Designer antigen receptors to re-direct T cells to the NY-ESO-1 tumor antigen

设计抗原受体将 T 细胞重新引导至 NY-ESO-1 肿瘤抗原

• 批准号: 8914546
• 负责人: Marcela Valderrama Maus
• 金额: --
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-19 至 2015-09-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8914546
• 关键词: Achyrocline; Adoptive Transfer; Adverse event; Advisory Committees; Affinity; Animal Model; Antibodies; Antigen Receptors; Antigen Targeting; Antigen-Presenting Cells; Antigens; Autologous; Binding; CD3 Antigens; CD8B1 gene; CTAG1 gene; Capsid; Cell Count; Cell Therapy; Cells; Clinical Trials; Communities; Data; Development; Doctor of Philosophy; Engineering; Fellowship; Frequencies; Gene Transfer; Gene-Modified; Goals; HLA-A2 Antigen; Hematologic Neoplasms; Hematology; Hemophilia B; Human; Immune; Immunotherapy; Investigation; K-Series Research Career Programs; Laboratories; Medical Oncologist; Medical Oncology; Memorial Sloan-Kettering Cancer Center; Mentors; Mutation; Normal tissue morphology; Outcome; Patients; Peptide/MHC Complex; Peptides; Physicians; Postdoctoral Fellow; Process; Proteins; Recording of previous events; Research; Research Project Grants; Research Proposals; Resources; Role; Safety; Scientist; Services; Signal Transduction; Site; Solid Neoplasm; Specificity; Structure; Surface Antigens; Synapses; T cell therapy; T memory cell; T-Cell Receptor; T-Lymphocyte; Testing; Training; Tube; Tumor Antigens; Work; base; cancer immunotherapy; career; cellular transduction; chimeric antigen receptor; design; effective therapy; gene therapy; in vivo; interest; melanoma; mouse model; mutant; neoplastic cell; novel; receptor; receptor binding; retroviral transduction; skills; synaptogenesis; tumor; tumor immunology

DESCRIPTION (provided by applicant): The candidate for this NCI Career Development Award is Marcela Valderrama Maus, MD, PhD, who is currently a hematology and medical oncology fellow at Memorial Sloan-Kettering Cancer Center (MSKCC). Dr. Maus has a long-standing interest in tumor immunology and gene and cell therapies. Her thesis work was on the activation and costimulation requirements of human CD4 and CD8 T cells, which was explored with the use of artificial antigen presenting cells bearing multiple costimulatory molecules, most notably 4-1BB. Dr. Maus also completed a brief post-doctoral fellowship where she identified capsid-specific memory T cells in patients who had undergone gene transfer in a clinical trial of hemophilia B. At MSKCC, Dr. Maus has joined the laboratory of Michel Sadelain, a worldwide leader in the field of T cell therapy and gene transfer. An immediate term goal of the candidate is to complete the Aims in this proposal, which center around designing and testing new forms of antigen receptors directed to a cytoplasmic tumor antigen, NY-ESO-1. The completion of these aims will provide the candidate with the candidate with new technical skills, intellectual advancement, and a substrate on which to build her laboratory-based career in immunotherapy and gene transfer. The long-term goal of the candidate is to become an academic medical oncologist who develops and uses cell-based therapies to treat solid tumors such as melanoma. Over the past decade, the adoptive transfer of T cells has emerged as an effective therapy in some patients with hematological malignancies or melanoma, but the process of generating these cells has been labor-intensive and not widely applicable due to the low frequency of tumor-specific T cells. The candidate's mentor is at the forefront in the development of adoptive T cell therapy with cells transduced with chimeric antigen receptors that re-direct them toward native surface antigens. Here, the candidate proposes to expand the concept of chimeric antigen receptors by targeting a cytoplasmic antigen with an antibody-based receptor (Aim 1) and a modified T cell receptor (Aim 2). These two new forms of designer antigen receptors will be characterized and compared in re-directed T cells with respect to affinity, co-receptor binding, immune synapse formation, and ex vivo and in vivo effector functions (Aim 3). MSKCC is an ideal site for this project because of the intellectual and technical resources available, and because of the institutional history and commitment to this line of research. The tumor antigen targeted here was initially described at MSKCC; the physician-scientist community and melanoma service are ideally suited to support and aid the candidate as she transitions to independent investigation, and there is evidence of their unconditional support for the candidate. The candidate has access to prior mentors, all highly respected physician scientists, and her current mentor has a track record of successfully training and launching other physician scientists; in addition, she has enlisted three leaders in the field of immunotherapy to serve on an advisory committee as she navigates the transition to independent investigation. This career development award will greatly enhance Dr. Marcela Valderrama Maus's research proposal and professional development.

描述（由申请人提供）：该NCI职业发展奖的候选人是Marcela Valderrama Maus，医学博士，博士，目前是纪念斯隆-凯特琳癌症中心（MSKCC）的血液学和医学肿瘤学研究员。Maus博士对肿瘤免疫学、基因和细胞疗法有着长期的兴趣。她的论文工作是对人类CD 4和CD 8 T细胞的激活和共刺激需求，这是探索与使用人工抗原呈递细胞携带多种共刺激分子，最显着的4-1BB。Maus博士还完成了一项简短的博士后研究，在那里她在血友病B临床试验中接受基因转移的患者中鉴定了captain特异性记忆T细胞。在MSKCC，Maus博士加入了T细胞治疗和基因转移领域的全球领导者Michel Sadelain的实验室。候选人的近期目标是完成本提案中的目标，其中心是设计和测试针对细胞质肿瘤抗原NY-ESO-1的抗原受体的新形式。这些目标的完成将为候选人提供新的技术技能，智力进步，以及建立她在免疫治疗和基因转移方面的实验室职业生涯的基础。候选人的长期目标是成为一名学术医学肿瘤学家，开发和使用基于细胞的疗法来治疗实体瘤，如黑色素瘤。 在过去的十年中，T细胞的过继转移已经成为某些血液恶性肿瘤或黑色素瘤患者的有效疗法，但由于肿瘤特异性T细胞的频率低，产生这些细胞的过程一直是劳动密集型的，并且不广泛适用。候选人的导师是在过继性T细胞疗法的发展与嵌合抗原受体转导的细胞，重新引导他们对天然表面抗原的最前沿。在这里，候选人提出通过用基于抗体的受体（Aim 1）和修饰的T细胞受体（Aim 2）靶向细胞质抗原来扩展嵌合抗原受体的概念。这两种新形式的设计抗原受体将在重定向T细胞中就亲和力、共受体结合、免疫突触形成以及离体和体内效应子功能进行表征和比较（目的3）。 MSKCC是一个理想的网站，因为这个项目的智力和技术资源，并因为机构的历史和承诺，这条线的研究。这里靶向的肿瘤抗原最初是在MSKCC描述的;医生-科学家社区和黑色素瘤服务非常适合支持和帮助候选人，因为她过渡到独立调查，并且有证据表明他们对候选人的无条件支持。候选人可以接触到以前的导师，所有备受尊敬的医生科学家，她目前的导师有成功培训和推出其他医生科学家的记录;此外，她还招募了免疫治疗领域的三位领导人担任咨询委员会成员，因为她正在向独立调查过渡。这一职业发展奖将大大提高Marcela Valderrama Maus博士的研究建议和专业发展。