Targeting metastatic tumors with engineered cellular therapies

通过工程细胞疗法靶向转移性肿瘤

• 批准号: 10774430
• 负责人: Khalid A Shah
• 金额: $ 40.55万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-19 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10774430
• 关键词: Adult; Agonist; Allogenic; Apoptosis; Arteries; Belgium; Biological Assay; Boston; Brain; Brain Neoplasms; Breast; Breast Cancer Cell; Breast Cancer Model; Breast Cancer Patient; CD8-Positive T-Lymphocytes; Cancer Patient; Caspase; Cell Death; Cell Therapy; Cells; Clinic; Clinical; Clinical Research; Collaborations; Communication; Cytotoxic Chemotherapy; Cytotoxic agent; Data; Dendritic Cells; Engineering; Ensure; Epidermal Growth Factor Receptor; Estrogen Receptors; FOXP3 gene; Flow Cytometry; Goals; Home; Human; Human Engineering; IL2RA gene; Immune; Immune response; Immunohistochemistry; Immunotherapy; Incidence; Induction of Apoptosis; Inhibition of Cell Proliferation; Injections; Intracarotid; Intracranial Neoplasms; Laboratories; Lead; Leptomeningeal Neoplasms; Leptomeninges; Ligands; Mammary Neoplasms; Mediating; Mesenchymal Stem Cells; Metastatic breast cancer; Metastatic malignant neoplasm to brain; Modality; Modeling; Molecular; Mus; Myeloid-derived suppressor cells; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Paclitaxel; Pathway interactions; Patients; Pattern; Phase; Phase I Clinical Trials; Phase I/II Trial; Positron-Emission Tomography; Predisposition; Primary Brain Neoplasms; Progesterone Receptors; Proteins; Publishing; Recombinants; Regulatory T-Lymphocyte; Reporter; Resistance; Safety; Science; Signal Pathway; Simplexvirus; T-Lymphocyte; TNFRSF10A gene; TNFSF10 gene; Testing; Therapeutic; Therapeutic Agents; Thymidine Kinase; Toxic effect; Translating; Translations; Treatment Efficacy; Treatment-related toxicity; Tumor Antigens; advanced breast cancer; anti-PD-1; anti-PD-L1 antibodies; anti-PD1 antibodies; carcinogenicity; cell killing; cellular engineering; clinical translation; clinically relevant; design; efficacy evaluation; genotoxicity; home test; humanized mouse; imaging agent; immune cell infiltrate; immune checkpoint blockade; immune modulating agents; immunoregulation; improved; mouse model; nanobodies; neoplastic cell; next generation; novel; preclinical study; programmed cell death protein 1; receptor; recruit; response; safety assessment; systemic toxicity; targeted treatment; therapeutic target; transcriptome sequencing; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor microenvironment

SUMMARY Metastatic brain tumors are the most commonly observed intracranial tumors. Patients with advanced breast cancer have a high propensity to metastasize to the brain with human epidermal growth factor receptor (EGFR) positive and triple-negative breast cancer (TNBC; estrogen and progesterone receptor and Her2 negative) subtypes showing the highest incidence of brain metastases. To effectively treat multiple highly aggressive brain metastatic breast tumors (BMBT), there is an urgent need to develop therapeutics that target aberrant signaling pathways in tumor cells and the immune cells in the tumor microenvironment (TME) of BMBT. Recently, we have shown that intrathecal (IT) and intracarotid artery (ICA) injection of adult allogeneic “off the shelf” mesenchymal stem cells (MSC) expressing bifunctional protein simultaneously targeting EGFR and (DR)4/5), EvDRL have therapeutic efficacy in mouse models of BMBT that mimic clinical settings. These findings although promising, have raised fundamental questions on the potential of combining MSC released EvDRL induced tumor cell killing with therapeutic agents that simultaneously activate immune effector functions against BMBT. Our recently published studies indicate that DRL (TRAIL) component of EVDRL is the key driver of EVDRL mediated cell death in patient derived BMBT cells. Previous studies have shown that in addition to tumor cells, DRL induces apoptosis in myeloid derived suppressor cells (MDSC) and CD4+ CD25+ FoxP3+ Tregs and simultaneously increases recruitment of CD8+ T cells in the TME. Furthermore, clinical and pre-clinical studies using combined cytotoxic therapy and immune checkpoint (ICI) blockade have shown increased efficacy in breast metastatic tumors thus offering the potential to combine of MSC-EVDRL with immunomodulatory agents to treat BMBT. In this proposal, we will first evaluate the efficacy and influence of MSC-EVDRL induced tumor cell death in the TME in humanized (hu) NSG breast to brain metastatic tumor models generated from BMBT cells that have varying response to EVDRL mediated apoptosis. Next, we will create bimodal MSC releasing EVDRL and anti- programmed cell death protein (PD)-1 nanobodies (Nb-PD1) and evaluate the mechanism combined efficacy of engineered MSC in huNSG breast to brain metastatic tumor models. We hypothesize that human MSC-EvDRL will lead to specific killing of local and widely disseminated BMBT cells and Nb-PD1 will target T cells recruited to the TME. To ease clinical translation, we will incorporate activatable kill switch/PET imaging agent, herpes simplex virus-thymidine kinase (HSV-TK) into MSC and assess their fate by PET imaging and selective eradication mediated by HSV-TK activation. Given that engineered MSC are in phase I clinical trial in non-small cell lung cancer patients; a phase I/II trial using IT of anti-PD-1 antibody is currently ongoing in leptomeningeal metastatic patients; and our MSC-DRL therapy in primary brain tumor (GBM) patients is under consideration by FDA; successful execution of the proposed studies will facilitate translation of our strategy into clinics. We anticipate that our findings will have a major contribution towards developing novel mechanism based targeted therapies for BMBT and thus a major impact in saving the lives of many metastatic breast cancer patients.

