IL-2 scintigraphy as a guide to cancer immunotherapy

描述（申请人提供）：ipilimumab最近获得FDA批准抗CTLA 4抗体）用于治疗转移性黑色素瘤并将其引入临床实践，已经将癌症免疫治疗的一个长期公认的困境带到了最前沿：临床上可检测到的肿瘤增大是免疫细胞浸润肿瘤的结果吗结果表明，肿瘤炎症（肿瘤炎症;良好结果）或癌细胞数量增加（肿瘤进展;不良结果）。这在今天特别相关，因为伊匹单抗（IPI）在日常临床实践中，50%的转移性黑素瘤治疗患者在开始治疗的12周内面临肿瘤扩大。尽管存在共识建议，允许在有限的肿瘤进展（免疫应答RECIST标准）情况下继续IPI治疗，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有最佳临床判断。目前，还没有临床工具来进行这种区分 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，由Dr. Sinore等人的工作已经导致了使用基于白细胞介素-2（IL 2）的免疫组织化学的非侵入性检测T淋巴细胞器官浸润的方法学的发展。该小组最新的放射性药物（99 mTc-HYNIC-IL 2）建立在先前的IL 2标记工作（123 I-IL 2和99 mTc-N2 S-IL 2）的基础上，使用简化的标记程序，对人体组织中的活化T淋巴细胞进行了出色的检测，包括皮肤黑色素瘤。我们假设99 mTc-HYNIC-IL 2放射性显像可以在临床上鉴别接受IPI治疗的转移性黑色素瘤患者的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，以解决：（1）在接受IPI治疗的转移性黑色素瘤患者中进行99 mTc-HYNIC-IL 2放射成像的可行性/安全性;（2）通过99 mTc-HYNIC-IL 2放射成像与组织学评估肿瘤浸润淋巴细胞（TIL）侵袭的相关性（TIL的总和亚群），以及外周血相关性的筛选;和（3）TIL侵袭（肿瘤学/组织学）与肿瘤直径（RECIST）的相关性和与2年生存期的相关性。 本研究的成功完成将产生关于99 mTc-HYNIC-IL 2放射成像作为晚期黑色素瘤IPI治疗指南的实用性的必要的初步数据。我们预期，99 mTc-HYNIC-IL 2造影将能够在肿瘤块的CT图像上非侵入性地区分肿瘤进展（低99 mTc-HYNIC-IL 2摄取）与肿瘤炎症（高99 mTc-HYNIC-IL 2摄取）。本研究将为未来充分把握度的研究提供必要数据，该研究旨在确定99 mTc-HYNIC-IL 2放射成像预测接受标准IPI治疗的转移性黑色素瘤患者良好临床结局（2年生存率）的能力 公共卫生相关性：将易普利姆玛引入转移性黑色素瘤的临床实践中，使区分肿瘤炎症（免疫细胞浸润导致良好结果）导致的肿瘤扩大与肿瘤进展（进一步肿瘤增殖导致不良结果）的问题成为最前沿。在这项研究中，我们试图测试放射性标记的白细胞介素-2免疫显像放射性药物（99 mTc-HYNIC-IL 2），已知检测人体自身免疫性疾病中的器官浸润T细胞，也将能够检测转移性黑色素瘤患者接受伊匹单抗治疗的肿瘤浸润T淋巴细胞，并区分肿瘤炎症与肿瘤进展的可能性。

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 PUBLIC HEALTH RELEVANCE: The introduction of ipilimumab into clinical practice of metastatic melanoma has brought to the forefront the issue of discriminating tumor enlargement as a result of tumor inflammation (infiltration by immune cells leading to good outcomes) versus tumor progression (further tumor proliferation leading to poor outcomes). In this study we seek to test the possibility that a radiolabeled interleukin-2 scintigraphic radiopharmaceutical (99mTc-HYNIC-IL2), known to detect organ infiltrating T cells in human autoimmune diseases, will also be able to detect tumor infiltrating T lymphocytes in metastatic melanoma patients undergoing ipilimumab therapy and discriminate tumor inflammation from tumor progression.