Immunotherapy of Epithelial Ovarian Cancer using Autologous Gamma Delta T-cells

使用自体 Gamma Delta T 细胞对上皮性卵巢癌进行免疫治疗

• 批准号: MR/M024733/1
• 负责人: John Maher
• 金额: $ 64.01万
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FM024733%2F1
• 关键词: Immunotherapy; Epithelial; Ovarian; Cancer; using

Ovarian cancer remains one of the most deadly tumours, largely because patients do not develop symptoms until the disease is advanced. Our goal here is to develop a new form of treatment for this disease.Our treatment is a combination of two elements. The first component involves a drug called a bisphosphonate. These drugs are widely used to treat patients with bone diseases and a variety of cancer types. Bisphosphonates can exert some direct toxic effects on cancer cells. However, they also cause cancer cells to become more "visible" to immune white blood cells called gamma delta T-cells, and which comprise the second element in this treatment strategy.Gamma delta T-cells patrol throughout the body, helping to identify cancer at its early stages and eliminating it. These cells can be isolated from a blood sample taken from the patient. To generate sufficient numbers for treatment purposes, gamma delta T-cells cells can then be expanded using medical-grade bags over a 2 week period. We have recently developed a greatly improved system to "grow" these cells, such that the number of cells and their ability to kill cancer cells are both substantially increased. Throughout the world, a number of groups have already infused expanded gamma delta T-cells into patients with various cancers, in the hope of exploiting their ability to kill cancer cells. Although the results have not been very impressive, these studies are important since they have demonstrated the safety of this approach. In our study, we plan to test these "improved" gamma delta T-cells to treat patients with ovarian cancer. We will test the gamma delta T-cells alone and in combination with a bisphosphonate drug.In this project we want to:- deliver bisphosphonates to ovarian cancer cells by injection of the drug into the abdominal space (called the peritoneal cavity), because that is where ovarian cancer spreads. - Next, we will inject gamma delta T-cells (expanded from the patient) into the same location.The project must be carried out in mice that have no immune system, meaning that we can test human cancer cells and human gamma delta T-cells in this model. The purpose of these animal experiments is to show two things: evidence that the treatment has anti-cancer activity and evidence that side effects are acceptable. This is an appropriate requirement of regulatory bodies in the UK before "first in man" testing can be carried out.Once this approach is optimised in mice, the next step would entail its clinical development to treat women with ovarian cancer. Gamma delta cells would be grown from the patients own blood over a period of 2 weeks in an "ultraclean" laboratory which we have within our clinical research facility. The patient would receive the bisphosphonate injected into the peritoneal cavity using a tube. Twenty-four hours later, the gamma delta T-cells would be infused through the same tube. Depending on results obtained, we may wish to repeat this cycle of treatment on more than one occasion.

卵巢癌仍然是最致命的肿瘤之一，主要是因为患者直到疾病进展才出现症状。我们的目标是开发一种治疗这种疾病的新形式。我们的治疗是两种元素的结合。第一种成分涉及一种叫做双膦酸盐的药物。这些药物被广泛用于治疗骨疾病和各种癌症患者。双膦酸盐可以对癌细胞产生一些直接的毒性作用。然而，它们也会使癌细胞变得更容易被称为γ δ T细胞的免疫白色血细胞所“看见”，而γ δ T细胞是这种治疗策略中的第二个元素。γ δ T细胞在全身巡逻，有助于在癌症的早期阶段识别并消除它。这些细胞可以从患者的血液样本中分离出来。为了产生足够的数量用于治疗目的，然后可以使用医用级袋在2周的时间内扩增γ δ T细胞。我们最近开发了一种大大改进的系统来“培养”这些细胞，使得细胞的数量及其杀死癌细胞的能力都大大增加。在世界各地，许多研究小组已经将扩增的γ δ T细胞注入各种癌症患者体内，希望利用它们杀死癌细胞的能力。虽然结果并不令人印象深刻，但这些研究很重要，因为它们证明了这种方法的安全性。在我们的研究中，我们计划测试这些“改进的”γ δ T细胞来治疗卵巢癌患者。我们将测试单独的γ δ T细胞和与双膦酸盐药物的组合。在这个项目中，我们想：-通过将药物注射到腹腔（称为腹膜腔），将双膦酸盐输送到卵巢癌细胞，因为那是卵巢癌扩散的地方。- 接下来，我们将把γ δ T细胞（从患者体内扩增）注射到相同的位置。该项目必须在没有免疫系统的小鼠中进行，这意味着我们可以在这个模型中测试人类癌细胞和人类γ δ T细胞。这些动物实验的目的是证明两件事：证明该治疗具有抗癌活性的证据和证明副作用是可以接受的证据。这是英国监管机构在进行“首次人体试验”之前的一项适当要求。一旦这种方法在小鼠中得到优化，下一步将涉及其治疗卵巢癌女性的临床开发。γ-δ细胞将在我们的临床研究机构内的“超净”实验室中从患者自身血液中培养2周。患者将接受使用管注射到腹膜腔中的双膦酸盐。24小时后，γ δ T细胞将通过同一管输注。根据所获得的结果，我们可能希望在不止一次的情况下重复这个治疗周期。

项目成果

Prospects for combined use of oncolytic viruses and CAR T-cells.

• DOI: 10.1186/s40425-017-0294-6
• 发表时间: 2017-11-21
• 期刊: Journal for immunotherapy of cancer
• 影响因子: 10.9
• 作者: Ajina A;Maher J
• 通讯作者: Maher J

Pre-clinical development of chimeric antigen receptor T-cell immunotherapy: Implications of design for efficacy and safety.

嵌合抗原受体 T 细胞免疫疗法的临床前开发：设计对功效和安全性的影响。

• DOI: 10.1016/j.beha.2018.04.002
• 发表时间: 2018
• 期刊: Best practice & research. Clinical haematology
• 作者: Halim L

Strategies to Address Chimeric Antigen Receptor Tonic Signaling.

• DOI: 10.1158/1535-7163.mct-17-1097
• 发表时间: 2018-09
• 期刊: Molecular cancer therapeutics
• 影响因子: 5.7
• 作者: Ajina A;Maher J
• 通讯作者: Maher J

CAR T-cell immunotherapy of B-cell malignancy: the story so far.

• DOI: 10.1177/2515135520927164
• 发表时间: 2020-01-01
• 期刊: Therapeutic advances in vaccines and immunotherapy
• 作者: Halim, Leena;Maher, John
• 通讯作者: Maher, John