First-in-Humans Imaging with 89Zr-Df-IAB22M2C Anti-CD8 Minibody in Patients with Solid Malignancies: Preliminary Pharmacokinetics, Biodistribution, and Lesion Targeting.
89Zr-Df-IAB22M2C Anti-CD8 小型实体瘤患者的首次人体成像: 初步药代动力学、生物分布和病变靶向性。
- 作者列表："Pandit-Taskar N","Postow MA","Hellmann MD","Harding JJ","Barker CA","O'Donoghue JA","Ziolkowska M","Ruan S","Lyashchenko SK","Tsai F","Farwell M","Mitchell TC","Korn R","Le W","Lewis JS","Weber WA","Behera D","Wilson I","Gordon M","Wu AM","Wolchok JD
:Immunotherapy is becoming the mainstay for treatment of a variety of malignancies, but only a subset of patients responds to treatment. Tumor-infiltrating CD8-positive (CD8+) T lymphocytes play a central role in antitumor immune responses. Noninvasive imaging of CD8+ T cells may provide new insights into the mechanisms of immunotherapy and potentially predict treatment response. We are studying the safety and utility of 89Zr-IAB22M2C, a radiolabeled minibody against CD8+ T cells, for targeted imaging of CD8+ T cells in patients with cancer. Methods: The initial dose escalation phase of this first-in-humans prospective study included 6 patients (melanoma, 1; lung, 4; hepatocellular carcinoma, 1). Patients received approximately 111 MBq (3 mCi) of 89Zr-IAB22M2C (at minibody mass doses of 0.2, 0.5, 1.0, 1.5, 5, or 10 mg) as a single dose, followed by PET/CT scans at approximately 1-2, 6-8, 24, 48, and 96-144 h after injection. Biodistribution in normal organs, lymph nodes, and lesions was evaluated. In addition, serum samples were obtained at approximately 5, 30, and 60 min and later at the times of imaging. Patients were monitored for safety during infusion and up to the last imaging time point. Results:89Zr-IAB22M2C infusion was well tolerated, with no immediate or delayed side effects observed after injection. Serum clearance was typically biexponential and dependent on the mass of minibody administered. Areas under the serum time-activity curve, normalized to administered activity, ranged from 1.3 h/L for 0.2 mg to 8.9 h/L for 10 mg. Biodistribution was dependent on the minibody mass administered. The highest uptake was always in spleen, followed by bone marrow. Liver uptake was more pronounced with higher minibody masses. Kidney uptake was typically low. Prominent uptake was seen in multiple normal lymph nodes as early as 2 h after injection, peaking by 24-48 h after injection. Uptake in tumor lesions was seen on imaging as early as 2 h after injection, with most 89Zr-IAB22M2C-positive lesions detectable by 24 h. Lesions were visualized early in patients receiving treatment, with SUV ranging from 5.85 to 22.8 in 6 target lesions. Conclusion:89Zr-IAB22M2C imaging is safe and has favorable kinetics for early imaging. Biodistribution suggests successful targeting of CD8+ T-cell-rich tissues. The observed targeting of tumor lesions suggests this may be informative for CD8+ T-cell accumulation within tumors. Further evaluation is under way.
: 免疫治疗正在成为治疗多种恶性肿瘤的主要手段，但只有一部分患者对治疗有反应。肿瘤浸润 CD8-positive (CD8 +) T 淋巴细胞在抗肿瘤免疫反应中发挥核心作用。CD8 + T 细胞的无创成像可能为免疫治疗的机制提供新的见解，并潜在地预测治疗反应。我们正在研究 89Zr-IAB22M2C，一种针对 CD8 + T 细胞的放射性标记小体，用于癌症患者 CD8 + T 细胞靶向成像的安全性和效用。方法: 这项首次人体前瞻性研究的初始剂量递增阶段包括 6 例患者 (黑色素瘤，1 例; 肺，4 例; 肝细胞癌，1 例)。患者接受约 111 MBq (3 mCi) 的 89Zr-IAB22M2C (0.2，0.5，1.0，1.5，5 或 10 mg 的微小体质量剂量) 作为单剂量,然后在注射后约 1-2 、 6-8 、 24 、 48 和 96-144 h 进行 PET/CT 扫描。评估正常器官、淋巴结和病变的生物分布。此外，在大约 5 、 30 和 60 min 以及之后的成像时间获得血清样本。在输注期间和最后一个成像时间点监测患者的安全性。结果: 89Zr-IAB22M2C 输注耐受性良好，注射后未观察到即刻或延迟的副作用。血清清除率通常为双指数，并依赖于给药的小体质量。血清时间-活性曲线下面积，标准化为给药活性，范围为 1.3 mg 0.2 h/L 至 10 mg 8.9 h/L。生物分布依赖于施用的小体质量。脾脏摄取最高，其次是骨髓。肝脏摄取在较高的微小体块中更明显。肾摄取通常较低。注射后 2 h 多个正常淋巴结见显著摄取，注射后 24-48 h 达高峰。注射后 2 h 显像可见肿瘤病灶内摄取，24 h 可检出大多数 89zr-iab22m2c 阳性病灶。在接受治疗的患者中早期显示病变，6 个目标病变的 SUV 范围为 5.85-22.8。结论: 89Zr-IAB22M2C 成像是安全的，对早期成像具有有利的动力学。生物分布提示成功靶向富含 CD8 + T 细胞的组织。观察到的肿瘤病灶的靶向性表明这可能对肿瘤内 CD8 + T 细胞聚集有信息。进一步评估正在进行中。
