Ex vivo generation of tumor-reactive T cells for adoptive cell transfer using an immune enhanced, patient derived tumor organoid-on-a-chip (iTOC)

使用免疫增强的、患者来源的肿瘤类器官芯片 (iTOC) 体外生成肿瘤反应性 T 细胞，用于过继细胞转移

• 批准号: 10571848
• 负责人: Joal D Beane
• 金额: $ 17.79万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-14 至 2024-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10571848
• 关键词: Adoptive Cell Transfers; Adoptive Transfer; Advanced Malignant Neoplasm; Antigen-Presenting Cells; Antigens; Autologous; Autologous Tumor Cell; Back; Biomedical Engineering; Blood Cells; CD8B1 gene; Cell Proliferation; Cell Survival; Cell Therapy; Cells; Circulation; Clinical; Coculture Techniques; Complex; Cytolysis; Cytometry; Dendritic Cells; Development; Devices; Generations; Genetic Engineering; Genomics; Good Manufacturing Process; Heterogeneity; Hour; Immune; Immune checkpoint inhibitor; Immune response; Immune system; Immunooncology; Immunotherapy; In Vitro; Infusion procedures; Interferon Type II; Licensing; Malignant Neoplasms; Mediating; Memory; Microfluidics; Morbidity - disease rate; Mutation; Operative Surgical Procedures; Organoids; Patients; Perfusion; Phenotype; Population; Production; Proliferating; Publishing; Research; Risk; Source; System; T cell response; T cell therapy; T-Cell Receptor; T-Lymphocyte; TRB@ gene cluster; Technology; Testing; Time; Tumor Antigens; Tumor Expansion; Tumor-Infiltrating Lymphocytes; adaptive immune response; cancer cell; chimeric antigen receptor T cells; clinical application; complementarity-determining region 3; draining lymph node; efficacy evaluation; experimental study; high dimensionality; improved; lymph nodes; melanoma; neoantigens; neoplastic cell; novel strategies; objective response rate; peripheral blood; programmed cell death protein 1; recruit; response; targeted treatment; tool; tumor; tumor infiltrating lymphocyte therapy; tumor microenvironment; tumor-immune system interactions

PROJECT SUMMARY Adoptive T cell therapy (ACT) is a form of immunotherapy that involves the repopulation of the host immune system with a selective population of ex vivo expanded, tumor reactive T cells. Tumor reactive T cells can be isolated from the tumor (tumor infiltrating lymphocytes, TIL) or created through genetic engineering (TCR or CAR T cells). By expanding and activating the cells ex vivo, outside of the suppressive tumor microenvironment, and infusing them back into the host, successful response rates can be induced. However, many tumors have high genomic heterogeneity, which can result in decreased neoantigen expression by some cells within the tumor, allowing for immune-escape, limiting the efficacy of checkpoint inhibitors or T cell-based therapies that target a single antigen (CAR-T, TCR). A more robust T cell response that targets a diverse and greater number of tumor neoantigens may lead to more effective immunotherapies. Proponents of TIL therapy contend that these T cells may be a more effective approach to ACT due their ability to recognize a greater number of tumor neoantigens as they are found within a patient’s tumor. Response rates can be induced in up to 72% of patients. However, some patients are unable to undergo surgery to obtain TIL, others are unable to wait the 4-6 weeks required to expand TIL to numbers sufficient for therapy, and other patients may not have sufficient TIL at all. Lastly, while tumor reactive T cells are found in peripheral blood, previous attempts to isolate, increase tumor antigen recognition, and expand these T cells to numbers sufficient for therapy have been futile. However, peripheral blood could serve as a potentially limitless source of T cells, if one can enrich them for tumor antigen recognition. To overcome these limitations, we will employ a bioengineered immune-enhanced tumor-on-a-chip platform (iTOC) to enrich tumor antigen recognition and expand tumor-reactive T cells from peripheral blood. In the iTOC microfluidic platform, tumor cells and autologous lymph node-derived immune cells are combined to form immune-enhanced patient tumor organoids whereby the heterogeneity of and the interplay between the patient’s tumor, stroma, and immune cells remain intact. We hypothesize that circulation of T cells from peripheral blood through the iTOC will result in an enriched population of tumor reactive T cells that are capable of mounting a more robust immune response than TIL or uncirculated peripheral blood T cells. Aim 1 will determine the effect of iTOC perfusion on T cell viability, proliferation, and phenotype. Aim 2 will determine how iTOC perfusion impacts T cell receptor diversity and tumor-specific effector function compared to TIL and uncirculated peripheral blood T cells. These studies will establish the efficacy of the iTOC to improve a patient’s tumor-specific adaptive immune response through on demand generation of a product suitable for adoptive T cell transfer. While our test vehicle is melanoma, functional ex vivo and in vitro immune systems like the iTOC, will be used to guide clinical therapy and serve as important research tools to study the complex tumor-immune microenvironment.

