Immune Activating CAR-Modified Antigen Presenting Cells

免疫激活 CAR 修饰的抗原呈递细胞

基本信息

批准号：
10487444
负责人：
Carl DeSelm
金额：
$ 39.38万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-19 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10487444
关键词：
Antigen Presentation Antigen-Presenting Cells Antigens Antitumor Response Area Award Binding Biological Markers CAR T cell therapy CD19 gene CTLA4 gene Cancer Etiology Cancer Patient Cell Death Cell Therapy Cells Cessation of life Clinical Country Disease Disseminated Malignant Neoplasm Doctor of Philosophy Dose Drug Design Eating Employment Engineering Exhibits Extracellular Domain Floor Funding Genetic Health Immune Immune Targeting Immune checkpoint inhibitor Immunization Immunocompetent Immunologic Monitoring Immunology Immunomodulators Immunotherapy In Vitro In complete remission Institutes Laboratories Leadership Legal patent Liquid substance Malignant Neoplasms Malignant neoplasm of pancreas Mediating Memorial Sloan-Kettering Cancer Center Mentors Modeling Mus Osteoclasts Osteoporosis Pancreas Pathway interactions Patients Penetration Phagocytes Phagocytosis Pharmacology Positioning Attribute Proliferating Property Protein Secretion Radiation Radiation Dose Unit Radiation Oncology Radiation therapy Receptor Activation Relapse Research Role Series Solid Neoplasm Surface Antigens T cell response T-Lymphocyte TLR4 gene TNFSF5 gene Technical Expertise Techniques Testing Time Tissues Training Tumor Antigens Tumor Biology United States National Academy of Sciences Universities Wages Washington Work adaptive immune response anti-cancer antigen binding bone cell killing cellular targeting checkpoint therapy chimeric antigen receptor chimeric antigen receptor T cells cost cytokine design engineered T cells exhaustion experience extracellular immune checkpoint immune function immunogenic improved in vivo inhibitor macrophage member monocyte neoplastic cell novel novel therapeutic intervention novel therapeutics pancreatic cancer cells programmed cell death protein 1 programs promoter public health relevance receptor recoverin protein response small molecule square foot success tissue culture tumor tumor microenvironment

项目摘要

Project Summary/Abstract The most successful cancer immune therapies thus far rely on anticancer T cells to eliminate tumor. If a patient is fortunate enough to possess these antitumor T cells, immune checkpoint inhibitor (CI) therapy can induce a lasting complete response (CR) (Robert et al. 2015). If those T cells are not present, but the patient is fortunate enough to possess a tumor that universally expresses an antigen not also expressed by critical tissues (exemplified by CD19 on ALL), Chimeric Antigen Receptor (CAR) T cells may eliminate the tumor and induce a lasting CR (Sadelain 2015). However, what if a patient does not have antitumor T cells, and has an antigenically diverse, solid tumor that cannot be eliminated by CAR T cells engineered to target one or two antigens? These are the majority of metastatic cancer patients, who continue to succumb to their disease. Pancreatic cancer is one such example of a highly incurable, poorly immunogenic cancer with inhomogenous tumor antigen expression, unresponsive thus far to immune therapies. Antitumor T cells arise through a series of steps. They first require encounter with an Antigen Presenting Cell (APC). The APC must have engulfed a tumor cell, expressed (rather than degraded) the tumor antigens, encountered a reactive T cell, AND expressed costimulatory molecules to activate the T cell (without which, the T cell would have undergone activation-induced cell death). That T cell must then proliferate, maintain activation, and avoid exhaustion. Here, I describe a new therapeutic approach that endows APCs with the genetic responsibility to generate an adaptive antitumor T cell response by achieving all of the above steps. The first component of this approach utilizes a CAR consisting of intracellular phagocytic receptor domains (either TLR4 or FcGRIIA), attached to a tumor-targeting scFv extracellular domain, introduced into APCs. These CAR APCs engulf tumor cells that express the targeted surface antigen (in this case, Lewis A, expressed on 90% of pancreatic cancer cells), and present endogenous tumor antigens. Aim 1 will characterize TLR4 and FcGRIIA CAR APCs’ ability to selectively engulf tumor and present endogenous tumor antigens in vitro (1A), and eliminate orthotopic pancreatic cancer in vivo (1B). The second component of this approach utilizes CAR APCs that upon tumor antigen encounter synthesize and express immune modulating molecules that facilitate an adaptive antitumor T cell response. Aim 2 will determine the in vivo function of “Immune Activating CAR APCs,” which engulf antigen positive (Ag+) tumor cells and subsequently produce a T cell stimulator (41BBL), an APC stimulator (CD40L), or soluble PD1-CTLA4 CIs induced by tumor antigen binding. Ag+ tumor will be injected in the mouse flank, while Ag- tumor will be injected in the pancreas, to separately assess direct CAR APC killing and indirect killing through an adaptive immune response. Finally, I test the additional role of immunogenic and immune sensitizing doses of radiation therapy with CAR APCs to maximize the systemic antitumor response. By developing and characterizing these Immune Activating CAR APCs, I hope to define the steps required to reliably induce an adaptive antitumor T cell response in vivo, and eventually extend a curative immune therapy option to a broader range of cancer patients.