METHODS::Macrophages (MΦ) play a critical role in tumor growth, immunosuppression and inhibition of adaptive immune responses in cancer. Hence, targeting signaling pathways in MΦs that promote tumor immunosuppression will provide therapeutic benefit. PI3Kγ has been recently established by our group and others as a novel immuno-oncology target. Herein, we report that a macrophage Syk-PI3K axis drives polarization of immunosuppressive MΦs which establish an immunosuppressive tumor microenvironment in in vivo syngeneic tumor models. Genetic or pharmacological inhibition of Syk and/or PI3Kγ in MΦs promotes a pro-inflammatory MΦphenotype, restores CD8+ T cell activity, destabilizes HIF under hypoxia, and stimulates an antitumor immune response. Assay for Transposase-accessible Chromatin using Sequencing (ATAC-seq) analyses on the bone marrow derived macrophages (BMDMs) show that inhibition of Syk kinase promotes activation and binding of NF-κB motif in SykMC-KO BMDMs, thus stimulating immunostimulatory transcriptional programming in MΦs to suppress tumor growth. Finally, we have developed in silico the "first in class" dual Syk/PI3K inhibitor, SRX3207, for the combinatorial inhibition of Syk and PI3K in one small molecule. This chemotype demonstrates efficacy in multiple tumor models and represents a novel combinatorial approach to activate antitumor immunity.
METHODS::Dysfunction of invariant natural killer T (iNKT) cells in tumor microenvironment hinders their anti-tumor efficacy, and the underlying mechanisms remain unclear. Here we report that iNKT cells increase lipid biosynthesis after activation, and that is promoted by PPARγ and PLZF synergically through enhancing transcription of Srebf1. Among those lipids, cholesterol is required for the optimal IFN-γ production from iNKT cells. Lactic acid in tumor microenvironment reduces expression of PPARγ in intratumoral iNKT cells and consequently diminishes their cholesterol synthesis and IFN-γ production. Importantly, PPARγ agonist pioglitazone, a thiazolidinedione drug for type 2 diabetes, successfully restores IFN-γ production in tumor-infiltrating iNKT cells from both human patients and mouse models. Combination of pioglitazone and alpha-galactosylceramide treatments significantly enhances iNKT cell-mediated anti-tumor immune responses and prolongs survival of tumor-bearing mice. Our studies provide a strategy to augment the anti-tumor efficacy of iNKT cell-based immunotherapies via promoting their lipid biosynthesis.
METHODS::Near-infrared photoimmunotherapy (NIR-PIT) is a newly developed and selective cancer treatment that induces necrotic and immunogenic cell death and utilizes a monoclonal antibody conjugated to a photo-absorber dye, IR700DX, activated by NIR light. Although CD44 is surface cancer marker associated with drug resistance, anti-CD44-IR700 NIR-PIT results in inhibited cell growth and prolonged survival in multiple tumor types. Meanwhile, anti-CD25-IR700-targeted NIR-PIT has been reported to achieve selective and local depletion of FOXP3+CD25+CD4+ regulatory T cells (Tregs), which are primary immunosuppressive cells in the tumor microenvironment (TME), resulting in activation of local antitumor immunity. Combined NIR-PIT with CD44- and CD25-targeted agents has the potential to directly eliminate tumor cells and also amplify the immune response by removing FOXP3+CD25+CD4+ Tregs from the TME. We investigated the difference in therapeutic effects of CD44-targeted NIR-PIT alone, CD25-targeted NIR-PIT alone, and the combination of CD44- and CD25-targeted NIR-PIT in several syngeneic tumor models, including MC38-luc, LL/2, and MOC1. The combined NIR-PIT showed significant tumor growth inhibition and prolonged survival compared with CD44-targeted NIR-PIT alone in all tumor models and showed prolonged survival compared with CD25-targeted NIR-PIT alone in MC38-luc and LL/2 tumors. Combined CD44/CD25 NIR-PIT also resulted in some complete remissions, whereas this was not achieved with either type of NIR-PIT alone. Therefore, combined NIR-PIT simultaneously targeting cancer antigens and immunosuppressive cells in the TME may be more effective than either type of NIR-PIT alone and may have potential to induce prolonged immune responses in treated tumors.