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Thoracic Surgery

Research Summary

Characterization of micrometastatic nodal disease in lung cancer through the real-time identification of sentinel lymph nodes in lung cancer patients using near-infrared imaging

This NCI-funded Phase I/II clinical trial explores the clinical application of an optical imaging technology that uses safe, invisible near-infrared (NIR) fluorescent light to permit SLN identification via real-time image guidance during surgery. Optimized NIR fluorescent lymphotropic contrast agents have been developed to permit nonradioactive real-time lymphatic mapping and we have enhanced and validated the technology in large animal models. Our hypothesis is that real-time image-guideFd detection and excision of the tumor-specific SLN using NIR fluorescent technology will provide a safe and clinically applicable means to improve surgical staging with therapeutic benefit to patients with early stage lung cancer.

Design and validation of drug-eluting polymers for peri-operative locoregional drug delivery

Currently the primary focus is the development and testing of novel drug delivery platforms for administering chemotherapeutic agents in a controlled and targeted manner in order to prevent the locoregional recurrence of cancers following surgical resection either at the suture line or within regional lymph nodes. We have generated numerous polymer constructs that effectively encapsulate several chemotherapy drugs (i.e. Paclitaxel, 10-hydroxycamptothecin) with subsequent time- and chemical-mediated release profiles. The two main avenues of research are oriented towards polymer nanoparticles with pH-sensitive intracellular drug release mechanisms and copolymer films capable of long-term drug elution and biocompatibility. Cancer models include standard subcutaneous and intraperitoneal tumor models and a unique model for tumor recurrence in which our copolymer films loaded with paclitaxel have proven effective at preventing growth of recurrent disease following resection of primary tumor nodules. Furthermore, we have recently begun working on large animal (porcine) models to explore real-time imaging of these nanoparticles as they migrate through lymphatic channels to deliver the encapsulated payload within regional lymph nodes.

Induction of transplantation tolerance

Engraftment of both donor and recipient hematopoietic stem cells (SC) results in mixed bone marrow (BM) chimerism, induces donor-specific tolerance for allogeneic and xenogeneic solid organ grafts, preserves recipient immunocompetence, and is not associated with chronic rejection. We have been extensively involved in the characterization of a rare BM-derived cell population known as the facilitating cell (FC), that “facilitates” engraftment of highly purified murine SC in completely MHC-disparate recipients and induce transplantation tolerance without evidence of graft vs. host disease. Our laboratory has identified a novel member of the T cell receptor β (TCRβ) heterodimer family. The TCRβ-FCp33 receptor has been shown to be responsible for the unique properties of allogeneic SC facilitation and donor-specific tolerance induction exhibited by the FC in vivo. Isolation, purification, and characterization of this FCp33 receptor and the signaling pathways utilized for tolerance induction form a major research focus of the current NIH funded laboratory.

Recent studies have demonstrated that FC-mediated SC alloengraftment results from the invivo induction of a regulatory T cell network. Understanding the mechanism by which FC induce regulatory T cells in vivo is the current focus of this research.

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Equipment & Techniques

Animal models, polymers, flow cytometric techniques, near infrared imaging, grantsmanship

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Patents

1. Colson, YL; Patent Application Filed (No. 60, 121,108), January 1, 2000
"Stem Cell Engraftment Enhancing Cellular Proteins and Their Uses"

2. Colson YL, Grinstaff M, Azouz S, Wolinsky J, Griset A.; Patent Application Filed (PCT/US2007/070159), May 31, 2007
"Films and Particles for Delayed and Locoregional Delivery of Agents"

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Funding

1. CIMIT (PI: Colson, 03/2008 - 02/2009) -- “Validation of Imaging System for Near-Infrared Image-Guided Sentinel Lymph Node Dissection in Lung Cancer”

2. CIMIT (PI: Colson, 03/2008 - 02/2009 -- “Clinical Prototype For Intraoperative Aerosolized Nanoparticle Drug-Delivery”

3. CIMIT – Johnson and Johnson Award (PI: Colson, 01/2007 - 12/2008) -- “Drug-Eluting Closure Device for Surgical Resection Margins to Prevent Recurrence of Lung Cancer”

4. American College of Surgeons – George H.A. Clowes, JR, MD, FACS Memorial Research Career Development Award (PI: Colson, 07/2006 - 06/2011) -- “The Mechanism of Facilitating Cell Induced Regulatory T Cell Networks”

5. NIH/NHLBI 1 R01 HL074150 (PI: Colson, 09/2003 - 06/2008) -- “Mechanism of Facilitating Cell-Mediated Tx Tolerance”

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