Monitoring adoptive immunotherapy of breast cancer with MR imaging

利用 MR 成像监测乳腺癌的过继免疫治疗

• 批准号: 7599264
• 负责人: Heike Elizabeth Daldrup-Link
• 金额: $ 14.06万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7599264
• 关键词: Acute; Address; Adoptive Immunotherapy; Antigen Receptors; Antigens; Berlex brand of ferumoxides; Breast; Breast Cancer Cell; Breast Cancer Model; Breast Carcinoma; Cell Culture Techniques; Cell Therapy; Cells; Characteristics; Clinical; Clinical Trials; Clinical assessments; Contrast Media; Cytolysis; Data; Detection; Diagnosis; ERBB2 gene; Engineering; Exhibits; Experimental Models; FDA approved; Germ Cells; Goals; Human; Image; Imaging Techniques; Immunohistochemistry; Immunotherapy; Implant; In Vitro; Injection of therapeutic agent; Investigation; Label; Leukocytes; Lymphocyte; MCF7 cell; Magnetic Resonance; Magnetic Resonance Imaging; Measurable; Measures; Microscopic; Monitor; Morphology; Natural Killer Cells; Nude Rats; Particulate; Patients; Pre-Clinical Model; Procedures; Rattus; Relaxation; Research Project Grants; Resolution; Signal Transduction; Specimen; Techniques; Tumor Tissue; Weight; base; cancer cell; cancer type; clinical practice; cytotoxicity; design; ferumoxides; improved; in vivo; intravenous injection; iron oxide; macrophage; malignant breast neoplasm; nanoparticle; pre-clinical; public health relevance; research study; response; translational clinical trial; tumor; tumor growth; uptake; Acute; Address; Adoptive Immunotherapy; Antigen Receptors; Antigens; Berlex brand of ferumoxides; Breast; Breast Cancer Cell; Breast Cancer Model; Breast Carcinoma; Cell Culture Techniques; Cell Therapy; Cells; Characteristics; Clinical; Clinical Trials; Clinical assessments; Contrast Media; Cytolysis; Data; Detection; Diagnosis; ERBB2 gene; Engineering; Exhibits; Experimental Models; FDA approved; Germ Cells; Goals; Human; Image; Imaging Techniques; Immunohistochemistry; Immunotherapy; Implant; In Vitro; Injection of therapeutic agent; Investigation; Label; Leukocytes; Lymphocyte; MCF7 cell; Magnetic Resonance; Magnetic Resonance Imaging; Measurable; Measures; Microscopic; Monitor; Morphology; Natural Killer Cells; Nude Rats; Particulate; Patients; Pre-Clinical Model; Procedures; Rattus; Relaxation; Research Project Grants; Resolution; Signal Transduction; Specimen; Techniques; Tumor Tissue; Weight; base; cancer cell; cancer type; clinical practice; cytotoxicity; design; ferumoxides; improved; in vivo; intravenous injection; iron oxide; macrophage; malignant breast neoplasm; nanoparticle; pre-clinical; public health relevance; research study; response; translational clinical trial; tumor; tumor growth; uptake

DESCRIPTION (provided by applicant): A new treatment option for breast cancer is the administration of tumor-targeted natural killer (NK) cells, specialized white blood cells, which have been genetically modified to specifically recognize and lyse cancer cells in vivo. Central aim of this project is to develop a non-invasive magnetic resonance (MR) imaging technique for monitoring the in vivo distribution, tumor accumulation and cytotoxicity of NK cells, which are directed against ErbB2-positive breast cancers. The imaging approach takes advantage of the well- documented physicochemical characteristics of particulate iron oxide nanoparticles, which can be incorporated into leukocytes and which can be depicted with MR imaging. The overall hypothesis is that NK-cells, labeled with clinically applicable iron oxide nanoparticles, can be traced non-invasively in vivo with MR imaging and that a tumor accumulation of the labeled cells can be proven with this imaging technique by significant tumor signal changes. Genetically engineered NK cells, directed against the ErbB2 antigen on breast cancer cells, will be labeled with iron oxide nanoparticles. Initial cell culture experiments will be carried out to prove, that the labeled NK cells can be depicted with clinical MR scanners and that the iron oxide label does not impair the cytotoxicity of the NK cells against breast cancer cells. Subsequent in vivo studies will be performed before and after intravenous injection of ErbB2-directed NK cells or non-directed control cells into athymic rats with implanted ErbB2-positive and ErbB2-negative human breast carcinomas. The in vivo distribution of the labeled NK cells will be monitored with MR imaging, using a 3T clinical MR scanner and T1-, T2- and T2*-weighted sequences. We hypothesize, that the tumor accumulation of the labeled NK-cells can be depicted by a significant decline in tumor signal intensity on these MR images. Conversely, a lack of signal changes of the tumor tissue after injection of labeled NK cells should be indicative of a lack of NK cell accumulation in the tumor tissue. Finally, the NK cell accumulation in the tumor tissue, as diagnosed by MR imaging on day 1 and 2 after NK cell administration, will be correlated with a subsequent NK-cell induced tumor cytotoxicity, as measured by an impaired tumor growth several days after NK cell administration. Complementary histopathologic and spectrometric studies, correlated with the MR findings, will examine the underlying NK cell tumor accumulation that influences the observed MR signal characteristics and potentially impaired tumor growth. Planned endpoints are (1) to establish a non-invasive MR imaging technique to monitor the accumulation of iron-oxide labeled, genetically engineered NK cells in ErbB2-positive breast cancers and (2) to detect the accumulation of labeled ErbB2 targeted NK cells in ErbB2 positive breast by a significant decline in tumor signal intensity on MR images. Since we use clinically applicable contrast agents and MR scanners, our imaging technique would be in principle readily accessible to patients. PUBLIC HEALTH RELEVANCE: The planned research project is designed to develop a non-invasive MR imaging technique for in vivo tracking of tumor-targeted natural killer cells (specialized white blood cells) to breast cancers. This imaging technique could help to correlate the presence and duration of natural killer cell accumulations in target tumors with the presence and extent of an expected natural-killer cell induced tumor growth inhibition. The information provided by this new MR imaging technique could be helpful for preclinical assessments of new tumor immunotherapies, for the design of translational clinical trials, and later, the assessment of those adoptive immunotherapies in clinical practice.

