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

项目摘要/摘要 近十年来癌症免疫治疗的一个重大突破是嵌合抗原的发展。 受体(CAR)T细胞治疗。尽管抗B细胞成熟抗原(BCMA)指导CART细胞治疗 在复发/难治性B细胞恶性肿瘤或 对于多发性骨髓瘤(MM)，持久反应有限。CART后复发的机制 细胞疗法还没有完全揭开面纱。我的提议的长期目标是揭示 抵抗CART细胞疗法并发展专注于靶向的独立研究事业 肿瘤微环境与CART细胞同步。此应用程序的统一目标是 根据我的临床经验设计治疗和预防肿瘤免疫逃逸的新策略 相关初步数据，以BCMA购物车细胞为模型。核心假设是癌症相关 成纤维细胞通过复杂机制和肿瘤细胞双靶向诱导CART功能障碍 CAFS是安全的，可提高CART细胞治疗的疗效。为了验证这一假设，我设计了 三个特定目标：目的1)确定CAF诱导MM患者BCMA CART细胞功能障碍的机制 患者；目的#2)研究双靶向CART细胞在同基因人源化MM-瘤中的潜在毒性 微环境(TME)模型；目标3)利用接受BCMA CART治疗的患者的样本 细胞疗法来研究CAFS和CART细胞之间的相互作用。这项建议的理由是 我建立的MM-TME模型中，CART细胞向肿瘤部位的转运受到明显抑制。我的初选 数据还显示，CAF通过分泌转化生长因子-β和抑制性细胞因子如 以及改变Pd-1/Pd-L1轴。双靶向肿瘤细胞和CAF显著改善CART细胞 功能。这项研究将具有重要意义，因为它将有助于深入了解CART细胞 对针对NOT的免疫治疗策略的抗药性)和广度(新的潜在治疗方法) 只有多发性骨髓瘤，还有实体瘤。最终，这些发现有可能在垂直方向上推进 CART细胞免疫疗法以及其他靶向免疫疗法。这个项目具有创新性，因为它 结合高通量筛选技术研究可能的抗药性机制 免疫疗法，因此，产生新的治疗方法。拟议的研究活动对 申请者发展成为一名独立资助的科学家，专注于细胞免疫疗法。 我将从我的导师那里接受分子生物学、转化医学和免疫学方面的进一步培训。 以及梅奥诊所经验丰富的合作者提供的癌症生物学和生物信息学方面的培训。因此， 在培训结束时，我将获得一套独特的智力和技术技能， 将使我能够将自己提升为一名独立的翻译研究员。

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.