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Study Description

Numerous environmental and iatrogenic pro-oxidative stressors ranging from chemotherapy to ultraviolet radiation have been demonstrated to induce immunosuppression in preclinical murine (mouse) models. These stressors have also been shown to be potent inducers of the lipid mediator platelet-activating factor (PAF), which exerts immunosuppressive effects in murine models. The previous work has characterized the exact pathways by which PAF-dependent immunosuppression occurs and have identified a major role of regulatory T cells (Treg). PAF released from injury acts upon the mast cell PAF receptor resulting in the formation of immunosuppressive Tregs. This process is dependent upon the cytokine IL-10 and cyclooxygenase-2 (COX-2) generated prostaglandins. Though high levels of PAF has been shown to be generated in humans in response to many of the immunosuppressive stressors that induce PAF in animal models, studies are needed to define if this PAF COX-2Treg pathway is functional in humans.

The study team has found that topical photodynamic therapy (PDT) is a very potent inducer of PAF in murine skin, and induces systemic immunosuppression only in mice expressing PAF receptors. Therefore, this study is designed to test if the PAF COX-2 Treg pathway is involved in PDT-induced effects and could be pharmacologically modulated with COX-2 inhibitors to block the immunosuppression and potentially improve PDT efficacy in treating precancerous actinic keratoses lesions.

The study will test if standard PDT performed in dermatology clinics generates: 1) PAF and related oxidized glycerophosphocholines in skin; 2) systemic isoprostanes in response to reactive oxygen species; and 3) systemic COX-produced prostaglandins. The study team will also characterize the immunosuppressive effects of PDT in humans by both skin testing, and assaying Tregs and T cell responses against established and neo-antigens. The ability of short-term post-PDT treatment with the COX-2 inhibitor celecoxib to modulate PDT-mediated immunosuppression and clinical effectiveness will also be defined. These translational studies will thus define if a previously unappreciated immunomodulatory pathway is engaged following PDT which can be exploited to enhance treatment outcomes. If successful, these studies will change the standard of care for how PDT is administered.

ELIGIBILITY CRITERIA:

Ages Eligible for Study:           45 Years and older   (Adult, Older Adult)

Sexes Eligible for Study:          All

Accepts Healthy Volunteers:  Yes

Inclusion Criteria:

Inclusion Criteria for Control Subjects:

• Adult age 45 or older
• Caucasian (Fair skin, Fitzpatrick types I and II)
• Ability to understand and consent to the instructions of the study
• Have access to stable transportation

Inclusion Criteria for Study Subjects:

• Wright State University dermatologist has prescribed PDT for the treatment of actinic damage (Presence of precancerous actinic keratoses whose treatment necessitates PDT with the BLU-U).
• Undergoing PDT on greater than 5% body surface area: face and scalp, face and dorsal surface of arms, face and chest, face and back, or dorsal surface of arms alone, chest alone, or back alone.
• Caucasian (Fair skin, Fitzpatrick types I and II)
• Adult-age 45 or older
• Ability to understand the informed consent and comply with instructions and have stable transportation.

Exclusion Criteria:

• PDT on less than 5% body surface area (eg, forehead)
• Present treatment with corticosteroids or Non-steroidal inflammatory drugs (e.g., cyclooxygenase inhibitors) within past 2 months (except low-dose 81 mg aspirin).
• On antioxidant supplements (e.g., vitamin C) for past 2 months
• Tanning bed use within last 3 months
• PDT treatments within last 3 months
• Significant health issues that could affect the immune system (e.g., uncontrolled Diabetes Mellitus, Rheumatoid arthritis, skin rashes, psoriasis) that could interfere with testing
• Pregnant or nursing
• No immunosuppression, and on no immunosuppressive medications or NSAIDS within past 30 days (except low-dose [81 mg daily] aspirin).
• No significant underlying diseases that could potentially interfere with the immune assays or cardiac or renal or liver problems.
• History of blood clot or hypercoagulable state or GI bleed/ulceration.

Study Design:

Allocation: Randomized

Intervention Model: Parallel Assignment

Masking: Double (Participant, Investigator)

Primary Purpose: Prevention

Study Location(s):

Wright State University, Dayton, Ohio, United States, 45435

Study Website:

https://clinicaltrials.gov/ct2/show/NCT03643744?term=NCT03643744&rank=1