Immune cell control of ovarian cancer

卵巢癌的免疫细胞控制

• 批准号: 10486968
• 负责人: Christina Annunziata
• 金额: $ 60.3万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10486968
• 关键词: Antibodies; Antigen Targeting; Antigens; Antineoplastic Agents; Autologous; Breast; CAR T cell therapy; CEA Family Protein; Cancer Patient; Cancer Vaccines; Carcinomatosis; Cell Culture Techniques; Cells; Cellular immunotherapy; Chemical Models; Clinic; Clinical; Clinical Research; Clinical Trials; Colorectal Cancer; Combined Modality Therapy; Complex; Disease Resistance; Endometrial Carcinoma; Engineering; Generations; Genes; Genetic; Goals; Greater sac of peritoneum; Growth; HLA Antigens; Half-Life; Hour; Human; Image; Immune; Immune response; Immune system; Immunize; Immunohistochemistry; Immunologic Surveillance; Immunotherapeutic agent; In Vitro; Interferon Type II; Interferon-alpha; Interferons; Intravenous; Location; Longevity; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of ovary; Malignant neoplasm of pancreas; Membrane Glycoproteins; Membrane Proteins; Mesothelioma; Messenger RNA; Methods; Modeling; Modification; Monoclonal Antibodies; Mucinous; Natural Immunity; Natural Killer Cells; Normal Cell; Ovarian Serous Adenocarcinoma; Pancreatic Adenocarcinoma; Pathology; Pathway interactions; Patients; Peritoneal; Peritoneal Fluid; Phase I Clinical Trials; Play; Preparation; Process; Prognosis; Property; Proteins; Proteomics; Recombinants; Relapse; Risk; Role; Route; Running; Safety; Sampling; Series; Serous; Signal Transduction; Site; Solid Neoplasm; Specimen; Stains; Study models; T-Lymphocyte; Therapeutic; Therapeutic antibodies; Time; Tissue Microarray; Tissue Sample; Tissues; Tumor Antigens; Tumor Cell Line; Viral; Woman; adaptive immunity; antigen binding; base; cancer cell; cancer initiation; cancer type; cell growth; chimeric antigen receptor; chimeric antigen receptor T cells; cytokine; design; extracellular; fighting; human tissue; immune activation; improved; innovation; intraperitoneal; malignant breast neoplasm; member; mesothelin; monocyte; mouse model; neoantigens; neoplastic cell; novel; peripheral blood; phase I trial; preclinical study; receptor; safety testing; side effect; synergism; transcription factor; triple-negative invasive breast carcinoma; tumor

Goal 1: Monocytes It has been shown in mouse models of chemically induced cancer that Interferons (IFNs) are important in the immune-surveillance and immune-editing of tumors. While IFNs alpha (IFNa) and gamma (IFNg) have been shown to have potent anti-neoplastic and anti-proliferative properties in vitro, they have shown little efficacy in the clinic. Our observations that IFNs play an important role in killing tumor cells in the presence of monocytes suggests that combination therapy of monocytes and IFNs may have a more potent effect than IFNs alone. We and others have shown that IFNs are more potent anti-cancer agents when used in combination with monocytes isolated from the peripheral blood. Based on these studies we have completed a Phase 1 clinical trial of immune cell therapy using autologous transfer of ex vivo monocytes stimulated with IFNs into the peritoneal cavity of patients who have resistant disease. We are now in the process of defining the mechanism of IFN-induced monocyte killing of ovarian cancer cells. we found that IFNs induce a unique set of genes regulated in monocytes that occurs only with the combination of IFNa and IFNg, and this signature may be driven by the transcription factor MZF1. In order to better mimic the peritoneal microenvironment of ovarian cancer, we developed a new model of growing complex ovarian cancer neoplasms from cell culture lines and primary samples. We are able to image and quantify complex interactions of IFNs-stimulated monocytes and cancer growths, providing a superior model for studying functional proteomic interactions. In addition, I have the ability to examine tissue and peritoneal fluid samples from women on our