IL-2 scintigraphy as a guide to cancer immunotherapy

IL-2 闪烁扫描术作为癌症免疫治疗的指南

• 批准号: 8547041
• 负责人: SVETOMIR Nenad MARKOVIC
• 金额: $ 30.59万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-21 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8547041
• 关键词: Accounting; Address; Antibodies; Autoimmune Diseases; Biopsy; CTLA4 gene; Caliber; Caring; Cells; Clinical; Clinical Trials; Consensus; Cutaneous Melanoma; Data; Detection; Development; Disease Progression; Dose; Down-Regulation; Enrollment; Evaluation; Funding; Future; Health; Histologic; Histology; Human; Image; Immune; Immune response; Immunotherapeutic agent; Infiltration; Inflammation; Interleukin-2; Intestines; Judgment; Label; Lead; Left; Malignant Neoplasms; Measures; Metastatic Melanoma; Methodology; Modification; Needles; Non-Invasive Cancer Detection; Oncologist; Organ; Outcome; Patients; Physicians; Pilot Projects; Procedures; Progression-Free Survivals; Radiolabeled; Radionuclide Imaging; Radiopharmaceuticals; Recommendation; Safety; Solid Neoplasm; Survival Rate; T-Lymphocyte; Testing; Time; Toxic effect; Tumor Volume; Tumor-Infiltrating Lymphocytes; Wit; Work; X-Ray Computed Tomography; autoimmune thyroid disease; base; cancer cell; cancer immunotherapy; clinical practice; experience; human tissue; melanoma; neoplastic cell; peripheral blood; premature; prevent; radiotracer; response; single photon emission computed tomography; tool; tumor; tumor growth; tumor progression; uptake

DESCRIPTION (provided by applicant): The recent FDA approval of ipilimumab (Yervoy(R), anti-CTLA4 antibody) for the treatment of metastatic melanoma and its introduction to clinical practice, have brought to the forefront a long recognized dilemma of cancer immunotherapy: is clinically detectable tumor enlargement the result of tumor infiltration by immune cells (tumor inflammation; good outcome) or an increased number of cancer cells (tumor progression; bad outcome). This is particularly relevant today as ipilimumab (IPI) is in daily clinical practice wit 50% of treated patients with metastatic melanoma facing tumor enlargement within 12 weeks of initiation of treatment. Albeit consensus recommendations do exist to allow for continuation of IPI therapy in the face of limited tumor progression (immune response RECIST criteria), oncologists in clinical practice are left with their best clinical judgment in differentiating tumo inflammation vs. tumor progression. Presently, there are no clinical tools to make this distinction and guide therapy decisions in this unique clinical setting of cancer immunotherapeutics. Over the past decade, work by Dr. Signore et al has resulted in the development of methodology for non-invasive detection of T lymphocyte organ infiltration using interleukin-2 (IL2) based scintigraphy. The group's most recent radiopharmaceutical (99mTc-HYNIC-IL2) builds upon prior IL2 labeling efforts (123I-IL2 and 99mTc-N2S-IL2) using a simplified labeling procedure with excellent detection of activated T lymphocytes in human tissues, including melanoma of the skin. We hypothesize that99mTc-HYNIC-IL2 scintigraphy will allow clinical differentiation of tumor inflammation vs tumor progression in patients undergoing IPI therapy for metastatic melanoma. We seek funding in support of a pilot clinical trial addressing: (1) feasibility/safety of 99mTc-HYNIC-IL2 scintigraphy in patients with metastatic melanoma undergoing IPI therapy; (2) correlation of tumor infiltrating lymphocyte (TIL) invasion assessed by 99mTc-HYNIC-IL2 scintigraphy vs. histology (total and subsets of TIL), as well as screen for peripheral blood correlates; and (3) correlation of TIL invasion (scintigraphy/histology) with tumor diameter (RECIST) and association with 2 year survival. Successful completion of this study will generate necessary preliminary data regarding the utility of 99mTc-HYNIC-IL2 scintigraphy as a guide for IPI therapy in advanced melanoma. We anticipate that 99mTc- HYNIC-IL2 scintigraphy will be able to non-invasively discriminate between tumor progression (low 99mTc- HYNIC-IL2 uptake) vs. tumor inflammation (high99mTc-HYNIC-IL2 uptake) on CT images of tumor masses. The current study will provide necessary data for a future, adequately powered study aimed at establishing the ability of 99mTc-HYNIC-IL2 scintigraphy to predict good clinical outcomes (survival at 2 years) in patients with metastatic melanoma undergoing standard-of-care IPI therapy

