American Society for Photobiology

ASP Conference 2016: 21-26 May 2016
Tampa Marriott Waterside Hotel & Marina


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25 - ASP/ESP Lecture: Combinational Approaches in PDT

Florida 4-5   08:30 - 11:45

Chair(s): Theresa Busch, Arjan Griffioen
 
25-1   08:30  Targeting the tumor vasculature; extracellular vimentin as an ideal target for the treatment of cancer AW Griffioen*, VU Medical Center ; EJ Huijbers, VU Medical Center; P Nowak-Sliwinska, VU Medical Center; JR van Beijnum, VU Medical Center

Abstract: The identification of specific markers of the tumor vasculature is of key importance. We have identified the intermediate filament protein vimentin as being overexpressed in colorectal carcinoma endothelial cells, as compared to normal colon- and angiogenic placenta endothelial cells. Although vimentin is known to be a cytoskeletal protein, evidence accumulates that it is not exclusively an intracellular protein. Here, we demonstrate that vimentin is excreted by, and expressed at the surface of, angiogenically activated endothelial cells, and that this externalization of vimentin is dynamic. Surface expressed vimentin is involved in migration and sprouting and can be targeted using antibodies to inhibit these processes. Furthermore, targeting tumor endothelial vimentin in a preclinical tumor model using a monoclonal antibody impairs tumor angiogenesis and tumor growth. The role of a splice variant of vimentin will be discussed, as well as the translational development towards a clinically used treatment regimen against cancer. Both combination of such treatment with phototherapy and the use of extracellular vimentin as marker to target photosensitizers will be discussed in this presentation.

25-2   09:00  Informing and Implementing Combinational Approaches in Photodynamic Therapy TM Busch*, University of Pennsylvania

Abstract: Multimodality combinations of surgery, chemotherapy, molecular therapy, and radiotherapy play a major role in the treatment of cancer. Photodynamic therapy (PDT) can also uniquely contribute to cancer treatment in the combinational setting. The integration of PDT in a multimodality approach can be guided by pre-existing or therapy-altered characteristics of a tumor, such as its microenvironment or molecular signature. In this way, treatment can be rationally designed to synergize the anti-tumor effects of the separate modalities. However, in other circumstances, combined modality therapy is not designed. Rather, it is implicit to PDT delivery. For example, there is necessarily the combination of surgery with PDT when PDT is delivered intraoperatively to the site of tumor resection. Irrespective of whether combined therapy is designed or dictated, both the positive and negative interactions of the multiple therapies must be considered to guide clinical application. We discuss several combined modality approaches to PDT that are studied preclinically and clinically, considering the potential effects of each on the subsequent modality. In the case of intraoperative PDT, we've observed an effect of preceding surgery on the therapeutic potential of PDT that immediately follows. In combinations of PDT with molecular targeting drugs, we describe our recent data on the activation of epidermal growth factor receptor (EGFR) after high fluence rate PDT and consider fluence rate for its potential influence on the design of this multimodality approach. Ultimately, the elucidation and exploitation of interactions between PDT and other therapies will guide the design of new multi-modality treatments, as well as inform approaches to improve delivery of combinations that are already used clinically.

25-3   09:30  Tumor vascular shutdown after photochemical internalization (PCI). Impact on treatment outcome M Vikdal, Oslo University Hospital -Radium Hospital, Oslo, Norway ; PK Selbo, Oslo University Hospital -Radium Hospital, Oslo, Norway; T Hompland, Oslo University Hospital -Radium Hospital, Oslo, Norway; S Sellevold, Oslo University Hospital -Radium Hospital, Oslo, Norway; AS Fremstedal, Oslo University Hospital -Radium Hospital, Oslo, Norway; EK Rofstad, Oslo University Hospital -Radium Hospital, Oslo, Norway; A Weyergang, Oslo University Hospital -Radium Hospital, Oslo, Norway; Q Peng, Oslo University Hospital -Radium Hospital, Oslo, Norway; K Berg*, Oslo University Hospital -Radium Hospital, Oslo, Norway