phase 1 trial receiving intraperitoneal autologous monocytes stimulated with IFNs, providing another platform for defining dual-IFN induced mechanisms of monocyte activity in the context of the complete immune response. Goal 2: ADCC A monoclonal antibody was developed against a semi-purified human membrane protein preparation derived from cancer tissues. The protein preparation was used in previous clinical trials for use as a cancer vaccine, where it was demonstrated to be safe and efficacious. The antibody, NEO201, was shown to react with the immunizing antigen preparation, as well as several human tumor cell lines and tissues from colorectal, pancreas, lung, and ovarian cancer patients. NEO201did not cross-react significantly with normal human tissues, thus representing a potential therapeutic product. The target of NEO201was studied and shown to be related to CEACAM-5/6, a member of the carcinoembryonic antigen family of proteins, which has been shown to be associated with several cancer types. Endometrial, breast and ovarian cancer have specifically been found to have increased expression in human tumor samples. In endometrial cancer, 45/88 (51%) of tissue samples show reactivity through immunohistochemistry, 38/72 (53%) of breast, and although 16/129 (12%) of ovarian cancer specimens stain positive in this series, two subtypes, mucinous 15/22 (68%)and signet cell 2/2 (100%) ovarian cancers, shows significant reactivity (50%) in an IHC of ovarian cancer tissue arrays representing over 600 samples. Our phase 1 clinical trial is ongoing to demostrate safety and preliminary activity of the NEO201 in patients with solid tumors likely to express the target. Goal 3: T cells Mesothelin (MESO) is a 41-kD cell surface glycoprotein that is highly expressed in many human cancers, including high grade serous adenocarcinoma of the ovary (75%), pancreatic adenocarcinoma (85%), triple negative breast cancer (66%), epitheliod mesothelioma (95%) of patients with MESO-expressing malignancies. While the function of MESO on normal cells is non-essential, the expression of MESO on cancer cells may contribute to the pathology of cancer, with higher expression associated with poorer prognosis, increased metastatic spread, and activation of cell growth pathways. A tremendously innovative immunotherapeutic approach is the use of chimeric antigen receptor-modified T cells (CAR). CAR T-cell therapy relies on re-engineering autologous T cells to express a receptor that allows the T cells to recognize tumor cells. A CAR is a recombinant receptor composed of an extracellular antigen-binding domain and an intracellular T-cell signaling domain. When expressed in T cells, CARs redirect the T cells to target the cancer cells that express the targeted antigen in a human leukocyte antigen (HLA)-independent manner. The most widely used method for T-cell modification is viral transduction, integration and expression of a genetic construct that expresses the chimeric receptor. Another approach to the generation of CAR T-cell therapies that may provide potent anti-tumor activity and improve safety and product preparation involves the use of mRNA to modify T-cells. Using mRNA to re-engineer a patient's T-cells to express a tumor-antigen targeted CAR T-cell can be accomplished in a few hours, allowing on-site preparation and deployment to multiple treatment locations. mRNA CAR T-cells have the safety factor of a limited lifespan, with half-life times similar to antibody therapeutics, and lack of rapid immune activation and proliferation, limiting the risk for severe cytokine release side effects. Meso-targeted CAR T-cells using mRNA have demonstrated significant promise in preclinical studies and clinical studies by intratumoral, intraperitoneal and intravenous of routes of administration. We are running a phase 1 clinical trial testing the safety of intraperitoneal administration of the CARMA MCY-M11 in women with ovarian cancer and peritoneal carcinomatosis.

