The Issue: Surgically-Induced Inflammation
Cancer is notorious in its ability to escape the body's natural immune defenses in order to grow without restriction. Tumors can escape detection by the cells of the immune system, and can even confiscate their functions to promote activities such as the formation of new blood vessels (angiogenesis) or escape to distant tissue (metastasis). These functions are performed by several inflammatory cells of the "tumor microenvironment" - that is, the summation of cells that make up the tumor. These cells are particularly interesting in that they can play two roles in cancer, depending on the situation: they can either (1) focus on killing the tumor ("anti-tumoral") and engaging the necessary immunity to keep cancer cells limited or (2) exacerbate the tumor ("pro-tumoral") by assisting it in obtaining oxygen and escaping immunity.
Surgery is a useful way to reduce the tumor burden of patients with locally advanced cancer. After surgery, subsequent therapies (called "adjuvant therapies") may be necessary to help keep cancer cells in check. Although surgery is useful in reducing the tumor, it can also modify the number and/or exacerbate the function of inflammatory cells. Therefore, it is important to study the means to remind these cells of their anti-tumor activity to take advantage of the body's natural "cancer-killing" function.
Surgery is a useful way to reduce the tumor burden of patients with locally advanced cancer. After surgery, subsequent therapies (called "adjuvant therapies") may be necessary to help keep cancer cells in check. Although surgery is useful in reducing the tumor, it can also modify the number and/or exacerbate the function of inflammatory cells. Therefore, it is important to study the means to remind these cells of their anti-tumor activity to take advantage of the body's natural "cancer-killing" function.
Investigated Applications:
Photodynamic Therapy.
Photo: Penn Medicine
Immunotherapy. Source: Penn Medicine
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Photodynamic TherapyPhotodynamic therapy (PDT) is a form of non-ionizing radiation in which patients are administered a photosensitizer (PS), which accumulates in the membrane, mitochondria, and lysosomes of tumor cells. The tumor is then treated with laser light, causing the photosensitizer to activate and generate highly-energetic oxygen species (singlet oxygen). This oxygen can then modify the chemical composition of the biomolecules, leading to cell death.
Although the initial treatment can kill many tumor cells, residual disease can be kept at bay by the immune effects of PDT. PDT is well-known to re-establish a pro-inflammatory, anti-tumoral inflammatory state marked by neutrophil influx and the engagement of dendritic cells. This results, in many cases, to the restoration of anti-tumor immunity. ImmunotherapyImmunotherapy exploits the signaling of immune cells (or even the immune cells themselves) in order to utilize the body's own immune system against the tumor. Although the approaches of this wide field are vast, they all seek to do one thing: teach the body how to fight the cancer itself. If surgery and/or PDT initiate an inflammatory response, it follows that we might be able to exploit that response to enhance immunotherapy.
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Project Highlights:
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Developing a model of surgical inflammation: As a first step, we needed a murine model of surgical inflammation that would allow tumors to enter a study at the same time and size as those which would not receive any insults from surgery.
We developed a model we term "tumor incision" (TI). In this model, the tumor is exposed via creation of a skin flap, the tumor is incised across its longest diameter, and the skin is sutured shut. This generates the same release of inflammatory cytokines as was observed in patients from our ongoing clinical trial for advanced-stage (Stage III/IV) mesothelioma. |
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Neutrophil activity predicts the response to PDT: Neutrophils are truly unique cells in inflammation. Based on the environment they are in, neutrophils can either help or hinder the growth of cancer cells. If surgery, which is required to remove the bulk of the disease, attracted and modified neutrophils, what if we could control their function to achieve the best response from adjuvant PDT?
First, we needed to demonstrate the direct correlation between neutrophil function and PDT response. We also needed a way to measure their presence in the tumor over the course of treatment. During the course of my graduate work, I observed the use of luminol to detect the activity of the enzyme myeloperoxidase to produce measurable light ('chemiluminescence'). As neutrophils contain myeloperoxidase, we determined luminol would be a useful tool for measuring PDT-generated inflammation. Taking it one step further, we demonstrated that the level of chemiluminescence predicted tumors that wouldn't regrow after 90 days. |
Additional Experience:
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Bioinformatics
Bioinformatics utilizes computers to analyze biological data. In my graduate work, I determined ways to combine various genetic data to automate the construction and analyze the content of bacterial genomes. This was useful in investigating a strain of bacteria isolated in the 1940's as a "time capsule" of antibiotic resistance. Multi-spectral Optoacoustic Tomography (MSOT)
MSOT is a new tool in imaging small animal biology. The technology works by exciting tissue using a high-powered laser, and measuring the sound released as that tissue relaxes. As in other imaging modalities, two-dimensional ultrasound images can be reconstructed into three-dimensional volumes. Due to the nature of the device, detection of probes is based on their excitation capacity, and not emission through tissue (and therefore ignores many tissue-based effects). I had the opportunity to develop protocols using an iThera Medical MSOT imaging device. |