Dataset Information

Improved resection and prolonged overall survival with PD-1-IRDye800CW fluorescence probe-guided surgery and PD-1 adjuvant immunotherapy in 4T1 mouse model.

ABSTRACT: An intraoperative technique to accurately identify microscopic tumor residuals could decrease the risk of positive surgical margins. Several lines of evidence support the expression and immunotherapeutic effect of PD-1 in breast cancer. Here, we sought to develop a fluorescence-labeled PD-1 probe for in vivo breast tumor imaging and image-guided surgery. The efficacy of PD-1 monoclonal antibody (PD-1 mAb) as adjuvant immunotherapy after surgery was also assessed. PD-1-IRDye800CW was developed and examined for its application in tumor imaging and image-guided tumor resection in an immunocompetent 4T1 mouse tumor model. Fluorescence molecular imaging was performed to monitor probe biodistribution and intraoperative imaging. Bioluminescence imaging was performed to monitor tumor growth and evaluate postsurgical tumor residuals, recurrences, and metastases. The PD-1-IRDye800CW exhibited a specific signal at the tumor region compared with the IgG control. Furthermore, PD-1-IRDye800CW-guided surgery combined with PD-1 adjuvant immunotherapy inhibited tumor regrowth and microtumor metastases and thus improved survival rate. Our study demonstrates the feasibility of using PD-1-IRDye800CW for breast tumor imaging and image-guided tumor resection. Moreover, PD-1 mAb adjuvant immunotherapy reduces cancer recurrences and metastases emanating from tumor residuals.

SUBMITTER: Du Y

PROVIDER: S-EPMC5701610 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Improved resection and prolonged overall survival with PD-1-IRDye800CW fluorescence probe-guided surgery and PD-1 adjuvant immunotherapy in 4T1 mouse model.

Du Yang Y Sun Ting T Liang Xiaolong X Li Yuan Y Jin Zhengyu Z Xue Huadan H Wan Yihong Y Tian Jie J

International journal of nanomedicine 20171121

An intraoperative technique to accurately identify microscopic tumor residuals could decrease the risk of positive surgical margins. Several lines of evidence support the expression and immunotherapeutic effect of PD-1 in breast cancer. Here, we sought to develop a fluorescence-labeled PD-1 probe for in vivo breast tumor imaging and image-guided surgery. The efficacy of PD-1 monoclonal antibody (PD-1 mAb) as adjuvant immunotherapy after surgery was also assessed. PD-1-IRDye800CW was developed an ...[more]

PMID: 29200846

Similar Datasets

Project description:Glioblastoma (GBM) is a devastating cancer with basically no curative treatment. Even with aggressive treatment, the median survival is disappointing 14 months. Surgery remains the key treatment and the postoperative survival is determined by the extent of resection. Unfortunately, the invasive growth with irregular infiltrating margins complicates an optimal surgical resection. Precise intraoperative tumor visualization is therefore highly needed and molecular targeted near-infrared (NIR) fluorescence imaging potentially constitutes such a tool. The urokinase-type Plasminogen Activator Receptor (uPAR) is expressed in most solid cancers primarily at the invading front and the adjacent activated peritumoral stroma making it an attractive target for targeted fluorescence imaging. The purpose of this study was to develop and evaluate a new uPAR-targeted optical probe, IRDye800CW-AE344, for fluorescence guided surgery (FGS). Methods: In the present study we characterized the fluorescent probe with regard to binding affinity, optical properties, and plasma stability. Further, in vivo imaging characterization was performed in nude mice with orthotopic human patient derived glioblastoma xenografts, and we performed head-to-head comparison within FGS between our probe and the traditional procedure using 5-ALA. Finally, the blood-brain barrier (BBB) penetration was characterized in a 3D BBB spheroid model. Results: The probe effectively visualized GBM in vivo with a tumor-to-background ratio (TBR) above 4.5 between 1 to 12 h post injection and could be used for FGS of orthotopic human glioblastoma xenografts in mice where it was superior to 5-ALA. The probe showed a favorable safety profile with no evidence of any acute toxicity. Finally, the 3D BBB model showed uptake of the probe into the spheroids indicating that the probe crosses the BBB. Conclusion: IRDye800CW-AE344 is a promising uPAR-targeted optical probe for FGS and a candidate for translation into human use.