描述（由申请人提供）： FDA 最近批准 ipilimumab（Yervoy(R)，抗 CTLA4 抗体）用于治疗转移性黑色素瘤并将其引入临床实践，使癌症免疫治疗长期以来公认的困境成为人们关注的焦点：临床上可检测到的肿瘤增大是免疫细胞肿瘤浸润的结果（肿瘤炎症；良好结果）或癌细胞数量增加（肿瘤进展；不良结果）。这在今天尤其重要，因为伊匹单抗（IPI）在日常临床实践中，50% 的转移性黑色素瘤治疗患者在开始治疗后 12 周内面临肿瘤扩大。尽管确实存在共识建议，允许在有限的肿瘤进展情况下继续 IPI 治疗（免疫反应 RECIST 标准），但临床实践中的肿瘤学家在区分肿瘤炎症与肿瘤进展方面仍具有最佳临床判断。目前，没有临床工具可以做出这种区分 并在这种独特的癌症免疫治疗临床环境中指导治疗决策。 在过去的十年中，Signore 博士等人的工作开发了使用基于白细胞介素 2 (IL2) 的闪烁扫描技术对 T 淋巴细胞器官浸润进行无创检测的方法。该小组最新的放射性药物 (99mTc-HYNIC-IL2) 基于之前的 IL2 标记工作（123I-IL2 和 99mTc-N2S-IL2），使用简化的标记程序，能够出色地检测人体组织（包括皮肤黑色素瘤）中的活化 T 淋巴细胞。我们假设 99mTc-HYNIC-IL2 闪烁扫描将允许在接受 IPI 治疗转移性黑色素瘤的患者中临床区分肿瘤炎症与肿瘤进展。我们寻求资金支持一项试点临床试验，该试验涉及：(1) 99mTc-HYNIC-IL2 闪烁扫描在接受 IPI 治疗的转移性黑色素瘤患者中的可行性/安全性； (2) 通过 99mTc-HYNIC-IL2 闪烁扫描评估肿瘤浸润淋巴细胞 (TIL) 侵袭与组织学（TIL 总数和子集）的相关性，以及外周血相关性的筛选； (3) TIL 侵袭（闪烁扫描/组织学）与肿瘤直径 (RECIST) 的相关性以及与 2 年生存率的相关性。 这项研究的成功完成将产生关于 99mTc-HYNIC-IL2 闪烁扫描作为晚期黑色素瘤 IPI 治疗指南的实用性的必要初步数据。我们预计 99mTc-HYNIC-IL2 闪烁扫描将能够在肿瘤块的 CT 图像上非侵入性地区分肿瘤进展（低 99mTc-HYNIC-IL2 摄取）与肿瘤炎症（高 99mTc-HYNIC-IL2 摄取）。目前的研究将为未来的充分动力研究提供必要的数据，该研究旨在建立 99mTc-HYNIC-IL2 闪烁扫描技术预测接受标准护理 IPI 治疗的转移性黑色素瘤患者良好临床结果（2 年生存率）的能力

项目成果

Non-invasive visualization of tumor infiltrating lymphocytes in patients with metastatic melanoma undergoing immune checkpoint inhibitor therapy: a pilot study.

接受免疫检查点抑制剂治疗的转移性黑色素瘤患者肿瘤浸润淋巴细胞的无创可视化：一项试点研究。

• 发表时间: 2018-07-13
• 作者: Markovic, Svetomir N;Galli, Filippo;Suman, Vera J;Nevala, Wendy K;Paulsen, Andrew M;Hung, Joseph C;Gansen, Denise N;Erickson, Lori A;Marchetti, Paolo;Wiseman, Gregory A;Signore, Alberto
• 通讯作者: Signore, Alberto