Targeting metastatic tumors with engineered cellular therapies

通过工程细胞疗法靶向转移性肿瘤

基本信息

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
项目类别：
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

项目摘要

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。患有晚期乳房的患者癌症具有很高的前景，可以用人表皮生长因子受体（EGFR）转移到大脑阳性和三阴性乳腺癌（TNBC；雌激素和孕酮受体以及HER2阴性）亚型显示出最高的脑转移入射。有效治疗多个高度侵略性的大脑转移性乳腺肿瘤（BMBT），迫切需要开发靶向异常信号的治疗 BMBT的肿瘤细胞和免疫细胞的途径。最近，我们有表明鞘内（IT）和核内动脉（ICA）注射成人同种异体“离架子”间充质表达双功能蛋白的干细胞（MSC）同时靶向EGFR和（DR）4/5），EVDRL具有模仿临床环境的BMBT小鼠模型中的治疗效率。这些发现虽然很有希望，关于将MSC释放的EVDRL诱导肿瘤细胞杀死的潜在的潜力提出了基本问题与仅激活针对BMBT的免疫效应功能的治疗剂。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力在患者衍生的BMBT细胞中。先前的研究表明，除了肿瘤细胞外，DRL还诱导髓样衍生的抑制细胞（MDSC）和CD4+ CD25+ FOXP3+ Tregs的凋亡增加TME中CD8+ T细胞的募集。此外，使用合并的临床和临床前研究细胞毒性疗法和免疫检查点（ICI）封锁显示乳房转移的效率提高因此，肿瘤提供了将MSC-EVDRL与免疫调节剂相结合以治疗BMBT的潜力。在该提案，我们将首先评估MSC-EVDRL诱导肿瘤细胞死亡的效率和影响在人源化（HU）NSG乳房中，从具有不同的BMBT细胞产生的脑转移性肿瘤模型对EVDRL介导的凋亡的反应。接下来，我们将创建双峰MSC释放EVDRL和反抗程序性细胞死亡蛋白（PD）-1纳米型（NB-PD1），并评估机制的结合效率在HUNSG乳房中设计为脑转移性肿瘤模型的MSC。我们假设人类MSC-EVDRL 将导致特异性杀死局部和广泛传播的BMBT细胞，而NB-PD1将靶向招募的T细胞 TME。为了简化临床翻译，我们将结合可激活的杀伤开关/宠物成像剂，疱疹单纯胸腺胰岛素激酶（HSV-TK）进入MSC，并通过PET成像和选择性评估其命运消除由HSV-TK激活介导的。鉴于工程硕士在非小型的I期临床试验中细胞肺癌患者； I/II期使用抗PD-1抗体的I/II试验目前正在瘦脑脑中正在进行转移性患者；以及我们在原发性脑肿瘤（GBM）患者中的MSC-DRL疗法正在考虑 fda;拟议研究的成功执行将有助于将我们的战略转化为诊所。我们预计我们的发现将对开发基于机制的针对性的新颖机制有重大贡献 BMBT的疗法，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。