Radio-immunotherapy to Target Cancer Stem Cells in Solid Tumor Malignancies

放射免疫疗法靶向实体瘤恶性肿瘤中的癌症干细胞

基本信息

批准号：
8910940
负责人：
WILLIAM JOSEPH MURPHY
金额：
$ 36.4万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-03-06 至 2020-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8910940
关键词：
Activated Natural Killer Cell Address Adjuvant Aftercare Allogenic Animal Hospitals Animal Model Animals Antibodies Autologous Biological Assay Bioluminescence Biopsy Bone Tissue Breast Breast Sarcoma Cancer Center Cancer Relapse Canis familiaris Cell Communication Cell Line Cells Cessation of life Cetuximab Clinical Clinical Trials Combined Modality Therapy Cytokine Receptors Cytotoxic Chemotherapy Data Drug Kinetics Effector Cell Epidermal Growth Factor Receptor Experimental Models Future Goals Hematologic Neoplasms Hematopoietic stem cells Human Immune Immune Targeting Immunotherapy Implant In Vitro In complete remission Infusion procedures Laboratories Ligands Lung Lymphocyte Magnetic Resonance Imaging Malignant Neoplasms Malignant neoplasm of pancreas Mediating Methods Modeling Monitor Mus NK Cell Activation Natural Killer Cells Neoplasm Metastasis Pancreatic Sarcoma Patients Pharmacodynamics Play Population Pre-Clinical Model Primary Neoplasm Production Proliferating Radiation Radiation therapy Radio Recruitment Activity Recurrence Research Resistance Role Safety Sampling Seeds Site Solid Solid Neoplasm Stem cells System Testing Therapeutic Tissue Grafts Tissues Toxic effect Translations Treatment Efficacy Tumor Cell Line Tumor Debulking Tumor Tissue Xenograft procedure antibody-dependent cell cytotoxicity antitumor effect base cancer cell cancer stem cell cell transformation chemokine chemotherapy clinically relevant companion animal comparative conventional therapy cytotoxic cytotoxicity efficacy testing efficacy trial improved in vivo innovation irradiation killings malignant breast neoplasm mouse model neoplastic cell novel palliative pancreatic neoplasm public health relevance receptor sarcoma scale up soft tissue stem cell population success tumor tumor eradication tumor growth tumor xenograft

项目摘要

DESCRIPTION (provided by applicant): Cancer stem cells (CSCs) or tumor-initiating cells are a small subset of malignant cells which are resistant to chemotherapy and radiotherapy (RT) and are able to repopulate a tumor after cytotoxic treatment. It is these quiescent cells which can seed cancer relapse and metastasis, even in cases of apparent complete response to treatment. Immunotherapy offers a tremendous advantage over cytotoxic therapies to target CSCs because immune effector cells do not require targets to be actively proliferating. Therefore, immune-mediated killing appears to be an attractive candidate for targeting CSCs following the depletion of non-CSCs. Natural killer (NK) cells are cytotoxic lymphocytes which play a major role in eliminating transformed cells. NK cells not only attack hematologic malignancies and circulating solid tumor cells, but they also appear to have the unique ability to spontaneously recognize and reject allogeneic hematopoietic stem cells. Our laboratory has extensive preliminary data demonstrating that ex vivo activated NK cells can preferentially target CSCs in multiple experimental models, including tumor cell lines, primary tumor samples, and xenograft mouse models. In parallel, we have observed that RT and chemotherapy enrich for CSCs due to preferential targeting of non-CSCs by cytotoxic therapy. In addition, we have shown that RT sensitizes tumor cells, especially CSCs, to NK cell attack and recruitment. The central hypothesis of this proposal is that the combination of RT and NK immunotherapy will be more effective than standard anti-proliferative therapy or immunotherapy alone because we will be able to simultaneously target both non-CSCs and CSCs. To test this hypothesis, we propose the following 3 Specific Aims: The first specific aim will determine the mechanism by which NK cells recognize and kill CSCs. This aim will also examine the effects of RT on the sensitization of the CSC to NK killing. Specific Aim 1: To demonstrate that activated NK cells recognize and preferentially attack CSC populations compared with non-CSC in breast, pancreatic, and sarcoma malignancies. We hypothesize that RT debulking of non-CSCs will augment the ability of NK cells to destroy the CSC population resulting in the greatest anti-tumor effects. Our second specific aim will test the efficacy of combination of NK and local RT against xenograft tumor models including both orthotopic breast, pancreatic, and sarcomas and patient-derived xenografts. Specific Aim 2: To demonstrate that RT will improve NK immunotherapy by decreasing tumor bulk, enriching CSCs, sensitizing CSCs to NK attack, and recruiting NK cells to the tumor site. Our third specific aim will utilize the world-class UC Davis Veterinary Cancer Center to establish a clinical trial in canine companion animals. This trial will involve the use o autologous NK cells from canine sarcoma patients in combination with palliative RT or chemotherapy directed towards either primary or metastatic tumors. Specific Aim 3: To demonstrate that NK cell radio-immunotherapy will show local and systemic anti-tumor effects targeting CSCs and non-CSCS with minimal toxicities in canine patients. The aims of this research will elucidate the role of adoptive NK immunotherapy to target CSCs with the goal of translation to meaningful clinical benefit for patients with solid cancers.