概括 转移性脑肿瘤是最常见的颅内肿瘤。晚期乳腺患者 人类表皮生长因子受体（EGFR）的癌症很容易转移到大脑 阳性和三阴性乳腺癌（TNBC；雌激素和孕激素受体且 Her2 阴性） 显示脑转移发生率最高的亚型。有效治疗多发性高度侵袭性大脑 转移性乳腺肿瘤（BMBT），迫切需要开发针对异常信号传导的治疗方法 BMBT 肿瘤微环境 (TME) 中肿瘤细胞和免疫细胞的通路。最近，我们有 研究表明，鞘内（IT）和颈内动脉（ICA）注射成人同种异体“现成”间充质 干细胞 (MSC) 表达同时靶向 EGFR 和 (DR)4/5 的双功能蛋白，EvDRL 具有 模拟临床环境的 BMBT 小鼠模型的治疗效果。这些发现虽然很有希望， 提出了关于结合 MSC 释放的 EvDRL 诱导肿瘤细胞杀伤的潜力的基本问题 使用同时激活针对 BMBT 的免疫效应器功能的治疗剂。我们最近 已发表的研究表明，EVDRL 的 DRL (TRAIL) 成分是 EVDRL 介导的细胞死亡的关键驱动因素 源自患者的 BMBT 细胞。先前的研究表明，除了肿瘤细胞外，DRL 还会诱导 骨髓源性抑制细胞 (MDSC) 和 CD4+ CD25+ FoxP3+ Tregs 中的细胞凋亡，同时 增加 TME 中 CD8+ T 细胞的募集。此外，结合使用的临床和临床前研究 细胞毒疗法和免疫检查点 (ICI) 阻断已显示出对乳腺转移的疗效增强 因此，MSC-EVDRL 与免疫调节剂相结合来治疗 BMBT 具有潜力。在 在这个提案中，我们将首先评估 MSC-EVDRL 诱导肿瘤细胞死亡在 TME 中的功效和影响 在由 BMBT 细胞生成的人源化 (hu) NSG 乳腺至脑转移肿瘤模型中，这些细胞具有不同的 对 EVDRL 介导的细胞凋亡的反应。接下来，我们将创建双峰 MSC 释放 EVDRL 和抗 程序性细胞死亡蛋白（PD）-1纳米抗体（Nb-PD1）并评估其机制组合功效 在 huNSG 乳腺至脑转移肿瘤模型中工程化 MSC。我们假设人类 MSC-EvDRL 将导致对局部和广泛传播的 BMBT 细胞的特异性杀伤，并且 Nb-PD1 将靶向招募到的 T 细胞 TME。为了简化临床转化，我们将结合可激活的杀伤开关/PET 显像剂、疱疹 将单纯病毒-胸苷激酶 (HSV-TK) 注入 MSC，并通过 PET 成像和选择性评估其命运 HSV-TK 激活介导的根除。鉴于工程化 MSC 正在非小规模临床试验中 细胞肺癌患者；目前正在软脑膜中使用抗 PD-1 抗体 IT 进行 I/II 期试验 转移性患者；我们正在考虑对原发性脑肿瘤 (GBM) 患者进行 MSC-DRL 治疗 美国食品和药物管理局；拟议研究的成功执行将有助于将我们的战略转化为临床。我们 预计我们的研究结果将为开发基于靶向的新机制做出重大贡献 BMBT 疗法，从而对挽救许多转移性乳腺癌患者的生命产生重大影响。