项目概要 过继性 T 细胞疗法 (ACT) 是一种免疫疗法，涉及宿主免疫的重建 具有选择性体外扩增的反应性 T 细胞群的系统可以是肿瘤反应性 T 细胞。 从肿瘤中分离（肿瘤浸润淋巴细胞，TIL）或通过基因工程（TCR 或 CAR）创建 通过在抑制性肿瘤微环境之外体外扩增和激活细胞， 将它们输回宿主体内，可以诱导成功的缓解率。然而，许多肿瘤的缓解率很高。 基因组异质性，可能导致肿瘤内某些细胞的新抗原表达减少， 允许免疫逃逸，限制检查点抑制剂或基于 T 细胞的疗法的功效 单一抗原（CAR-T、TCR）针对多种和更多肿瘤的更强大的 T 细胞反应。 TIL 疗法的支持者认为，新抗原可能会带来更有效的免疫疗法。 由于它们能够识别更多的肿瘤新抗原，因此可能是更有效的 ACT 方法 因为它们存在于患者的肿瘤中，因此可以在高达 72% 的患者中产生缓解率。 一些患者无法通过手术获得 TIL，另一些患者则无法等待 4-6 周的时间来获得 TIL。 将 TIL 扩大到足以进行治疗的数量，而其他患者可能根本没有足够的 TIL。 外周血中发现反应性肿瘤T细胞，之前尝试分离、增加肿瘤抗原 识别，并将这些 T 细胞扩大到足以进行治疗的数量是徒劳的。 如果能够富集血液以识别肿瘤抗原，那么血液可以作为潜在无限的 T 细胞来源。 为了克服这些限制，我们将采用生物工程免疫增强肿瘤芯片平台 (iTOC) 丰富肿瘤抗原识别并扩大 iTOC 中的肿瘤反应性 T 细胞。 微流控平台，肿瘤细胞和自体淋巴结来源的免疫细胞结合形成 免疫增强的患者肿瘤类器官，其中患者肿瘤类器官的异质性和相互作用 我们从外周血中取出循环的 T 细胞，肿瘤、基质和免疫细胞保持完整。 通过 iTOC 将产生丰富的肿瘤反应性 T 细胞群，这些细胞能够安装 比 TIL 或非循环外周血 T 细胞更强大的免疫反应将决定效果。 iTOC 灌注对 T 细胞活力、增殖和表型的影响 目标 2 将决定 iTOC 灌注的方式。 与 TIL 和非循环外周血相比，影响 T 细胞受体多样性和肿瘤特异性效应器功能 这些研究将确定 iTOC 改善患者肿瘤特异性适应性的功效。 在我们的测试中，通过按需生成适合过继 T 细胞转移的产品来产生免疫反应。 载体是黑色素瘤，功能性离体和体外免疫系统（如 iTOC）将用于临床指导 治疗并作为研究复杂的肿瘤免疫微环境的重要研究工具。

项目成果

αCT1 peptide sensitizes glioma cells to temozolomide in a glioblastoma organoid platform.

αCT1 肽使胶质瘤细胞对胶质母细胞瘤类器官平台中的替莫唑胺敏感。

• 发表时间: 2023-04
• 影响因子: 3.8
• 作者: Che, Jingru;DePalma, Thomas J;Sivakumar, Hemamylammal;Mezache, Louisa S;Tallman, Miranda M;Venere, Monica;Swindle;Veeraraghavan, Rengasayee;Skardal, Aleksander
• 通讯作者: Skardal, Aleksander

A 3D adrenocortical carcinoma tumor platform for preclinical modeling of drug response and matrix metalloproteinase activity.

用于药物反应和基质金属蛋白酶活性临床前建模的 3D 肾上腺皮质癌肿瘤平台。

• 发表时间: 2023-09-19
• 影响因子: 4.6
• 作者: Dedhia, Priya H;Sivakumar, Hemamylammal;Rodriguez, Marco A;Nairon, Kylie G;Zent, Joshua M;Zheng, Xuguang;Jones, Katie;Popova, Liudmila V;Leight, Jennifer L;Skardal, Aleksander
• 通讯作者: Skardal, Aleksander