Doctor of Medicine, Unlisted School (2007)
Doctor of Science, Unlisted School (2017)
PURPOSE: Immunomonitoring of chimeric antigen receptor (CAR) T cells relies primarily on their quantification in the peripheral blood, which inadequately quantifies their biodistribution and activation status in the tissues. Non-invasive molecular imaging of CAR T cells by positron emission tomography (PET) is a promising approach with the ability to provide spatial, temporal and functional information. Reported strategies rely on the incorporation of reporter transgenes or ex vivo biolabeling, significantly limiting the application of CAR T cell molecular imaging. In the present study, we assessed the ability of antibody-based PET (immunoPET) to non-invasively visualize CAR T cells.EXPERIMENTAL DESIGN: After analyzing human CAR T cells in vitro and ex vivo from patient samples to identify candidate targets for immunoPET, we employed a syngeneic, orthotopic murine tumor model of lymphoma to assess the feasibility of in vivo tracking of CAR T cells by immunoPET using the 89Zr-DFO-anti-ICOS tracer we previously reported.RESULTS: Analysis of human CD19-CAR T cells during activation identified the Inducible T-cell COStimulator (ICOS) as a potential target for immunoPET. In a preclinical tumor model, 89Zr-DFO-ICOS mAb PET-CT imaging detected significantly higher signal in specific bone marrow-containing skeletal sites of CAR T cell treated mice compared with controls. Importantly, administration of ICOS-targeting antibodies at tracer doses did not interfere with CAR T cell persistence and function.CONCLUSIONS: This study highlights the potential of ICOS-immunoPET imaging for monitoring of CAR T cell therapy, a strategy readily applicable to both commercially available and investigational CAR T cells.
View details for DOI 10.1158/1078-0432.CCR-20-2770
View details for PubMedID 33087332
View details for Web of Science ID 000568290500003
Immunotherapy is innovating clinical cancer management. Nevertheless, only a small fraction of patients benefit from current immunotherapies. To improve clinical management of cancer immunotherapy, it is critical to develop strategies for response monitoring and prediction. In this study, we describe Inducible T cell Costimulator (ICOS) as a conserved mediator of immune response across multiple therapy strategies. ICOS expression was evaluated by flow cytometry, 89Zr-DFO-ICOS mAb PET/CT imaging was performed on Lewis lung cancer models treated with different immunotherapy strategies, and the change in tumor volume was used as a read-out for therapeutic response. ImmunoPET imaging of ICOS enabled sensitive and specific detection of activated T cells and early benchmarking of immune response. A STING agonist was identified as a promising therapeutic approach in this manner. The STING agonist generated significantly stronger immune responses as measured by ICOS ImmunoPET and delayed tumor growth compared to PD-1 checkpoint blockade. More importantly, ICOS ImmunoPET enabled early and robust prediction of therapeutic response across multiple treatment regimens. This data shows that ICOS is an indicator of T cell-mediated immune response and suggests ICOS ImmunoPET as a promising strategy for monitoring, comparing, and predicting immunotherapy success in cancer.
View details for DOI 10.1158/0008-5472.CAN-19-3265
View details for PubMedID 32156777
Fluorescence imaging in the second near-infrared window (NIR-II, 1000-1700 nm) holds great promise for deep tissue visualization. Development of novel clinical translatable NIR-II probes is crucial for realizing the medical applications of NIR-II fluorescence imaging. Herein, the glutathione-capped gold nanoclusters (AuNCs, specifically Au25 (SG)18 ) demonstrate highly efficient binding capability to hydroxyapatite in vitro for the first time. Further in vivo NIR-II fluorescence imaging of AuNCs indicate that they accumulate in bone tissues with high contrast and signal-background ratio. AuNCs are also mainly and quickly excreted from body through renal system, showing excellent ribs and thoracic vertebra imaging because of no background signal in liver and spleen. The deep tissue penetration capability and high resolution of AuNCs in NIR-II imaging render their great potential for fluorescence-guided surgery like spinal pedicle screw implantation. Overall, AuNCs are highly promising and clinical translatable NIR-II imaging probe for visualizing bone and bone related abnormalities.
