Project 2 Abstract: Recent results generated by the Program Project have shown that the overall survival after surgery/PDT exceeds any previous reported series. One hypothesis suggested by these data is that pPDT is inducing an immune response against the recurrent tumor and this response is inhibiting the growth of the tumor leading to prolonged survival. There is extensive animal data with PDT (without surgery) showing that, in addition to its direct cytotoxic effects, PDT also induces anti-tumor immune responses capable of affecting distant tumor. There are also a few clinical reports suggesting that PDT alone can induce anti-tumor immune responses. To date, we have no direct evidence from our patients to confirm or refute this immune hypothesis. The new randomized clinical trial design where patients will either receive surgery with pPDT or surgery alone provides a unique opportunity to test the immune response hypothesis and to define these immune responses. To do so, we will work with Project 1 and will evaluate the immune responses generated by surgery/pPDT versus surgery in patients with malignant mesothelioma (Specific Aim 1). This will be accomplished by: A) evaluating the blood leukocyte response to surgery/pPDT in comparison to surgery alone and in relationship to anti-tumor efficacy, B) evaluating anti-tumor humoral immune responses to known and unknown mesothelioma antigens induced by surgery/pPDT in comparison to surgery alone, c) evaluating anti- tumor cellular immune responses induced by surgery/pPDT in comparison to surgery alone, and d) evaluating the cytokine response to surgery/pPDT in relationship to anti-tumor efficacy. In addition to evaluating our clinical subjects, we propose one preclinical, translational aim with the goal of developing improved approaches based on exciting preliminary data. In conjunction with the Animal Core and Projects 3 and 4, we will use novel animal models of surgery/PDT to evaluate the hypothesis that the anti-tumor immune response generated by surgery/PDT can be augmented by inhibition of inflammation (COX-2 inhibitor or IL-6 inhibition) (Specific Aim 2). If supported by these aims, our goal would be to initiate a future clinical trial in which we will combine surgery/pPDT with COX-2 inhibition or anti-IL-6 antibodies.

Public Health Relevance

Project 2 Narrative By testing blood samples from patients in our clinical trial, this project will determine if using surgery plus photodynamic therapy (PDT) for treatment of mesothelioma induces anti-tumor immune responses that enhance the efficacy of treatment. New animal models of combined surgery/PDT will also be used to test ways to understand and improve the anti-tumor immune response.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
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Special Emphasis Panel (ZCA1-RPRB-B (M1))
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University of Pennsylvania
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Kim, Michele M; Ghogare, Ashwini A; Greer, Alexander et al. (2017) On the in vivo photochemical rate parameters for PDT reactive oxygen species modeling. Phys Med Biol 62:R1-R48
Friedberg, Joseph S; Simone 2nd, Charles B; Culligan, Melissa J et al. (2017) Extended Pleurectomy-Decortication-Based Treatment for Advanced Stage Epithelial Mesothelioma Yielding a Median Survival of Nearly Three Years. Ann Thorac Surg 103:912-919
Penjweini, Rozhin; Kim, Michele M; Zhu, Timothy C (2017) Three-dimensional finite-element based deformable image registration for evaluation of pleural cavity irradiation during photodynamic therapy. Med Phys 44:3767-3775
Ahn, Peter H; Finlay, Jarod C; Gallagher-Colombo, Shannon M et al. (2017) Lesion Oxygenation Associates with Clinical Outcomes in Premalignant and Early Stage Head and Neck Tumors Treated on a Phase 1 Trial of Photodynamic Therapy. Photodiagnosis Photodyn Ther :
Yan, Lesan; Miller, Joann; Yuan, Min et al. (2017) Improved Photodynamic Therapy Efficacy of Protoporphyrin IX-Loaded Polymeric Micelles Using Erlotinib Pretreatment. Biomacromolecules 18:1836-1844
Penjweini, Rozhin; Kim, Michele M; Liu, Baochang et al. (2017) Evaluation of the 2-(1-Hexyloxyethyl)-2-devinyl pyropheophorbide (HPPH) mediated photodynamic therapy by macroscopic singlet oxygen modeling [J. Biophotonics 9, No. 11-12, 1344-1354 (2016)]. J Biophotonics 10:473-474
Kennedy, Gregory Thomas; Newton, Andrew; Predina, Jarrod et al. (2017) Intraoperative near-infrared imaging of mesothelioma. Transl Lung Cancer Res 6:279-284
Zhu, Timothy C; Kim, Michele M; Ong, Yi-Hong et al. (2017) A summary of light dose distribution using an IR navigation system for Photofrin-mediated Pleural PDT. Proc SPIE Int Soc Opt Eng 10047:
Gemmell, Nathan R; McCarthy, Aongus; Kim, Michele M et al. (2017) A compact fiber-optic probe-based singlet oxygen luminescence detection system. J Biophotonics 10:320-326
Kim, Michele M; Penjweini, Rozhin; Zhu, Timothy C (2017) Evaluation of singlet oxygen explicit dosimetry for predicting treatment outcomes of benzoporphyrin derivative monoacid ring A-mediated photodynamic therapy. J Biomed Opt 22:28002

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