Center for Immunotherapeutic Transport Oncophysics

总体-摘要 美国食品和药物管理局最近批准了几种免疫疗法，用于治疗 转移性黑色素瘤和肺癌，基于其强大的抗癌活性。努力申请 许多其他癌症的免疫疗法，包括乳腺癌和胰腺癌，还没有遇到 类似的成功。大部分的努力都集中在不同的生物学方面的研究 免疫治疗，而不是肿瘤的物理时空特性和畸变（例如， 淋巴细胞浸润不良），我们认为这是改善 免疫疗法最近的证据强调了肿瘤内过程的重要性 微环境对治疗功效的全身药代动力学的影响。因此，运输的影响 应考虑免疫效力（和治疗耐药性）的现象， 开发新的免疫疗法策略。在这一概念框架内，拟议的中心 免疫转运肿瘤物理学（CITO）的重点是：1）了解运输限制， 免疫细胞和免疫治疗; 2）建立一个精确的免疫治疗框架， 运输物理学的基础;和3）利用基于运输的物理学线索， 基于转运表型的成功的个性化免疫治疗策略。我们的总体 战略包括许多创新，包括作为免疫疗法抗性的转运， 纳米疫苗，仿生结构，精确免疫治疗，生物分布理论， 用于运输、生物分布和肿瘤生长的肿瘤物理学模型。研究项目集中在乳房 和胰腺癌，因为这些癌症类型具有显著的临床挑战。特别是要 确定纳米DC疫苗和免疫细胞的运输，以及它们如何被调节以影响 免疫原性和治疗功效，主要关注乳腺癌（项目1）。我们还将 确定胰腺癌肿瘤微环境内的生物物理转运屏障， 调节以影响免疫疗法的功效（项目2）。这两个项目都专注于免疫细胞 跨越许多运输限制障碍的运输（例如，动脉粥样硬化、基质和血管渗漏）。他们 也共享一套动物模型，治疗和辅助剂，他们也得到了 运输肿瘤物理学核心（TOC）。首席信息技术干事在拟议供资期间的总体目标是： 1)确定免疫抑制剂在乳腺和胰腺肿瘤中的转运特性; 2） 建立用于癌症免疫治疗的预测性计算转运肿瘤物理学框架; 3） 以确定由治疗转运限制引起的治疗抗性的程度及其 癌症进展过程中的演变;以及4）优化和个性化全身免疫 根据前三个目标的结果制定战略。

OVERALL – SUMMARY The US Food and Drug Administration recently approved several immunotherapies for the treatment of metastatic melanoma and lung cancer, based on their robust anti-cancer activities. Intense effort to apply immunotherapies for many other cancers, including breast and pancreatic cancers, have not yet met with similar success. Much of the effort has been focused on the study of the biological aspects of different immunotherapeutics, rather than the physical spatio-temporal peculiarities and aberrations of tumors (e.g., poor lymphocyte infiltration), which we believe are key parameters for improving the efficacy of immunotherapies. Recent evidence emphasizes the importance of processes within the tumor microenvironment over systemic pharmacokinetics for therapeutic efficacy. Thus, the impact of transport phenomena on immunotherapeutic efficacy (and therapeutic resistance) should be considered when developing strategies for new immunotherapies. Within this conceptual framework, the proposed Center for Immunotherapeutic Transport Oncophysics (CITO) focuses on: 1) understanding transport limitations of immune cells and immunotherapeutics; 2) establishing a precision immunotherapeutics framework on the basis of transport oncophysics; and 3) exploiting oncophysical transport-based cues for the development of successful personalized immunotherapeutics strategies based on transport phenotypes. Our overarching strategy comprise many innovations, including transport as a resistance for immunotherapies, nanotherapeutic vaccines, biomimetic constructs, precision immunotherapeutics, biodistribution theory, and oncophysics models for transport, biodistribution and tumor growth. The research projects focus on breast and pancreatic cancers, as those are cancer types with significant clinical challenges. In particular, we will determine the transport of Nano-DC vaccines and immune cells, and how they can be modulated to affect immunogenicity and therapeutic efficacy, with primary focus on breast cancer (Project 1). We will also determine the biophysical transport barrier(s) within the pancreatic cancer tumor microenvironment that can be modulated to affect the efficacy of immunotherapies (Project 2). Both projects focus on immune cell transport across many transport-limiting barriers (e.g., lymphatics, stroma, and vascular leakiness). They also share a set of animal models, therapeutic, and adjuvant agents, and they are also supported by the Transport Oncophysics Core (TOC). The CITO's overall objectives for the proposed funding period are: 1) to determine transport properties of immunotherapeutic agents in breast and pancreatic tumors; 2) to establish a predictive computational transport oncophysics framework for cancer immunotherapeutics; 3) to determine the extent of therapeutic resistance caused by therapeutic transport limitations and their evolution during cancer progression; and 4) to optimize and personalize systemic immunotherapeutic strategies based on the results of the first three objectives.