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

• 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
• 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

 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（由适用提供）：癌症干细胞（CSC）或肿瘤发射细胞是对化学疗法和放疗（RT）具有抗性的恶性细胞的一小部分，并且能够在细胞毒性治疗后重新填充肿瘤。正是这些静止的细胞可以使癌症缓解和转移，即使在明显完全反应治疗的情况下。免疫疗法比细胞毒性疗法具有巨大的优势，因为免疫效应细胞不需要靶标积极增殖。因此，在部署非CSC之后，免疫介导的杀戮似乎是针对CSC的有吸引力的候选人。天然杀伤（NK）细胞是细胞毒性淋巴细胞，在消除转化的细胞中起主要作用。 NK细胞不仅攻击血液学恶性肿瘤和循环实体肿瘤细胞，而且它们似乎具有具有赞助并拒绝同种异体造血干细胞的独特能力。我们的实验室有广泛的初步数据，表明在多种实验模型中，体内活化的NK细胞可以优先针对CSC，包括肿瘤细胞系，原发性肿瘤样品和异种移植小鼠模型。同时，我们已经观察到，由于通过细胞毒性治疗对非CSC的优先靶向，RT和化学疗法富含CSC。此外，我们已经证明RT感应肿瘤细胞，尤其是CSC，以进行NK细胞攻击和募集。该提案的核心假设是，仅RT和NK免疫疗法的组合将比单独使用标准的抗增殖疗法或免疫疗法更有效，因为我们将能够轻松地靶向非CSC和CSC。为了检验这一假设，我们提出以下3个特定目的：第一个特定目的将决定NK细胞识别和杀死CSC的机制。该目标还将检查RT对CSC对NK杀戮的敏感性的影响。具体目标1：证明激活的NK细胞与乳腺癌，胰腺和肉瘤中的非CSC相比识别并优先攻击CSC种群。我们假设RT脱离非CSC将增强NK细胞破坏CSC群体的能力，从而产生最大的抗肿瘤作用。我们的第二个特定目的将测试NK和局部RT对异种移植肿瘤模型的有效性，包括原位乳腺，胰腺和肉瘤以及患者衍生的异种移植物。具体目标2：证明RT将通过减少肿瘤体积，丰富CSC，使CSC对NK攻击敏感并募集NK细胞到肿瘤部位来改善NK免疫疗法。我们的第三个特定目标将利用世界一流的戴维斯兽医癌症中心在犬伴侣动物中建立临床试验。该试验将涉及使用犬肉瘤患者的自体NK细胞与针对原发性或转移性肿瘤的姑息RT或化学疗法联合使用。特定目的3：证明NK细胞无线电免疫疗法将显示靶向CSC和非CSC的局部和全身性抗肿瘤效应，犬类患者的毒性最少。这项研究的目的将阐明收养NK免疫疗法对CSC的作用，目的是将固体癌症患者转化为有意义的临床益处。