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.