描述（由申请人提供）：癌症干细胞（CSC）或肿瘤起始细胞是一小部分恶性细胞，它们对化疗和放疗（RT）具有抵抗力，并且能够在细胞毒性治疗后重新增殖肿瘤。即使在对治疗有明显完全反应的情况下，免疫疗法也比针对癌症干细胞的细胞毒性疗法具有巨大的优势，因为免疫效应细胞不需要目标来进行治疗。因此，自然杀伤 (NK) 细胞是细胞毒性淋巴细胞，不仅在消除转化细胞方面发挥着重要作用，而且免疫介导的杀伤似乎是针对 CSC 的一个有吸引力的候选者。攻击血液恶性肿瘤和循环实体瘤细胞，但它们似乎也具有自发识别和排斥同种异体造血干细胞的独特能力，我们的实验室拥有大量初步数据证明离体激活的 NK 细胞可以。在多个实验模型中优先靶向 CSC，包括肿瘤细胞系、原发性肿瘤样本和异种移植小鼠模型，同时，我们观察到由于细胞毒性疗法优先靶向非 CSC，因此 CSC 得到富集。我们已经证明，RT 使肿瘤细胞，尤其是 CSC，对 NK 细胞的攻击和募集变得敏感。该提案的中心假设是，RT 和 NK 免疫疗法的结合将比标准的抗增殖疗法更有效。单独治疗或免疫治疗，因为我们将能够同时针对非 CSC 和 CSC。为了检验这一假设，我们提出以下 3 个具体目标：第一个具体目标将确定 NK 细胞识别和杀死 CSC 的机制。目标还将检查 RT 对 CSC 对 NK 杀伤的敏感性的影响具体目标 1：证明与乳腺中的非 CSC 相比，活化的 NK 细胞识别并优先攻击 CSC 群体。我们渴望非 CSC 的 RT 减灭能够增强 NK 细胞破坏 CSC 群体的能力，从而产生最大的抗肿瘤效果。针对异种移植肿瘤模型（包括原位乳腺癌、胰腺癌和肉瘤以及患者来源的异种移植物）的放疗具体目标 2：证明放疗将通过减少 NK 免疫治疗来改善。我们的第三个具体目标是利用世界一流的加州大学戴维斯分校兽医癌症中心在犬伴侣动物中开展一项临床试验。使用来自犬肉瘤患者的自体 NK 细胞与针对原发性或转移性肿瘤的姑息性放疗或化疗相结合。具体目标 3：证明 NK 细胞放射免疫疗法将有效。显示针对 CSC 和非 CSCS 的局部和全身抗肿瘤作用，且对犬患者的毒性最小。本研究的目的将阐明过继 NK 免疫疗法针对 CSC 的作用，旨在为实体瘤患者带来有意义的临床益处。癌症。