Dual-isotope SPECT imaging and immunophenotyping of immune cells to determine response to immunotherapy

双同位素 SPECT 成像和免疫细胞免疫表型分析以确定对免疫治疗的反应

• 批准号: 10590408
• 负责人: Harriet M. Kluger
• 金额: $ 66.8万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-07 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10590408
• 关键词: Affect; Affinity; Antibodies; Antigens; Binding; Biodistribution; Biological Markers; Biopsy; CD8-Positive T-Lymphocytes; CD8B1 gene; Cd68; Cells; Chelating Agents; Clinical Trials; Combination immunotherapy; Combined Modality Therapy; Complement; Cytotoxic T-Lymphocytes; Cytotoxic agent; Data; Early treatment; Foundations; Future; Goals; Image; Imaging Techniques; Immune; Immune system; Immunoglobulin G; Immunophenotyping; Immunotherapy; In Situ; In Vitro; Infiltration; Inflammatory; Isotopes; Macrophage; Macrophage Activation; Measures; Melanoma Cell; Metastatic Melanoma; Methods; Modeling; Mus; Neoplasm Metastasis; Pathology; Patients; Prediction of Response to Therapy; Property; Radioimmunoconjugate; Radioisotopes; Regimen; Renal Cell Carcinoma; Resistance; Resistance development; Spatial Distribution; Specificity; T-Lymphocyte; Techniques; Testing; Time; Tissues; Toxic effect; Tumor-associated macrophages; Work; anatomic imaging; biophysical chemistry; cancer cell; cancer imaging; clinically relevant; clinically significant; cytotoxic CD8 T cells; digital; financial toxicity; imaging probe; immunological status; in vitro Assay; in vivo; mouse model; non-invasive imaging; novel; pathology imaging; predicting response; preservation; radioligand; response; single photon emission computed tomography; subcutaneous; tool; treatment response; tumor; tumor microenvironment; uptake

SUMMARY While significant progress has been made in the past decade with immunotherapy for metastatic melanoma and renal cell carcinoma (RCC), not all patients respond, and others develop resistance over time. Hundreds of novel regimens are being developed to overcome primary and acquired resistance. Some combinations increase the infiltration of cytotoxic T cells in the tumor to kill cancer cells, while others modulate tumor-associated macrophages (TAMs) to enhance the T cell activity in the tumor microenvironment. However, toxicity to patients is an important limitation to immunotherapy regimens. Non-invasive imaging techniques are needed to determine response to combination therapy to save potential non-responders from unnecessary toxicity. Current imaging techniques do not assess the dynamic changes in the levels of T cells and TAMs at the same time. The overall hypothesis is that imaging the infiltration of cytotoxic T cells and TAMs concurrently can better determine response to immunotherapy regimens. The goal of this proposal is to develop non-invasive imaging probes for single photon emission computed tomography (SPECT) imaging of T cells and TAMs concurrently to determine response to combination therapy. We anticipate that SPECT will accurately recapitulate pathology and may ultimately replace on-treatment biopsies in patients who might have pseudoprogression. SPECT may also complement tissue-based analyses to further interrogate the tumor microenvironment through digital spatial profiling (DSP), an in situ profiling method that preserves spatial information. DSP can quantify multiple biomarkers simultaneously in immune cells responsible for the tumor’s sensitivity to combination therapy. In our preliminary work we developed the tools to implement the tracking of CD8+ T cells and CD68+ TAMs in vivo with radiolabeled antibodies. We will test our SPECT agents in established murine tumor models of melanoma and RCC in mice with intact immune systems. We will characterize their binding properties to CD8+ T cells and CD68+ TAMs in vitro (Aim 1). We will image tumoral T cell and TAM infiltration in vivo by SPECT imaging in syngeneic tumor models of melanoma and RCC and assess activation status of immune cells by DSP after immunotherapy in murine and patient tissues (Aim 2). These studies will lay the foundations for future clinical trials of dual-isotope SPECT in immunotherapy-treated patients.

概括 尽管过去十年在转移性黑色素瘤和免疫疗法方面取得了重大进展， 肾细胞癌 (RCC) 并非所有患者都有反应，其他患者随着时间的推移会产生数百种新的耐药性。 正在开发一些治疗方案来克服原发性和获得性耐药性。 细胞毒性 T 细胞在肿瘤中浸润以杀死癌细胞，而其他细胞则调节肿瘤相关细胞 巨噬细胞（TAM）可增强肿瘤微环境中的T细胞活性，但对患者有毒性。 是免疫治疗方案的一个重要限制，需要非侵入性成像技术来确定。 对联合治疗的反应，以避免潜在的无反应者免受不必要的毒性影响。 技术不能同时评估 T 细胞和 TAM 水平的动态变化。 假设同时对细胞毒性 T 细胞和 TAM 的浸润进行成像可以更好地确定 对免疫治疗方案的反应。 该提案的目标是开发用于单光子发射计算的非侵入性成像探针 同时对 T 细胞和 TAM 进行断层扫描 (SPECT) 成像，以确定对联合治疗的反应。 我们预计 SPECT 将准确地再现病理学并最终可能取代治疗 对可能出现假性进展的患者进行活检也可以补充基于组织的分析。 通过数字空间分析 (DSP)（一种原位分析）进一步探究肿瘤微环境 DSP 可以同时量化免疫细胞中的多个生物标志物。 在我们的前期工作中，我们开发了工具来解释肿瘤对联合治疗的敏感性。 我们将使用放射性标记抗体对体内 CD8+ T 细胞和 CD68+ TAM 进行跟踪。 SPECT 试剂用于在具有完整免疫系统的小鼠中建立黑色素瘤和肾细胞癌小鼠肿瘤模型。 我们将在体外表征它们与 CD8+ T 细胞和 CD68+ TAM 的结合特性（目标 1）。 SPECT 成像在黑色素瘤和肾细胞癌同基因肿瘤模型中体内肿瘤 T 细胞和 TAM 浸润 并通过 DSP 评估小鼠和患者组织免疫治疗后免疫细胞的激活状态（Aim 2).这些研究将为未来双同位素SPECT在免疫治疗中的临床试验奠定基础。 患者。