Project description:The standard treatment for glioblastoma multiforme (GBM) remains maximal safe surgical resection. Here, we evaluated the ability of a systemically administered antibody-dye probe conjugate (cetuximab-IRDye 800CW) to provide sufficient fluorescent contrast for surgical resection of disease in both subcutaneous and orthotopic animal models of GBM. Multiple luciferase-positive GBM cell lines (D-54MG, U-87MG, and U-251MG; n = 5) were implanted in mouse flank and tumors were fluorescently imaged daily using a closed-field near-infrared (NIR) system after cetuximab-IRDye 800CW systemic administration. Orthotopic models were also generated (n = 5), and tumor resection was performed under white light and fluorescence guidance using an FDA-approved wide-field NIR imaging system. Residual tumor was monitored using luciferase imaging. Immunohistochemistry was performed to characterize tumor fluorescence, epidermal growth factor receptor (EGFR) expression, and vessel density. Daily imaging of tumors revealed an average tumor-to-background (TBR) of 4.5 for U-87MG, 4.1 for D-54MG, and 3.7 for U-251MG. Fluorescence intensity within the tumors peaked on day-1 after cetuximab-IRDye 800CW administration, however the TBR increased over time in two of the three cell lines. For the orthotopic model, TBR on surgery day ranged from 19 to 23 during wide-field, intraoperative imaging. Surgical resection under white light on day 3 after cetuximab-IRDye 800CW resulted in an average 41% reduction in luciferase signal while fluorescence-guided resection using wide-field NIR imaging resulted in a significantly (P = 0.001) greater reduction in luciferase signal (87%). Reduction of luciferase signal was found to correlate (R (2) = 0.99) with reduction in fluorescence intensity. Fluorescence intensity was found to correlate (P < 0.05) with EGFR expression in D-54MG and U-251MG tumor types but not U-87MG. However, tumor fluorescence was found to correlate with vessel density for the U-87MG tumors. Here we show systemic administration of cetuximab-IRDye 800CW in combination with wide-field NIR imaging provided robust and specific fluorescence contrast for successful localization of disease in subcutaneous and orthotopic animal models of GBM.

Project description:Rationale: Intraoperative bleeding impairs physicians' ability to visualize the surgical field, leading to increased risk of surgical complications and reduced outcomes. Bleeding is particularly challenging during endoscopic-assisted surgical resection of hypervascular tumors in the head and neck. A tool that controls bleeding while marking tumor margins has the potential to improve gross tumor resection, reduce surgical morbidity, decrease blood loss, shorten procedure time, prevent damage to surrounding tissues, and limit postoperative pain. Herein, we develop and characterize a new system that combines pre-surgical embolization with improved visualization for endoscopic fluorescence image-guided tumor resection. Methods: Silk-elastinlike protein (SELP) polymers were employed as liquid embolic vehicles for delivery of a clinically used near-infrared dye, indocyanine green (ICG). The biophysical properties of SELP, including gelation kinetics, modulus of elasticity, and viscosity, in response to ICG incorporation using rheology, were characterized. ICG release from embolic SELP was modeled in tissue phantoms and via fluorescence imaging. The embolic capability of the SELP-ICG system was then tested in a microfluidic model of tumor vasculature. Lastly, the cytotoxicity of the SELP-ICG system in L-929 fibroblasts and human umbilical vein endothelial cells (HUVEC) was assessed. Results: ICG incorporation into SELP accelerated gelation and increased its modulus of elasticity. The SELP embolic system released 83 ± 8% of the total ICG within 24 hours, matching clinical practice for pre-surgical embolization procedures. Adding ICG to SELP did not reduce injectability, but did improve the gelation kinetics. After simulated embolization, ICG released from SELP in tissue phantoms diffused a sufficient distance to deliver dye throughout a tumor. ICG-loaded SELP was injectable through a clinical 2.3 Fr microcatheter and demonstrated deep penetration into 50-µm microfluidic-simulated blood vessels with durable occlusion. Incorporation of ICG into SELP improved biocompatibility with HUVECs, but had no effect on L-929 cell viability. Principle Conclusions: We report the development and characterization of a new, dual-functional embolization-visualization system for improving fluorescence-imaged endoscopic surgical resection of hypervascular tumors.