View details for DOI 10.1002/smll.202003851
View details for PubMedID 33000882
Elevated expression of the c-Met receptor plays a crucial role in cancers. In non-small cell lung cancer (NSCLC), aberrant activation of the c-Met signaling pathway contributes to tumorigenesis and cancer progression and may mediate acquired resistance to epidermal growth factor receptor-targeted therapy. c-Met is therefore emerging as a promising therapeutic target for NSCLC, and methods for noninvasive in vivo assessment of c-Met expression would improve NSCLC treatment and diagnosis. Methods: We developed a new c-Met-binding peptide (cMBP) radiotracer, 99mTc-hydrazine nicotinamide (HYNIC)-cMBP, for SPECT imaging. Cell uptake assays were performed on 2 NSCLC cell lines with different c-Met expressions: H1993 (high expression) and H1299 (no expression). In vivo tumor specificity was assessed by SPECT imaging in tumor-bearing mice at 0.5, 1, 2, and 4 h after injection of the probe. Blocking assays, biodistribution, and autoradiography were also conducted to determine probe specificity. Results:99mTc-HYNIC-cMBP was prepared with high efficiency and showed higher uptake in H1993 cells than in H1299 cells. Biodistribution and autoradiography also showed significantly higher percentages of the injected dose for 99mTc-HYNIC-cMBP in H1993 tumors than in H1299 tumors at 0.5 h (4.74 ± 1.43%/g and 1.00 ± 0.37%/g, respectively; P < 0.05). H1993 tumors were clearly visualized at 0.5 h in SPECT images, whereas H1299 tumors were not observed at any time. The specificity of 99mTc-HYNIC-cMBP for c-Met was demonstrated by a competitive block with an excess of nonradiolabeled peptide. Conclusion: For c-Met-targeted SPECT imaging of NSCLC, we developed 99mTc-HYNIC-cMBP, a tracer that specifically binds to c-Met with favorable pharmacokinetics in vitro and in vivo.
View details for PubMedID 29777004
Tumor heterogeneity and changes in epidermal growth factor receptor (EGFR) mutation status over time challenge the design of effective EGFR tyrosine kinase inhibitor (TKI) treatment strategies for non-small cell lung cancer (NSCLC). Therefore, there is an urgent need to develop techniques for comprehensive tumor EGFR profiling in real time, particularly in lung cancer precision medicine trials. We report a positron emission tomography (PET) tracer, N-(3-chloro-4-fluorophenyl)-7-(2-(2-(2-(2-18F-fluoroethoxy) ethoxy) ethoxy) ethoxy)-6-methoxyquinazolin-4-amine (18F-MPG), with high specificity to activating EGFR mutant kinase. We evaluate the feasibility of using 18F-MPG PET for noninvasive imaging and quantification of EGFR-activating mutation status in preclinical models of NSCLC and in patients with primary and metastatic NSCLC tumors. 18F-MPG PET in NSCLC animal models showed a significant correlation (R2 = 0.9050) between 18F-MPG uptake and activating EGFR mutation status. In clinical studies with NSCLC patients (n = 75), the concordance between the detection of EGFR activation by 18F-MPG PET/computed tomography (CT) and tissue biopsy reached 84.29%. There was a greater response to EGFR-TKIs (81.58% versus 6.06%) and longer median progression-free survival (348 days versus 183 days) in NSCLC patients when 18F-MPG PET/CT SUVmax (maximum standard uptake value) was ?2.23 versus <2.23. Our study demonstrates that 18F-MPG PET/CT is a powerful method for precise quantification of EGFR-activating mutation status in NSCLC patients, and it is a promising strategy for noninvasively identifying patients sensitive to EGFR-TKIs and for monitoring the efficacy of EGFR-TKI therapy.