项目概要/摘要迄今为止，最成功的癌症免疫疗法依赖于抗癌 T 细胞来消除患者的肿瘤。幸运的是拥有这些抗肿瘤 T 细胞，免疫检查点抑制剂 (CI) 疗法可以诱导持久的治疗如果这些 T 细胞不存在，但患者很幸运拥有，则称为完全缓解 (CR)。普遍表达关键组织不表达的抗原的肿瘤（例如 ALL 上的 CD19），嵌合抗原受体 (CAR) T 细胞可以消除肿瘤并诱导持久的 CR (Sadelain 2015)。如果患者没有抗肿瘤 T 细胞，并且患有抗原多样化、无法消除的实体瘤怎么办通过针对一种或两种抗原进行改造的 CAR T 细胞？这些是大多数转移性癌症患者，他们是谁？胰腺癌就是一种高度无法治愈、免疫原性差的例子。肿瘤抗原表达不均一的癌症，迄今为止对免疫疗法无反应。抗肿瘤 T 细胞通过一系列步骤产生，它们首先需要与抗原呈递细胞相遇。 (APC)。APC 必须吞噬肿瘤细胞、表达（而不是降解）肿瘤抗原、遇到肿瘤细胞。反应性 T 细胞，并表达共刺激分子来激活 T 细胞（如果没有共刺激分子，T 细胞就会然后 T 细胞必须增殖、维持激活并避免耗竭。在这里，我描述了一种新的治疗方法，该方法可以终止 APC 的遗传责任，从而产生通过实现上述所有步骤来产生适应性抗肿瘤 T 细胞反应。 CAR 由细胞内吞噬受体结构域（TLR4 或 FcGRIIA）组成，附着在肿瘤靶向上 scFv 胞外结构域，引入 APC 中，吞噬表达靶表面的肿瘤细胞。抗原（在本例中为 Lewis A，在 90% 的胰腺癌细胞上表达），并呈递内源性肿瘤抗原。目标 1 将表征 TLR4 和 FcGRIIA CAR APC 选择性吞噬肿瘤并呈现内源性的能力体外肿瘤抗原 (1A)，并消除体内原位胰腺癌 (1B)。该方法的第二个组成部分利用 CAR APC，在遇到肿瘤抗原时合成并表达促进适应性抗肿瘤 T 细胞反应的免疫调节分子。目标 2 将确定“免疫激活 CAR APC”的体内功能，该 APC 吞噬抗原阳性 (Ag+) 肿瘤细胞，随后产生 T 细胞刺激剂 (41BBL)、APC 刺激剂 (CD40L) 或可溶性 PD1-CTLA4 由肿瘤抗原结合诱导的CI将被注射到小鼠胁腹，而Ag-肿瘤将被注射到小鼠胁腹。胰腺，分别评估直接 CAR APC 杀伤和通过适应性免疫反应的间接杀伤。最后，我测试了 CAR APC 放射治疗的免疫原性和免疫敏化剂量的额外作用通过开发和表征这些免疫激活 CAR APC，我可以最大限度地发挥全身抗肿瘤反应。希望确定在体内可靠诱导适应性抗肿瘤 T 细胞反应所需的步骤，并最终延长为更广泛的癌症患者提供治愈性免疫治疗选择。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Intrinsic tumor resistance to CAR T cells is a dynamic transcriptional state that is exploitable with low-dose radiation.

肿瘤对 CAR T 细胞的内在抗性是一种动态转录状态，可通过低剂量辐射来利用。

DOI：
发表时间：
2023-09-26
期刊：
影响因子：
7.5
作者：
Kim, Alexander B.;Chou, Ssu-Yu;Kang, Solomon;Kwon, Eric;Inkman, Matthew;Szymanski, Jeff;Andruska, Neal;Colgan, Cian;Zhang, Jin;Yang, Joanna C.;Singh, Nathan;Deselm, Carl J.
通讯作者：
Deselm, Carl J.