描述（由申请人提供）：乳腺癌的一种新治疗选择是施用靶向肿瘤的天然杀伤（NK）细胞，专门的白细胞，这些白细胞已经过遗传修饰，以特异性地识别并在体内裂解癌细胞。该项目的核心目的是开发一种非侵入性磁共振（MR）成像技术，用于监测NK细胞的体内分布，肿瘤的积累和细胞毒性，这些NK细胞针对ERBB2阳性乳腺癌。成像方法利用了颗粒氧化铁纳米颗粒的文献记载的物理化学特征，可以将其掺入白细胞中，并可以用MR成像描绘。总体假设是，用临床上适用的氧化铁纳米颗粒标记的NK细胞可以通过MR成像在体内非侵入性地追溯，并且可以通过这种成像技术通过明显的肿瘤信号变化来证明标记细胞的肿瘤积累。针对乳腺癌细胞上ERBB2抗原的基因工程NK细胞将用氧化铁纳米颗粒标记。最初的细胞培养实验将进行证明，可以用临床MR扫描仪描绘标记的NK细胞，并且氧化铁标记不会损害NK细胞对乳腺癌细胞的细胞毒性。随后的体内研究将在静脉注射ERBB2定向的NK细胞或非导向对照细胞中进行植入的ERBB2阳性和ERBB2阴性的人类乳腺癌。标记为NK细胞的体内分布将使用3T临床MR扫描仪和T1-，T2-和T2*加权序列对MR成像进行监测。我们假设，标记为NK细胞的肿瘤积累可以通过这些MR图像上的肿瘤信号强度显着下降来描述。相反，注射标记的NK细胞后肿瘤组织缺乏信号变化应表明肿瘤组织中缺乏NK细胞的积累。最后，NK细胞在NK细胞给药后的MR成像诊断为NK细胞在肿瘤组织中的积累将与随后的NK细胞诱导的肿瘤细胞毒性相关，如NK细胞给药后几天通过肿瘤生长受损所测量。互补的组织病理学和光谱研究与MR发现相关，将检查潜在的NK细胞肿瘤积累，从而影响观察到的MR信号特征并潜在地损害肿瘤生长。计划的终点是（1）建立一种非侵入性的MR成像技术，以监测ERBB2阳性乳腺癌中标记的，基因设计的NK细胞的铁 - 氧化物的积累，（2）检测标记的ERBB2靶向NK靶向NK细胞在ERBB2阳性乳房中通过MIRS MIRS MR MIR MR MR MIM MIRS MR MIM MIRS MR MIM的阳性下降。由于我们使用临床上适用的对比剂和MR扫描仪，因此我们的成像技术原则上很容易被患者使用。公共卫生相关性：计划的研究项目旨在开发一种非侵入性的MR成像技术，用于在体内跟踪肿瘤靶向的天然杀伤细胞（专门的白细胞）到乳腺癌。这种成像技术可以有助于将靶肿瘤中天然杀伤细胞积累的存在和持续时间与预期的天然杀伤物细胞的存在和程度相关联会抑制肿瘤生长的抑制。这种新的MR成像技术提供的信息可能有助于对新肿瘤免疫疗法的临床前评估，对于翻译临床试验的设计，然后对临床实践中那些收养免疫疗法的评估进行评估。