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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA087971-11A1
Application #
8741243
Study Section
Special Emphasis Panel (ZCA1-RPRB-B (M1))
Project Start
2000-07-01
Project End
2015-06-30
Budget Start
2014-09-10
Budget End
2015-06-30
Support Year
11
Fiscal Year
2014
Total Cost
$215,933
Indirect Cost
$80,975
Name
University of Pennsylvania
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Kim, Michele M; Darafsheh, Arash; Ahmad, Mahmoud et al. (2016) PDT Dose Dosimeter for Pleural Photodynamic Therapy. Proc SPIE Int Soc Opt Eng 9694:96940Y
Sterman, Daniel H; Alley, Evan; Stevenson, James P et al. (2016) Pilot and Feasibility Trial Evaluating Immuno-Gene Therapy of Malignant Mesothelioma Using Intrapleural Delivery of Adenovirus-IFNα Combined with Chemotherapy. Clin Cancer Res 22:3791-800
Ong, Yi Hong; Zhu, Timothy C (2016) Analytic function for predicting light fluence rate of circular fields on a semi-infinite turbid medium. Opt Express 24:26261-26281
Ghogare, Ashwini A; Miller, Joann M; Mondal, Bikash et al. (2016) Fluorinated Photodynamic Therapy Device Tips and their Resistance to Fouling for In Vivo Sensitizer Release. Photochem Photobiol 92:166-72
Grossman, Craig E; Carter, Shirron L; Czupryna, Julie et al. (2016) Fluence Rate Differences in Photodynamic Therapy Efficacy and Activation of Epidermal Growth Factor Receptor after Treatment of the Tumor-Involved Murine Thoracic Cavity. Int J Mol Sci 17:
Penjweini, Rozhin; Kim, Michele M; Dimofte, Andrea et al. (2016) Deformable medical image registration of pleural cavity for photodynamic therapy by using finite-element based method. Proc SPIE Int Soc Opt Eng 9701:970106
Zhu, Timothy C; Lu, Amy; Ong, Yi-Hong (2016) An improved analytic function for predicting light fluence rate in circular fields on a semi-infinite geometry. Proc SPIE Int Soc Opt Eng 9706:97061D
Penjweini, Rozhin; Kim, Michele M; Liu, Baochang et al. (2016) Evaluation of the 2-(1-Hexyloxyethyl)-2-devinyl pyropheophorbide (HPPH) mediated photodynamic therapy by macroscopic singlet oxygen modeling. J Biophotonics 9:1344-1354
Penjweini, Rozhin; Kim, Michele M; Finlay, Jarod C et al. (2016) Investigating the impact of oxygen concentration and blood flow variation on photodynamic therapy. Proc SPIE Int Soc Opt Eng 9694:
Gemmell, Nathan R; McCarthy, Aongus; Kim, Michele M et al. (2016) A compact fiber-optic probe-based singlet oxygen luminescence detection system. J Biophotonics :

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