Deciphering the Acidic Tumor Environment: A Phase I/IIa Study of Pre-Operative Multiparametric MRI and pHLIP® ICG Intra-Operative Fluorescence Imaging of Primary Breast Cancer

项目摘要/摘要 乳腺癌是女性最常见的癌症，也是女性癌症死亡的最常见原因。 虽然带有NEO/辅助治疗的保乳手术(肿块切除术)是最理想的治疗方案， 当肿瘤未完全切除时，约25%的病例需要二次手术，可能还会增加 并发症，病人焦虑，以及转行乳房切除术。再切除率在以下人群中尤为高 肿瘤侵袭性较强，以酸性肿瘤微环境(TME)为特征。我们 建议开发和实施一种全面的肿瘤酸度成像方法，包括术前多项检查 参数磁共振成像(MpMRI)和新型PHLIP®ICG近红外荧光(NIRF)术中成像。菲利普-- ICG是一种ICG，FDA批准的NIRF吲哚青绿染料，连接到对pH敏感的pH低插入 靶向肿瘤细胞表面酸性和标记侵袭性酸性肿瘤间质的多肽(PHLIP) 界面，从而允许PHLIP-ICG靶向癌症病变和勾画阳性肿瘤边缘。我们的 临床研究包括一项预期的人类第一阶段试验和一项可行性阶段IIa试验。目标1(阶段 I和IIa)：在连续的BC中前瞻性地开发、实施和优化新的mpMRI序列 肿瘤切除术患者TME和组织酸度的临床无对比无创评估 包括体素内非相干运动扩散加权成像、扩散张量成像、乳酸磁共振 光谱学和化学交换饱和转移成像。目标2(阶段I)：评估安全性和 4个剂量水平的PHLIP-ICG静脉给药对初发BC患者的耐受性 肿瘤切除术，并确定将用于IIa期试验的“最佳”剂量。这个最佳剂量是 定义为安全的最低剂量，并允许使用PHLIP对BC进行最佳术中可视化- ICG NIRF成像。目的3(IIa期)：确定PHLIP-ICG靶向和术中应用的可行性 PHLIP-ICG最佳剂量下原发灶的组织病理学成像及边缘勾画 作为参考标准。目的4(IIa期)：对比TME酸度成像(无对比、无创、预检查) 手术mpMRI以及术中和体外PHLIP-ICG NIRF成像)具有标准的组织病理学和 探索性免疫组织化学检查BC可视化、边缘状态和 TME的性质包括不同程度的酸度、损伤程度和TME结构。最重要的是 长期目标是提高护理标准：i)术前无创、无造影剂的TME酸度 MpMRI成像将允许识别需要增强的更具侵袭性的肿瘤表型 治疗，改进手术和治疗战略的规划，并能够监测 肿瘤生物学与治疗；以及ii)术中PHLIP-ICG NIRF成像将允许改善前期 切除原发乳腺癌，这可能使更广泛的手术转向高度精确的手术 节省组织的肿块切除术--因此提高了患者的生活质量。

PROJECT SUMMARY/ABSTRACT Breast cancer (BC) is the most common cancer in women and the most common cause of female cancer deaths. While breast conserving surgery (lumpectomy) with neo/adjuvant therapy is the best desirable treatment option, about 25% of cases require secondary surgery when tumors are incompletely removed, with possible additional complications, patient anxiety, and conversion to mastectomy. Re-excision rates are especially high among patients with more aggressive tumors, which are characterized by acidic tumor microenvironment (TME). We propose to develop and implement a holistic approach for tumor acidity imaging with pre-operative multi- parametric MRI (mpMRI) and novel pHLIP® ICG near infrared fluorescent (NIRF) intra-operative imaging. pHLIP- ICG is an ICG, FDA-approved NIRF indocyanine green dye, conjugated to a pH-sensitive pH-Low Insertion Peptide (pHLIP) for targeting tumor cell surface acidity and for marking the invasive acidic tumor-stroma interface, thereby allowing pHLIP-ICG to target cancer lesions and to delineate positive tumor margins. Our clinical study consists of a prospective first-in-human phase I trial and a feasibility phase IIa trial. Aim 1 (phase I and IIa): To prospectively develop, implement, and optimize novel mpMRI sequences in consecutive BC patients undergoing lumpectomy for clinical non-contrast non-invasive assessment of the TME and tissue acidity including intravoxel incoherent motion diffusion-weighted imaging, diffusion tensor imaging, lactate MR spectroscopy, and chemical exchange saturation transfer imaging. Aim 2 (phase I): To evaluate the safety and tolerability of intravenous pHLIP-ICG administration in 4 dose levels in patients with primary BC undergoing lumpectomy, and to establish the “optimal” dose which will be used in the phase IIa trial. This optimal dose is defined as the lowest dose that is safe and that allows the best intra-operative visualization of BC with pHLIP- ICG NIRF imaging. Aim 3 (phase IIa): To establish the feasibility of pHLIP-ICG targeting and intra-operative imaging of primary BC and margin delineation at the selected optimal dose of pHLIP-ICG using histopathology as the reference standard. Aim 4 (phase IIa): To correlate TME acidity imaging (non-contrast non-invasive pre- operative mpMRI, and intra-operative and ex vivo pHLIP-ICG NIRF imaging) with standard histopathology and investigational immunohistochemistry for concordance and accuracy of BC visualization, margin status, and properties of the TME including different levels of acidity, lesion extent, and TME structure. The overarching long-term goal is to improve the standard of care: i) pre-operative non-invasive, non-contrast TME acidity imaging with mpMRI will allow the identification of more aggressive tumor phenotypes that require intensified treatment, improve planning of surgical and treatment strategies, and enable monitoring spatial-longitudinal of tumor biology with treatment; and ii) intra-operative pHLIP-ICG NIRF imaging will allow an improved up-front resection of primary breast cancer, which could allow a shift from more extensive surgeries to highly accurate tissue-sparing lumpectomies – therefore improving the quality of patients’ lives.