Syngeneic Macrophages for Personalized Cancer Therapy

用于个性化癌症治疗的同基因巨噬细胞

基本信息

批准号：
8787458
负责人：
FRANCIS C. SZOKA
金额：
$ 17.21万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-01-01 至 2015-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8787458
关键词：
4T1 Affect Animals Antibodies Autologous Back Blood flow Bone Marrow Bone Marrow Cells Brain Breast Cancer Model Cell Therapy Cells Cellular biology Characteristics Cytosine deaminase Development Distal Dose Drug Delivery Systems Drug Formulations Engineering Environment Excision Fatty acid glycerol esters Frequencies Genes Genetic Goals Health Homing Hydrostatic Pressure In Vitro Inbred BALB C Mice Interferon Type II Interleukin-12 Liposomes Luciferases Lung Mammary Neoplasms Mammary gland Methods Modality Mus Neoplasm Metastasis Patients Penetration Pharmaceutical Preparations Phenotype Primary Neoplasm Procedures Production Property Proteins Reporter Research Site Solid Neoplasm Testing Therapeutic Therapeutic Agents Time Tumor Tissue Yeasts arm cancer therapy chemotherapy cytotoxic extracellular functional loss improved macrophage nanocarrier nanoparticle personalized cancer therapy protein expression prototype self-renewal success therapeutic protein trafficking transcription factor tumor tumor eradication tumor growth yeast protein

项目摘要

DESCRIPTION (provided by applicant): A number of barriers impede anti-tumor activity of drugs, antibodies, and nanoparticles including: sieving properties of the extracellular tumor matrix, high intra-tumoral hydrostatic pressures and the low volume of blood flow that metastatic tumors receive. The combination of these factors restrict the delivery of high quantities of therapeutic agents into tumors. The tumor homing of macrophages is well documented and recent advances enable the ex-vivo production of self-renewable, syngeneic and fully differentiated normal macrophages (SSM). We propose to generate and then modify SSM from BALB/c mice via gene insertions or drug-loaded nanoparticles (liposomes) and then re-inject the "armed" SSM back into BALB/c mice with orthotopic 4T1 breast tumors. We will investigate factors that affect the time course and percent of the SSM dose that migrates into the 4T1-luc primary tumor as well as into metastatic sites distal to the mammary fat pad such as the brain or lung, identified using the luciferase reporter in the 4T1 line. We will load agents into the SSM that maintain macrophages in the M1 phenotype to enhance their anti-tumor activity. We will investigate the effect of the SSM and the agents they deliver on the phenotype of the tumor resident macrophages and determine if tumor resident macrophages can be returned to a M1 phenotype by IL12 and Interferon gamma secreted by the SSM. Finally, we will determine the anti-tumor activity of "armed" SSM against the 4T1 tumor in BALB/c mice. Three specific aims will be aggressively pursued. Aim 1. Devise liposome formulations and culture conditions for highly efficient in vitro loading of nanoparticles into RAW309 Cr1 cells as a macrophage prototype. Evaluate the rate, extent and tumor distribution of liposome-loaded macrophages in the 4T1 murine breast tumor model as a function of the number of macrophages injected. Completion of this aim will guide the loading, dosing and frequency of doses in aim 3. Aim 2. Generate and characterize self-renewing syngeneic macrophages from BALB/c derived normal bone marrow cells by genetic removal of c-Maf and MafB function. We will also modify the SSM with a red reporter protein and yeast cytosine deaminase or interferon gamma/IL12. Aim 3. Evaluate the tumor distribution and therapeutic activity of SSM created in aim 2 and loaded with drug nanocarriers or inducible proteins such as yeast cytosine deaminase, or Interferon gamma/IL12 in BALB/c 4T1 breast cancer model. Our studies will generate a quantitative understanding of the factors that control the trafficking of macrophages into tumors as well as the potential for this modality to control tumor growth and metastases. Success in this research could enable the development of new autologous macrophage cell-based therapies that greatly increase therapeutic agent delivery into and throughout tumors. It could also provide an effective means to re-educate tumor-associated type M2 macrophages to become tumor killers. If effective, "armed" SSM could also provide a personalized cancer treatment to eradicate metastatic tumors that cannot be achieved by currently available approaches.

描述（由申请人提供）：许多屏障会阻碍药物，抗体和纳米颗粒的抗肿瘤活性，包括：细胞外肿瘤基质的筛分特性，高肿瘤内静水压力以及转移性肿瘤接受的低血流量。这些因素的结合限制了大量的治疗剂传递到肿瘤中。巨噬细胞的肿瘤归巢已充分证明，最近的进步使得能够自我再生，同步和完全分化的正常巨噬细胞（SSM）产生。我们建议通过基因插入或吸毒的纳米颗粒（脂质体）从BALB/C小鼠中生成并修饰SSM，然后将“武装” SSM重新将“武装” SSM重新注入BALB/C小鼠中，以原位4T1乳腺肿瘤。我们将研究影响时间过程的因素和SSM剂量的百分比，这些因素迁移到4T1-LUC原发性肿瘤中，以及使用4T1线中的荧光素酶报道鉴定的乳腺脂肪垫（例如大脑或肺）远端的转移部位。我们将将代理加载到SSM中，以维持M1表型中的巨噬细胞以增强其抗肿瘤活性。我们将研究SSM及其对肿瘤常驻巨噬细胞表型的作用，并确定是否可以通过IL12将肿瘤驻留的巨噬细胞归还M1表型，而SSM分泌的干扰素Gamma则可以将其恢复为M1表型。最后，我们将确定“武装” SSM对BALB/C小鼠中4T1肿瘤的抗肿瘤活性。将积极追求三个具体目标。 AIM 1。设计脂质体配方和培养条件，以高效地将纳米颗粒在RAW309 CR1细胞中作为巨噬细胞原型进行体外负载。评估4T1鼠乳腺肿瘤模型中脂质体负载巨噬细胞的速率，程度和肿瘤分布，这是注射的巨噬细胞数量的函数。此目标的完成将指导AIM 3中的负载，给药和频率。目标2。通过遗传去除C-MAF和MAFB功能，从BALB/C得出的正常骨髓细胞产生并表征了自我更新的同性巨噬细胞。我们还将使用红色报告蛋白和酵母胞嘧啶脱氨酶或干扰素γ/IL12修改SSM。 AIM 3。评估在AIM 2中创建的SSM的肿瘤分布和治疗活性，并装有药物纳米载体或诱导蛋白，例如酵母胞嘧啶脱氨酶或BALB/C 4T1乳腺癌模型中的干扰素γ/IL12。我们的研究将对控制巨噬细胞运输的因素产生定量理解，以及这种方式控制肿瘤生长和转移的可能性。这项研究的成功可以使新的自体巨噬细胞疗法的发展大大增加了治疗剂到整个肿瘤的递送。它还可以提供一种有效的手段，以重新教育肿瘤相关的M2巨噬细胞成为肿瘤杀手。如果有效，“武装” SSM还可以提供个性化的癌症治疗，以消除当前可用方法无法实现的转移性肿瘤。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Macrophage-based cell therapies: The long and winding road.

DOI：
10.1016/j.jconrel.2016.07.018
发表时间：
2016-10-28
期刊：
Journal of controlled release : official journal of the Controlled Release Society
影响因子：
0
作者：
Lee S;Kivimäe S;Dolor A;Szoka FC
通讯作者：
Szoka FC

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