View details for PubMedID 29515002
Tyrosine kinase inhibitors (EGFR-TKIs) targeting the epidermal growth factor receptor (EGFR) have been used in non-small cell lung carcinoma (NSCLC) for years with promising results, in particular in patients with activating mutations in the EGFR kinase domain (exon 19 E746-A750 deletion or exon 21 L858R point mutation). However, despite their great success in the clinic, a significant number of patients do not respond to EGFR-TKIs, such as those carrying the L858R/T790M mutation or EGFR wild type. Thus, detecting the EGFR mutation status before EGFR-TKIs therapy is essential to ensure its efficacy. In this study, we report a novel SPECT tracer 99mTc-HYNIC-MPG that binds specifically to activating mutant EGFR and which could therefore be used to noninvasively select patients sensitive to EGFR-TKIs. We evaluated the capacity of 99mTc-HYNIC-MPG in detecting EGFR-activating mutations both in vitro and in vivo using four human NSCLC cell lines (PC9, H1975, H358 and H520). 99mTc-HYNIC-MPG had significantly higher accumulation in PC9 tumor cells when compared to H1975, H358 and H520 tumors cells, which may be due to the activating mutations (exon 19 deletion) in EGFR tyrosine kinase domain in PC9 cells. Thus, 99mTc-HYNIC-MPG SPECT imaging may be used to identify NSCLC tumors with a potential high response rate to EGFR-TKIs.
View details for DOI 10.18632/oncotarget.17251
View details for Web of Science ID 000404283700065
View details for PubMedID 28489575
View details for PubMedCentralID PMC5522229
To prepare and evaluate a new radiotracer 18F-IRS for molecular imaging mutant EGF Receptors in vitro and vivo. Uptake and efflux of 18F-IRS were performed with four NSCLC cell lines including HCC827, H1975, H358 and H520. In vivo tumor targeting and pharmacokinetics of the radiotracers were also evaluated in HCC827, H1975, H358 and H520 tumor-bearing nude mice by PET/CT imaging. Ex vivo biodistribution assays were performed to quantify the accumulation of 18F-IRS in vivo. We also performed 18F-IRS PET/CT imaging of three patients with NSCLC. We labeled this small molecule with QD620 for flow cytometry and confocal imaging analyses. The uptakes of 18F-IRS by HCC827 and HCC827 tumors were significantly higher than those of H358, H1975 and H520, and they were reduced by the addition of 100??M of gefitinib. Biodistribution experiments showed an accumulation of 18F-IRS in tumors of HCC827 xenografts. Flow cytometry and confocal imaging with QD620-IRS further demonstrated that binding specifically to HCC827 cells. 18F-IRS accumulation was preferential in the tumor, which was NSCLC with responsive EGFR exon 19 deleted. 18F-IRS showed high binding stability and specificity to 19 exon deleted EGFR mutation in vitro and vivo.
View details for PubMedID 28600491
EGFR (epidermal growth factor receptor) targeted therapy has shown great success in clinical comparing with chemotherapy in EGFR mutation NSCLCs. Such as, gefitinib, first generation EGFR TKI, has obviously prolonged the FPS (progression free survival) of the subgroup of patients, but to those who did not get a certain mutation in EGFR kinase domain, the outcome is poor. In view of this situation, scientists have synthesized many radiotracers for selecting the right people by PET/CT imaging to NSCLC TKI therapy. In this study, we developed a novel PET radiotracer 18F-IRS in one-step with a radio yield 20% (non-corrected), radiochemistry>98.5%, specific activity>105GBq/?mol, the pharmacokinetics and capacity of the tracer binding to mutant EGFR were evaluated both in vitro and in vivo.
View details for DOI 10.1016/j.bmcl.2016.10.084
View details for Web of Science ID 000389784500030
View details for PubMedID 27825546
Mutated epidermal growth factor receptor (EGFR) is an important biomarker for cancer diagnosis and molecular target for many anticancer drugs. Localizing EGFR and evaluating EGFR mutational status can help to identify patients who are potentially the most suitable ones for targeted treatments. Hence, we developed a novel EGFR tyrosine kinase inhibitor labeled with (99m)Tc ((99m)Tc-HYNIC-MPG) and evaluated its EGFR binding capacity in vitro and in vivo. This molecular probe was synthesized by one-step method that is simple and highly efficient. Importantly, the uptake rate for (99m)Tc-HYNIC-MPG in the liver was as low as 28.44 ± 0.15% (mean ± SD, n=3). This finding presents for the first time that (99m)Tc-HYNIC-MPG can bind to mutated EGFR efficiently and thus provides a novel molecular tool to detect mutated EGFR and suppress tumorigenesis.
View details for DOI 10.1016/j.bmcl.2014.12.074
View details for PubMedID 25716904