Targeting Cancer-Associated Fibroblasts Prevents Resistance to Chimeric Antigen Receptor T Cell Therapy

靶向癌症相关成纤维细胞可预防嵌合抗原受体 T 细胞疗法的耐药性

• 批准号: 10698161
• 负责人: Reona Sakemura
• 金额: $ 17.12万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10698161
• 关键词: Antigen Targeting; Antigens; Apoptosis; B lymphoid malignancy; B-Lymphocytes; Bioinformatics; Bone Marrow; CAR T cell therapy; CD34 gene; Cancer Biology; Cell Line; Cell Maturation; Cell physiology; Cell surface; Cells; Cellular immunotherapy; Clinic; Clinical Trials; Coculture Techniques; Complex; Data; Development; Disease remission; Engraftment; Exposure to; Fibroblasts; Flow Cytometry; Functional disorder; Funding; Future; Goals; Hematopoietic stem cells; Immune; Immunology; Immunotherapeutic agent; Immunotherapy; Infusion procedures; Luciferases; Malignant - descriptor; Malignant Neoplasms; Mentors; Modeling; Molecular Biology; Multiple Myeloma; Outcome; PD-1/PD-L1; Patients; Plasma Cells; Pre-Clinical Model; Prevention; Refractory; Relapse; Research; Research Activity; Resistance; Safety; Sampling; Scientist; Serious Adverse Event; Site; Solid; Solid Neoplasm; T-Lymphocyte; Technical Expertise; Techniques; Testing; Toxic effect; Training; Transforming Growth Factor beta; Treatment Failure; base; cancer cell; cancer immunotherapy; cancer type; career; chemokine; chimeric antigen receptor; chimeric antigen receptor T cells; clinically relevant; curative treatments; cytokine; design; experience; fibroblast-activating factor; high throughput screening; humanized mouse; improved; innovation; mouse model; neoplastic cell; novel; novel strategies; peripheral blood; prevent; programmed cell death ligand 1; programmed cell death protein 1; receptor; resistance mechanism; response; safety study; trafficking; translational medicine; translational scientist; treatment strategy; tumor; tumor microenvironment; tumor-immune system interactions

PROJECT SUMMARY/ABSTRACT A major breakthrough in cancer immunotherapy in the last decade is the development of chimeric antigen receptor (CAR) T cell therapy. Although anti-B cell maturation antigen (BCMA) directed CART cell therapy demonstrated unprecedented initial responses in patients with relapse/refractory B-cell malignancies or multiple myeloma (MM), respectively, durable responses are limited. The mechanisms of relapse after CART cell therapy are not fully unveiled yet. The long-term goal of my proposal is to uncover mechanisms of resistance to CART cell therapy and to develop an independent research career focused on targeting the tumor microenvironment simultaneously with CART cells. The unifying objective of this application is to design novel strategies for the treatment and prevention of tumor immunoescape based on my clinically relevant preliminary data, using BCMA CART cell as a model. The central hypothesis is cancer-associated fibroblast (CAFs) induce CART dysfunction through complex mechanisms and that dual targeting of tumor cells and CAFs is safe and enhances the efficacy of CART cell therapy. To test this hypothesis, I have designed three specific aims: Aim #1) Determine the mechanisms of CAF-induced BCMA CART cell dysfunction in MM patients; Aim #2) Study the potential toxicity of dual targeting CART cells in syngeneic humanized MM-tumor microenvironment (TME) models; Aim #3) Utilize samples from patients who were treated with BCMA CART cell therapy to study the interactions between CAFs and CART cells. The rationale for this proposal is that in my established MM-TME model, CART cell trafficking to the tumor site is significantly inhibited. My preliminary data also showed that CAFs suppressed CART cell functions by secreting TGF-β and inhibitory cytokines as well as altering the PD-1/PD-L1 axis. Dual targeting tumor cells and CAFs significantly improved CART cell functions. This research will be significant because it will contribute depth (of understanding the CART cell resistance) and breadth (of novel potentially curative therapy) to the immunotherapeutic strategy against not just MM but also solid tumors. Ultimately, such discoveries have the potential to vertically advance the field of CART cell immunotherapy as well as other targeted immunotherapies. This project is innovative because it combines high throughput screening techniques to study the possible mechanisms of resistance after immunotherapy and, therefore, to generate novel treatments. The proposed research activities are crucial to the development of the applicant as an independently funded scientist with a focus on cellular immunotherapy. I will receive further training in molecular biology, translational medicine, and immunology from my mentors and training in cancer biology and bioinformatics from experienced collaborators at the Mayo Clinic. Therefore, at the conclusion of the training period, I will have acquired a unique set of intellectual and technical skills that will allow me to promote myself to become an independent translational researcher.

项目摘要/摘要 过去十年中癌症免疫疗法的主要突破是嵌合抗原的发展 受体（CAR）T细胞疗法。尽管抗B细胞成熟抗原（BCMA）定向CART细胞疗法 在患有救济/难治性B细胞Malignancys或 多发性骨髓瘤（MM）分别有限耐用反应。购物车后的退休机制 细胞疗法尚未完全揭晓。我的提议的长期目标是发现 对推车细胞疗法的抵抗力，并发展独立研究职业，专注于目标 肿瘤微环境仅与手推车细胞。此应用程序的统一目标是 设计基于诊所的肿瘤免疫消性治疗和预防肿瘤免疫消防的新型策略 相关的初步数据，使用BCMA CART单元作为模型。中心假设是癌症相关的 成纤维细胞（CAFS）通过复杂机制诱导CART功能障碍，并将肿瘤细胞的双重靶向 CAF和CAF是安全的，可以提高CART细胞疗法的效率。为了检验这个假设，我设计了 三个特定目的：目标＃1）确定MM中CAF诱导的BCMA CART细胞功能障碍的机制 患者; AIM＃2）研究合成性人性化MM肿瘤中双重靶向CART细胞的潜在毒性 微环境（TME）模型； AIM＃3）利用接受BCMA手推车治疗的患者的样品 细胞疗法研究CAF和CART细胞之间的相互作用。该提议的理由是 我已建立的MM-TME模型，CART细胞运输到肿瘤部位受到显着抑制。我的初步 数据还表明，CAF通过分泌TGF-β和抑制性细胞因子抑制CART细胞功能 以及更改PD-1/PD-L1轴。双重靶向肿瘤细胞和CAF显着改善了CART细胞 功能。这项研究将很重要，因为它将有助于深度（了解购物车细胞 抗性）和宽（新的潜在治疗疗法）对免疫治疗策略的抗性 只是MM，但也是实体瘤。最终，此类发现有可能垂直发展 CART细胞免疫疗法以及其他靶向免疫疗法。这个项目是创新的，因为它 结合了高通量筛选技术，以研究抗药性的可能机制 免疫疗法，因此产生新的治疗方法。拟议的研究活动对 申请人作为一名独立资助的科学家的发展，重点是细胞免疫疗法。 我将从我的导师那里获得进一步的分子生物学，转化医学和免疫学培训 以及梅奥诊所经验丰富的合作者的癌症生物学和生物信息学培训。所以， 在培训期结束时，我将获得一套独特的智力和技术技能 将使我促进自己成为一名独立翻译的研究人员。