Program Project Grant (P01) / Biological Mechanisms involved with PDT in the treatment of MPM

NIH Grant P01-CA087971

Principal Investigators:

Project Leaders:

Project Overview:

Photodynamic therapy (PDT) relies on a light sensitive drug (a photosensitizer) to damage malignant or otherwise diseased tissues in areas where this photosensitizer is excited by specific wavelengths of visible light. The presence of oxygen in the treated tissues is also important for PDT with many clinically-utilized photosensitizers. PDT is well suited to the intraoperative setting, where it can be used to treat unresectable disease and surgical margins. This program project grant (P01) is investigating the local and systemic mechanisms through which PDT interacts with the surgical environment to determine local control and long-term outcome. The reduction of disease burden by surgery is undoubtedly an advantage, yet the accompanying induction of pro-inflammatory cytokines and survival signaling could alter the immunologic, molecular and physiologic environment to which PDT is delivered. For the clinical study of surgery-PDT interactions, we use as our model intraoperative PDT of malignant pleural mesothelioma (MPM). The overall, long-term goal of this P01 is to maximize the potential clinical utility of surgery/PDT as a treatment modality. We are conducting a randomized clinical trial to elucidate the potential benefit of PDT in this setting.

This P01 (Co-PIs, Drs. Busch and Cengel) consists of four highly integrated projects: Project 1 (Sunil Singhal) is conducting a prospective randomized Phase II clinical trial looking at surgery for radical pleurectomy, with and without intraoperative PDT to the pleura of the lung. Project 2 (Dr. Steven Albelda) is characterizing anti-tumor immune responses following surgery and pleural PDT (pPDT). Project 3 (Dr. Keith Cengel) is exploring baseline and surgically-induced activation of survival signaling pathways in patients. Project 4 (Dr. Theresa Busch) is studying the vascular microenvironment of MPM in patients receiving surgery/PDT.

Overall, this P01 provides the framework to align a highly significant clinical trial with investigations in clinical specimens and animal models that will serve to inform the future direction of intraoperative PDT. The work is performed by a multidisciplinary team of physicians, physicists and scientists, each an expert in his or her respective field. Thanks to the continuous funding of this P01 mechanism by the NIH since 2001, as evidenced by our publications, we have uniquely contributed to the body of clinical and scientific knowledge in many areas of PDT. These include, but are not limited to investigations in the study of pleural PDT, tumor microenvironment, PDT-induced molecular signaling, animal models of PDT delivery, PDT light dosimetry, and optical-based monitoring of tumor physiological and photophysical properties.

Project 1: A Randomized Clinical Trial for Patients with Malignant Pleural Mesothelioma comparing Radical Pleurectomy Alone to Radical Pleurectomy plus Photodynamic Therapy

Project 2: Evaluation and Augmentation of Anti-tumoral Immune Responses Induced by Surgery followed by pPDT in Mesothelioma

Project 3: Evaluating and Modulating the Impact of Surgically-Induced Cytokines on Tumor Response to Photodynamic Therapy

Project 4: Understanding and Optimizing Vascular Response to Intraoperative PDT of Malignant Mesothelioma

Core A: PDT Physics Core

Core B: Animal and Pathology Core

Core C: Biostatistics and Data Coordinating Core (BDCC)

Core D: Administrative Core

Two subcontracts further support the goals of this P01.  A subcontract under Project 1 to Roswell Park Cancer Institute provides for the treatment of additional patients on the clinical trial.  To support some aspects of the human immunology studies, Project 2 contains a subcontract to The Wistar Institute (Emmanouil Papasavvas, Ph.D. and Luis Montaner, D.V.M., D.Phil.).