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.

摘要 转移性脑肿瘤是最常见的颅内肿瘤。乳房晚期患者 通过人类表皮生长因子受体(EGFR)，癌症有很高的脑转移倾向 阳性和三阴性乳腺癌(TNBC；雌激素和孕激素受体，Her2阴性) 显示脑转移发生率最高的亚型。有效治疗多发性高侵袭性脑 转移性乳腺肿瘤(BMBT)，迫切需要开发针对异常信号的治疗方法 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 显示鞘内(IT)和颈内动脉(ICA)注射“现成”同种异体间充质 同时针对EGFR和(DR)4/5、EvDRL表达双功能蛋白的干细胞(MSC) 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， 已经提出了关于联合MSC释放的EvDRL诱导的肿瘤细胞杀伤的可能性的基本问题 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 在患者来源的BMBT细胞中。先前的研究表明，除了肿瘤细胞外，DRL还能诱导 髓系抑制细胞(MDSC)和CD4+CD25+FoxP3+Treg细胞的凋亡 增加CD8+T细胞在TME中的募集。此外，临床和临床前研究使用联合 细胞毒治疗和免疫检查点(ICI)阻断对乳腺转移瘤显示出更高的疗效 因此，肿瘤提供了将MSC-EVDRL与免疫调节剂相结合治疗BMBT的可能性。在……里面 本建议，我们将首先评估MSC-EVDRL诱导TME肿瘤细胞死亡的疗效和影响 在人源化(HU)NSG乳腺到脑转移肿瘤模型中，BMBT细胞产生了不同的 对EVDRL介导的细胞凋亡的应答。接下来，我们将创建双峰MSC发布EVDRL和反 程序性细胞死亡蛋白(PD)-1纳米体(NB-PD1)及其联合作用机制的研究 在huNSG乳腺到脑转移肿瘤模型中的基因工程MSC。我们假设人类MSC-EvDRL 将导致局部和广泛播散的BMBT细胞的特异性杀伤，而NB-PD1将靶向招募的T细胞 TME。为了方便临床翻译，我们将加入可激活的杀死开关/PET显像剂，疱疹 单纯疱疹病毒胸苷激酶(HSV-TK)基因导入间充质干细胞并通过PET显像和选择性检测评估其命运 HSV-TK激活介导的根除。鉴于工程骨髓间充质干细胞处于非小型的I期临床试验 细胞肺癌患者；使用IT抗PD-1抗体的I/II期试验目前正在软脑膜中进行 转移性患者；我们的MSC-DRL治疗原发性脑肿瘤(GBM)患者正在考虑 FDA；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 预计我们的发现将对开发基于目标的新机制做出重大贡献 治疗BMBT，因此在挽救许多转移性乳腺癌患者的生命方面产生了重大影响。