Project description:BackgroundComplete surgical resection remains the primary curative option for pancreatic ductal adenocarcinoma, with positive margins in 30-70% of patients. In this study, we aimed to evaluate the use of intraoperative tumour-specific imaging to enhance a surgeon's ability to detect visually occult cancer in real time.MethodsIn this single-centre, open-label, single-arm study, done in the USA, we enrolled patients who had clinically suspicious or biopsy-confirmed pancreatic ductal adenocarcinomas and were scheduled for curative surgery. Eligible patients were 19 years of age or older with a life expectancy of more than 12 weeks and a Karnofsky performance status of at least 70% or an Eastern Cooperative Oncology Group or Zubrod level of one or lower, who were scheduled to undergo curative surgery. Patients were sequentially enrolled into each dosing group and 2-5 days before surgery, patients were intravenously infused with 100 mg of unlabelled panitumumab followed by 25 mg, 50 mg, or 75 mg of the near-infrared fluorescently labelled antibody (panitumumab-IRDye800CW). The primary endpoint was to determine the optimal dose of panitumumab-IRDye800CW in identifying pancreatic ductal adenocarcinomas as measured by tumour-to-background ratio in all patients. The tumour-to-background ratio was defined as the fluorescence signal of the tumour divided by the fluorescence signal of the surrounding healthy tissue. The dose-finding part of this study has been completed. This study is registered with ClinicalTrials.gov, NCT03384238.FindingsBetween April, 2018, and July, 2019, 16 patients were screened for enrolment onto the study. Of the 16 screened patients, two (12%) patients withdrew from the study and three (19%) were not eligible; 11 (69%) patients completed the trial, all of whom were clinically diagnosed with pancreatic ductal adenocarcinoma. The mean tumour-to-background ratio of primary tumours was 3·0 (SD 0·5) in the 25 mg group, 4·0 (SD 0·6) in the 50 mg group, and 3·7 (SD 0·4) in the 75 mg group; the optimal dose was identified as 50 mg. Intraoperatively, near-infrared fluorescence imaging provided enhanced visualisation of the primary tumours, metastatic lymph nodes, and small (<2 mm) peritoneal metastasis. Intravenous administration of panitumumab-IRDye800CW at the doses of 25 mg, 50 mg, and 75 mg did not result in any grade 3 or higher adverse events. There were no serious adverse events attributed to panitumumab-IRDye800CW, although four possibly related adverse events (grade 1 and 2) were reported in four patients.InterpretationTo our knowledge, this study presents the first clinical use of panitumumab-IRDye800CW for detecting pancreatic ductal adenocarcinomas and shows that panitumumab-IRDye800CW is safe and feasible to use during pancreatic cancer surgery. Tumour-specific intraoperative imaging might have added value for treatment of patients with pancreatic ductal adenocarcinomas through improved patient selection and enhanced visualisation of surgical margins, metastatic lymph nodes, and distant metastasis.FundingNational Institutes of Health and the Netherlands Organization for Scientific Research.

Dataset Information

Improved resection and prolonged overall survival with PD-1-IRDye800CW fluorescence probe-guided surgery and PD-1 adjuvant immunotherapy in 4T1 mouse model.

Publications

Improved resection and prolonged overall survival with PD-1-IRDye800CW fluorescence probe-guided surgery and PD-1 adjuvant immunotherapy in 4T1 mouse model.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets