Tumor downstaging with small molecule therapeutics to enhance Uveal Melanoma metastasis eradication by B7-H3 CAR T cells

利用小分子疗法降低肿瘤期，增强 B7-H3 CAR T 细胞对葡萄膜黑色素瘤转移的根除

• 批准号: 10652851
• 负责人: Cristina R. Ferrone
• 金额: $ 16.7万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-20 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10652851
• 关键词: Affinity; Awareness; CAR T cell therapy; CASP9 gene; CD276 gene; Cell Line; Cell Survival; Cells; Cellular immunotherapy; Clinical; Collaborations; Complex; Cytolysis; Data; Diagnosis; Disease; FDA approved; Generations; Goals; HDAC4 gene; HLA-A2 Antigen; Histone Deacetylase Inhibitor; Human; Immunotherapeutic agent; Immunotherapy; In Vitro; Incidence; Investigation; Label; Literature; Liver; MEKs; Mediating; Melanoma Cell; Metastatic Neoplasm to the Liver; Methodology; Mitogen-Activated Protein Kinase Kinases; Monitor; Mus; Neoplasm Metastasis; Normal Cell; Normal tissue morphology; Operative Surgical Procedures; Patients; Play; Predisposition; Progression-Free Survivals; Proteins; Residual state; Role; SILV gene; Safety; Solid Neoplasm; Specificity; T cell therapy; T-Cell Receptor; T-Lymphocyte; Testing; Time; Tissue Sample; Toxic effect; Translating; Tumor Antigens; Tumor Burden; Tumor Debulking; Tumor Tissue; Tumor Volume; United States; Uveal Melanoma; bioluminescence imaging; cancer cell; chimeric antigen receptor; chimeric antigen receptor T cells; clinical investigation; combinatorial; cytokine release syndrome; cytotoxic; design; effective therapy; expectation; experience; experimental study; gp100 Antigen; improved; in vivo; inhibitor; kinase inhibitor; mortality; mouse model; novel; pre-clinical; rare cancer; response; small molecule therapeutics; tumor; tumor growth; tumor microenvironment

Project summary Uveal Melanoma (UM) is a rare cancer with an incidence of 5 cases per million in the United States. Nearly half UM patients develop isolated liver metastases due to the high tendency of UM cells to spread to the liver. No cure has been found for patients with metastatic UM (mUM). Tebentafusp, is the only FDA-approved therapy for mUM. However, it has shown modest improvements in terms of overall response and progression-free survival and its applicability is limited to only 40% of mUM patients. The lack of effective treatment options for mUM has prompted us to design a novel combinatorial immunotherapeutic strategy based on the use of Chimeric Antigen Receptor (CAR) T cells specifically redirected against B7-H3. The latter has been selected as the target of our immunotherapeutic strategy, since it is highly expressed on UM cell lines and mUM tumor tissue samples, but has a limited expression on normal tissues. It is a general experience that CAR T cell-based immunotherapy is not effective in eradicating solid tumors both in preclinical and clinical investigations. This result is likely caused by multiple mechanisms, among which the major role is played by their use in hosts with high tumor load; the resulting unfavorable effector to target (E:T) ratio in the tumor microenvironment has a negative impact on the antitumor activity of CAR T cells, as indicated by the results generated by preclinical and clinical investigations. The information in the literature and our preliminary results have provided the rationale to design a strategy which applies first a tumor debulking approach to reduce tumor load and then CAR T cell- based immunotherapy to eradicate UM metastases. We will use the combination of trametinib, a mitogen-activated protein kinase kinase inhibitor (MEKi) and of panobinostat, a histone deacetylase inhibitor (HDACi), since this combination has been shown to induce marked regression of UM liver metastases in mice. Furthermore, this combination does not affect B7- H3 expression by UM cells and the antitumor activity of B7-H3 CAR T cells. Therefore, after having shown that B7-H3 CAR T cells can recognize and eliminate UM cells surviving the treatment with the MEKi and HDACi combination, we will investigate whether tumor debulking induced by the MEKi and HDACi combination can enhance the ability of B7-H3 CAR T cells to eradicate UM liver metastases in NSG mice. Since one major limitation of CAR T cell-based therapy is represented by its potential toxicity and/or cytokine release syndrome, we have incorporated in our CAR construct an inducible caspase 9 safety switch which allows rapid elimination of CAR T cells in case of unexpected toxicities. If the results generated by our experiments are positive, they will have a major impact on the treatment of mUM.

项目概要 葡萄膜黑色素瘤 (UM) 是一种罕见的癌症，在美国发病率为每百万分之 5 例。近一半的 UM 患者 由于 UM 细胞极有可能扩散到肝脏，因此会发生孤立性肝转移。尚未找到治疗方法 转移性 UM (mUM) 患者。 Tebentafusp 是 FDA 唯一批准的 mUM 治疗方法。然而，它已经表明 总体反应和无进展生存期方面略有改善，其适用性仅限于 40% mUM 患者。 mUM 缺乏有效的治疗方案促使我们设计一种新型组合疗法 基于使用特异性重定向的嵌合抗原受体 (CAR) T 细胞的免疫治疗策略 B7-H3。后者已被选为我们免疫治疗策略的靶标，因为它在 UM 细胞上高度表达 系和 mUM 肿瘤组织样本中，但在正常组织中表达有限。 人们普遍的经验是，基于 CAR T 细胞的免疫疗法在根除实体瘤方面并不有效。 临床前和临床研究。这一结果可能是由多种机制引起的，其中最主要的作用是 由于它们在高肿瘤负荷宿主中的使用而发挥作用；由此产生的肿瘤中不利的效应子与靶点 (E:T) 比率 微环境对 CAR T 细胞的抗肿瘤活性有负面影响，如 临床前和临床研究。文献中的信息和我们的初步结果提供了 设计策略的基本原理是，首先应用肿瘤减灭方法来减少肿瘤负荷，然后应用 CAR T 细胞- 基于免疫疗法来根除UM转移。我们将使用曲美替尼（一种有丝分裂原激活蛋白）的组合 激酶激酶抑制剂 (MEKi) 和帕比司他 (一种组蛋白脱乙酰酶抑制剂 (HDACi))，因为该组合具有 已被证明可诱导小鼠 UM 肝转移的显着消退。此外，这种组合不会影响 B7- UM 细胞的 H3 表达和 B7-H3 CAR T 细胞的抗肿瘤活性。因此，在证明B7-H3之后 CAR T 细胞可以识别并消除在 MEKi 和 HDACi 组合治疗后幸存的 UM 细胞，我们 将研究MEKi和HDACi组合诱导的肿瘤减灭是否可以增强B7-H3的能力 CAR T 细胞可根除 NSG 小鼠的 UM 肝转移。由于基于 CAR T 细胞的疗法的一个主要限制是 以它的潜在毒性和/或细胞因子释放综合征为代表，我们在我们的 CAR 构建中加入了 诱导型 caspase 9 安全开关，可在出现意外毒性时快速消除 CAR T 细胞。 如果我们的实验结果是积极的，将对 mUM 的治疗产生重大影响。