目标一：在化学诱导癌症的小鼠模型中已经表明，干扰素（IFN）在肿瘤的免疫监视和免疫编辑中非常重要。虽然IFN α（IFNa）和IFN γ（IFNg）已显示出在体外具有有效的抗肿瘤和抗增殖特性，但它们在临床中几乎没有显示出功效。我们观察到IFN在单核细胞存在下杀死肿瘤细胞中起重要作用，这表明单核细胞和IFN的联合治疗可能比IFN单独治疗具有更有效的作用。我们和其他人已经表明，当与从外周血分离的单核细胞组合使用时，IFN是更有效的抗癌剂。基于这些研究，我们已经完成了免疫细胞疗法的1期临床试验，其使用用IFN刺激的离体单核细胞自体转移到具有抗性疾病的患者的腹膜腔中。我们现在正在确定IFN诱导的单核细胞杀死卵巢癌细胞的机制。我们发现IFN诱导单核细胞中一组独特的基因调控，这组基因仅在IFN α和IFN γ联合作用时才发生，并且这种标记可能由转录因子MZF 1驱动。为了更好地模拟卵巢癌的腹膜微环境，我们开发了一种新的模型，从细胞培养系和原代样品中生长复杂的卵巢癌肿瘤。我们能够成像和量化IFN刺激的单核细胞和癌症生长的复杂相互作用，为研究功能蛋白质组相互作用提供了一个上级模型。此外，我有能力检查组织和腹膜液样本的妇女在我们的第1期试验接受腹腔内自体单核细胞刺激IFN，提供另一个平台，定义双IFN诱导的单核细胞活性的机制，在完整的免疫反应的背景下。目标2：ADCC针对源自癌组织的半纯化人膜蛋白制剂开发了单克隆抗体。这种蛋白质制剂在以前的临床试验中用作癌症疫苗，在那里它被证明是安全和有效的。抗体NEO 201显示与免疫抗原制剂以及来自结直肠癌、胰腺癌、肺癌和卵巢癌患者的几种人类肿瘤细胞系和组织反应。NEO 201与正常人体组织无明显交叉反应，因此代表了潜在的治疗产品。研究表明NEO 201的靶点与CEACAM-5/6相关，CEACAM-5/6是癌胚抗原蛋白家族的成员，已被证明与几种癌症类型相关。已经特别发现子宫内膜癌、乳腺癌和卵巢癌在人类肿瘤样品中具有增加的表达。在子宫内膜癌中，45/88（51%）的组织样本通过免疫组织化学显示出反应性，38/72（53%）的乳腺癌，尽管16/129（12%）的卵巢癌标本在该系列中染色阳性，但两种亚型，粘液性15/22（68%）和印戒细胞2/2（100%）卵巢癌，在代表超过600个样本的卵巢癌组织阵列的IHC中显示出显著的反应性（50%）。我们的1期临床试验正在进行中，以证明NEO 201在可能表达靶点的实体瘤患者中的安全性和初步活性。目标3：T细胞间皮素（MESO）是一种41-kD的细胞表面糖蛋白，其在许多人类癌症中高度表达，包括卵巢的高级别浆液性腺癌（75%）、胰腺腺癌（85%）、三阴性乳腺癌（66%）、具有表达MESO的恶性肿瘤的患者的上皮样间皮瘤（95%）。虽然MESO在正常细胞上的功能是非必需的，但MESO在癌细胞上的表达可能有助于癌症的病理学，较高的表达与较差的预后、增加的转移扩散和细胞生长途径的激活相关。一种极具创新性的免疫学方法是使用嵌合抗原受体修饰的T细胞（CAR）。CAR T细胞疗法依赖于重新设计自体T细胞以表达允许T细胞识别肿瘤细胞的受体。CAR是由细胞外抗原结合结构域和细胞内T细胞信号传导结构域组成的重组受体。当在T细胞中表达时，汽车重定向T细胞以靶向以人白细胞抗原（HLA）非依赖性方式表达靶向抗原的癌细胞。最广泛使用的T细胞修饰方法是表达嵌合受体的遗传构建体的病毒转导、整合和表达。产生CAR T细胞疗法的另一种方法可以提供有效的抗肿瘤活性并改善安全性和产品制备，涉及使用mRNA修饰T细胞。使用mRNA来重新设计患者的T细胞以表达肿瘤抗原靶向的CAR T细胞可以在几个小时内完成，从而允许现场制备和部署到多个治疗位置。mRNA CAR T细胞具有有限寿命的安全因素，其半衰期与抗体治疗剂相似，并且缺乏快速免疫激活和增殖，限制了严重细胞因子释放副作用的风险。使用mRNA的中靶向CAR T细胞已经在临床前研究和通过肿瘤内、腹膜内和静脉内施用途径的临床研究中显示出显著的前景。我们正在进行一项I期临床试验，测试CARMA MCY-M11腹腔内给药在卵巢癌和腹膜癌转移女性中的安全性。