NATURAL KILLER CELLS: ACQUISITION OF CD16 AND REGULATION OF NEGATIVE SIGNALING

自然杀伤细胞：CD16 的获取和负信号传导的调节

基本信息

批准号：
8563847
负责人：
MICHAEL A CALIGIURI
金额：
$ 31.61万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-09-30 至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8563847
关键词：
Acute Myelocytic Leukemia Affinity Antibodies Bone Marrow Transplantation Cancer Patient Cell surface Clinic Clinical Clinical Trials Collaborations Cytotoxic T-Lymphocytes Development Disease-Free Survival Enhancing Antibodies FCGR3B gene Fc Immunoglobulins Fc Receptor Funding Granzyme Human Immune Immune Tolerance Immune system Immunity In Vitro Interferons Interleukin-18 Journals Laboratories Learning Ligands Liquid substance Lymphoid Tissue Lymphoma MHC Class I Genes MS4A1 gene Malignant - descriptor Malignant Neoplasms Mediating Medicine Methods MicroRNAs Modality Molecular Monoclonal Antibodies Monoclonal Antibody CD20 Monoclonal Antibody Therapy Mus NK Cell Activation Natural Immunity Natural Killer Cells Organism Outcome PTEN gene Patients Phase Phosphoric Monoester Hydrolases Process Publications Publishing Reagent Regulation Regulatory T-Lymphocyte Relapse Role Science Signal Transduction Solid Neoplasm Staging T-Lymphocyte The Sun Therapeutic Clinical Trial Toxic effect Transplantation Work base cancer therapy cell killing graft vs host disease improved in vivo insight interleukin-22 killer immunoglobulin-like receptor killings man melanoma member mouse model neoplastic cell novel preclinical study receptor tumor

项目摘要

PROJECT SUMMARY: The broad, long-term objective of this proposal is to understand how cancer evades and disarms the immune system at the molecular, cellular and organism level so this process can be interrupted for the successful treatment of cancer with monoclonal antibody (mAb) therapy. In the past 4.5 years, members of Project 3 have worked interdependently with other members of this P01 to produce 51 collaborative publications and accrue over 800 patients to therapeutic clinical trials that have directly emanated from our P01. Importantly, we have created impact in that we have advanced our understanding of mAb therapy for cancer and have introduced new reagents in man whose efficacy likely depends on the innate immune system. This P01 competitive renewal application continues to primarily investigate the human innate immune system and Project 3, while integrated with the efforts of Projects 1, 2 and 4, is focused on natural killer (NK) cells. During the past five years it has become clear that: 1) the affinity of the Fc receptor (R) for the Fc fragment of mAb can predict clinical outcome in the mAb therapy of certain cancers; 2) elimination of T regulatory (Treg) cells can enhance cytotoxic T cell adoptive therapy in patients with chemoresistant cancer; 3) blockade of CTLA-4, an inhibitory ligand on cytotoxic T cells, can improve survival in patients with melanoma; 4) avoiding the interaction of the killer immunoglobulin-like receptor (KIR) with its MHC Class I ligand, the NK cell can enhance long term survival in T cell depleted HLA-haploidentical bone marrow transplant for acute myeloid leukemia. We hypothesize that a better understanding of NK cell FcR expression and of NK cell tolerance will allow us to improve the outcome of cancer patients treated with mAb therapy. In the coming cycle, we will work to understand how developing NK cells acquire FcyRlll (CD16) on their cell surface and assess whether this process results in improved antibody dependent cellular cytoxicity (ADCC). Next we will characterize negative regulators of NK cell ADCC in an effort to block these and enhance ADCC of cancer. Finally, we will perform two Phase l/ll trials that will block the inhibitory KIR in an attempt to enhance tumor killing in man, one in combination with an anti-CD20 mAb for the treatment of lymphoma. The work outlined for Project 3 will be interdependent on Projects 1, 2 and 4 as well as Cores A, B, and C When completed, it will provide new insights as to how NK cells may be modulated in order to improve ADCC with mAb therapy in man. We expect our work to result in an improvement in disease free survival for cancer patients following the administration of mAb therapy.

项目摘要：该提案的广泛，长期目标是了解癌症如何在分子，细胞和生物体水平上逃避和解除免疫系统，因此可以中断此过程以成功地通过单克隆抗体（MAB）治疗成功治疗癌症。在过去的4。5年中，项目3的成员与该P01的其他成员相互依存，生产了51个协作出版物，并累积了800多名患者，用于直接从我们的P01中散发出来的治疗性临床试验。重要的是，我们产生了影响，因为我们已经提高了对MAB疗法对癌症的理解，并引入了人类的新试剂，其功效可能取决于先天免疫系统。 P01竞争性更新应用程序继续主要研究人类先天免疫系统和项目3，而与项目1、2和4的努力集成在一起，集中在自然杀手（NK）细胞上。在过去的五年中，很明显：1）FC受体（R）的亲和力 MAB的FC片段可以预测某些癌症的MAB治疗中的临床结果。 2）消除T调节性（TREG）细胞可以增强化学耐药性癌症患者的细胞毒性T细胞产卵治疗； 3）CTLA-4的阻断是细胞毒性T细胞上的抑制性配体，可以改善黑色素瘤患者的生存。 4）避免杀手免疫球蛋白样受体（KIR）与其MHC I类配体的相互作用，NK细胞可以增强T细胞中耗尽的HLA-HAPOLIDICAL骨髓移植的T细胞中的长期存活率，以提高急性髓样白血病。我们假设对NK细胞FCR表达和NK细胞耐受性有更好的了解将使我们能够改善接受MAB治疗治疗的癌症患者的结果。在接下来的周期中，我们将努力了解开发NK细胞如何在其细胞表面获得FCYRLLL（CD16），并评估该过程是否导致抗体依赖性依赖细胞细胞毒性（ADCC）。接下来，我们将表征NK细胞ADCC的负调节剂努力阻止这些并增强癌症的ADCC。最后，我们将进行两次L/LL试验，这些试验将阻止抑制性KIR，以增强人的肿瘤杀死，一项与抗CD20 MAB结合使用，用于治疗淋巴瘤。项目3所概述的工作将相互依赖于项目1、2和4以及核心A，B和C时，它将提供有关如何调制NK细胞的新见解，以通过MAB治疗改善ADCC在男人。我们预计我们的工作将在进行MAB治疗后的癌症患者无疾病生存率改善。