Abstract: Photochemical internalization (PCI) is a novel technology for release of endocytosed macromolecules into the cytosol. The technology is based on the use of photosensitizers located in endocytic vesicles that upon activation by light induce rupture of the endocytic vesicles and thereby release of the macromolecules into the cytosol. PCI has been shown to enhance the biological activity of a large variety of macromolecules and other molecules that do not readily penetrate the plasma membrane. Although PCI was developed for targeting the parenchyma cells of solid tumors recent studies have shown that the vasculature may also be damaged by this treatment as shown by e.g. in vitro studies of endothelial cells, CE-MRI studies of tumor perfusion and in vivo-ex vivo survival studies. The tumor rim seems to be less sensitive than the tumor center to PDT and also to some extent to PCI. CE-MRI studies indicate that the resistance in the tumor rim to PCI may be related to persistent vasculature. Accordingly, adjuvant bevacizumab treatment resulted in a strong curative effect in orthotopically located HT1080 fibrosarcomas not seen after PCI of bleomycin alone. However, in the highly different subcutaneously growing WiDr colon carcinoma bevacizumab showed no beneficial effect and even antagonistic effects in some treatment setups. In order to further understand the parameters regulating the response of the tumor vasculature to PCI we are currently performing more in-depth MRI studies that will be presented.

25-4   10:15  PDT Enhanced Anti-Tumor Immunity: Mechanisms and Exploitation SO Gollnick*, Roswell Park Cancer Institute

Abstract: Photodynamic therapy (PDT) enhancement of anti-tumor immunity has been demonstrated in both clinical and pre-clinical settings. The ability of PDT to enhance anti-tumor immunity is thought to be due to several factors including stimulation of immunogenic cell death, release of tumor-specific antigens, induction of acute inflammation and over-whelming of the host's clearance system. Interestingly PDT-enhancement of anti-tumor immunity appears to be regimen dependent suggesting that regimens that optimally enhance anti-tumor immunity can be developed. These findings suggest that PDT may provide both local and systemic control of disease and that PDT has the potential to be used in combination with other anti-cancer modalities that lack immune enhancing abilities. However, several recent studies have shown that enhancement of anti-tumor immunity can also result in immune escape via simultaneous enhancement of immune regulatory molecules. These studies suggest that combination of immune-enhancing PDT regimens with blockade of immune regulatory molecules may increase control of local and distant disease. Data supporting each of these concepts will be presented in this overview seminar.

25-5   10:45  Design of optimal combination therapy for the treatment of disease P Nowak-Sliwinska*, University of Geneva

Abstract: The concept of photodynamic therapy (PDT), i.e. the treatment of disease via the administration of a photosensitizer and the localized application of light, is nowadays successfully established in the clinic for some ocular disorders and to a limited extent in oncology. In oncological applications it is mostly applied for superficially growing tumors in the skin, or in hollow organs. It is now being realized that combining PDT with other treatment strategies may give opportunities to overcome some of the limitations that have precluded efficient PDT-based anti-cancer strategies. However, new combination treatments will only be efficient when designed in an optimal way. In order to do this many aspects should be considered, such a choice of drugs, doses applied, level of oxygenation, sequencing, synergistic/antagonistic activities and resistance issues. The biggest challenge in the design of combination therapies is the immense number of possible drug mixtures. We have developed a algorithm-based technology to rapidly identify optimal combination therapies, by testing only a limited number of drug mixtures. This talk will highlight the specifics of this technology and our effort to use this methodology for personalized cancer treatment.

25-6   11:15  Combination treatments in cancer therapeutics: role of spatiotemporal synchronization T Hasan*, Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School

Abstract: This talk will introduce platforms for cancer combination therapy that utilizes near infrared light activation not only for photodynamic damage but also as an extrinsic mechanism to initiate release of complimentary drugs to suppress dynamic bursts in molecular signaling networks that promote tumor cell survival and treatment escape. The targets are determined not only by the intrinsic biology of cancer cells but also by responses to external stimuli that change the microenvironment and induce stress. The goal is to achieve optimal therapeutic response by delivery/co-delivery with concomitant activity of photodynamic, molecular inhibitor and chemotherapeutic agents, selectively within the tumor in response to the microenvironment changes . This approach overcomes challenges in achieving synergistic interactions using sequential drug delivery, which is compromised by the differential pharmacokinetics of individual agents.



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