecules on tumour cells whilst targeting costimulatory receptors on immune cells within the tumour. As bs-ISAs do not require binding to FcgRs to work, they are likely to provide more effective treatment for cancer with fewer side effects.The aim of this study is to test the effectiveness of different ISAs and bs-ISAs in laboratory experiments using two common human skin cancers (melanoma and cutaneous squamous cell cancer (cSCC)) to investigate whether ISAs can be improved so that they can be used to treat these cancers. This research is much needed because skin cancers are amongst the commonest human cancers, and melanomas and advanced cSCCs are often fatal, yet current immune therapies are effective in less than 20% of melanomas and advanced cSCCs.I will investigate which costimulatory receptor target and format of ISA improves tumour immune responses most effectively. The Antibody and Vaccine group have generated anti-4-1BB, anti-CD27 and anti-DR3 ISAs in different versions (IgG1, IgG2 and IgG4 subclasses). Each of these ISAs will be tested in our 'tumour tissue slice culture' system, in which samples of melanomas and cSCCs from skin cancer surgery patients are thinly sliced and incubated, preserving the tumour and immune cells within each slice. In these experiments, the extent that immune cells called T-cells are activated to fight and kill tumour cells will be quantified for each ISA, and the effects on gene expression will be analysed to compare the mechanisms by which different ISAs work.As each IgG subclass binds to different types of FcgRs, and as a type of FcgR called FcgRIIb seems particularly important for how some ISAs work, FcgRs will be characterised on various immune cell subsets in melanoma and cSCC. To investigate the relationship between FcgRs and clinical outcome in skin cancer, FcgRs will be characterised in melanomas and cSCCs with known clinical outcomes, including whether the cancer had spread to other parts of the body (metastasised) or led to death. I will also investigate whether/which FcgRs are needed for each ISA to enhance function of T-cells isolated from melanomas and cSCCs, and will examine mechanisms by which ISAs bound by FcgR reduce certain cancer-promoting immune cells called regulatory T-cells.I will determine whether bs-ISAs which concurrently bind to costimulatory receptors (4-1BB, CD27 or DR3) on T-cells and a molecule called PD-L1 on tumour cells can improve the ability of ISAs to enhance immunity against the tumour. The different bs-ISAs will be tested to determine how well they activate costimulatory receptors and boost anti-tumour immunity in the tissue slice culture system. The effects of bs-ISAs will be compared to a combination of two separate antibody treatments (i.e. ISAs that only bind to costimulatory receptors and antibodies that bind to PD-L1) to determine whether bs-ISAs enhance tumour immunity more effectively.The results of this study will guide the development of more effective ISAs and help determine whether ISAs/bs-ISAs can improve treatment for aggressive skin cancers and other cancers.

尽管癌症治疗取得了进展，但目前的治疗方法对大多数癌症患者仍然不够有效。免疫刺激抗体（ISAs）结合免疫细胞上的“共刺激受体”以激活这些细胞攻击肿瘤，是未来治疗癌症的一种有前途的方法。然而，需要更多的研究来确定ISA是否可以像在小鼠中显示的那样完美地在人类癌症中发挥作用，并优化ISA，以便它们提高人类免疫系统摧毁癌症的能力，而不会在身体其他部位引起副作用。一些ISA通过与在全身细胞上发现的称为Fc γ受体（FcgR）的受体结合而引起副作用。使用一种新的方法，我们可以通过创建“双特异性”ISA（bs-ISA）来提高ISA针对癌症并保留在癌症中的能力，这种ISA可以粘附肿瘤细胞上的分子，同时靶向肿瘤内免疫细胞上的共刺激受体。由于bs-ISAs不需要与FcgRs结合才能发挥作用，因此它们可能为癌症提供更有效的治疗，副作用更少。本研究的目的是在实验室实验中使用两种常见的人类皮肤癌（黑色素瘤和皮肤鳞状细胞癌（cSCC））来测试不同ISAs和bs-ISAs的有效性，以调查ISAs是否可以改进，以便它们可以用于治疗这些癌症。这项研究非常必要，因为皮肤癌是人类最常见的癌症之一，黑色素瘤和晚期cSCC通常是致命的，但目前的免疫疗法对不到20%的黑色素瘤和晚期cSCC有效。我将研究哪种共刺激受体靶点和伊萨的形式最有效地改善肿瘤免疫反应。抗体和疫苗小组已经产生了不同版本（IgG 1、IgG 2和IgG 4亚类）的抗4-1BB、抗CD 27和抗DR 3 ISA。这些ISA中的每一种都将在我们的“肿瘤组织切片培养”系统中进行测试，在该系统中，来自皮肤癌手术患者的黑色素瘤和cSCC样本被薄切片并孵育，将肿瘤和免疫细胞保存在每个切片中。在这些实验中，称为T细胞的免疫细胞被激活以对抗和杀死肿瘤细胞的程度将针对每种伊萨进行量化，并且将分析对基因表达的影响以比较不同ISA工作的机制。由于每种IgG亚类结合不同类型的FcgR，并且作为一种称为FcgRIIb的FcgR类型对于一些ISA如何工作似乎特别重要，FcgR将在黑素瘤和cSCC中的各种免疫细胞亚群上表征。为了研究皮肤癌中FcgR与临床结局之间的关系，将在具有已知临床结局的黑素瘤和cSCC中表征FcgR，包括癌症是否扩散到身体的其他部位（转移）或导致死亡。我还将研究每种伊萨是否需要/需要哪些FcgR来增强从黑素瘤和cSCC分离的T细胞的功能，并将研究FcgR结合的ISA减少某些称为调节性T细胞的促癌免疫细胞的机制。T细胞上的4-1BB、CD 27或DR 3分子和肿瘤细胞上的PD-L1分子可以提高ISA增强抗肿瘤免疫力的能力。将测试不同的bs-isa，以确定它们在组织切片培养系统中激活共刺激受体和增强抗肿瘤免疫力的程度。bs-ISAs的效果将与两种单独的抗体治疗（即仅结合共刺激受体的ISAs和结合PD-L1的抗体）的组合进行比较，以确定bs-ISAs是否更有效地增强肿瘤免疫力。这项研究的结果将指导更有效的ISAs的开发，并帮助确定ISAs/bs-ISAs是否可以改善侵袭性皮肤癌和其他癌症的治疗。