Forging Forward in Photodynamic Therapy

Abstract

In 1978, a Cancer Research article by Dougherty and colleagues reported the first large-scale clinical trial of photodynamic therapy (PDT) for treatment of 113 cutaneous or subcutaneous lesions associated with ten different kinds of malignancies. In classic applications, PDT depends on excitation of a tissue-localized photosensitizer with wavelengths of visible light to damage malignant or otherwise diseased tissues. Thus, in this landmark article, photosensitizer (hematoporphyrin derivative) dose, drug-light interval, and fractionation scheme were evaluated for their therapeutic efficacy and normal tissue damage. From their observations came early evidence of the mechanisms of PDT's antitumor action, and in the decades since this work, our knowledge of these mechanisms has grown to build an understanding of the multifaceted nature of PDT. These facets are comprised of multiple cell death pathways, together with antivascular and immune stimulatory actions that constitute a PDT reaction. Mechanism-informed PDT protocols support the contribution of PDT to multimodality treatment approaches. Moreover, guided by an understanding of its mechanisms, PDT can be applied to clinical needs in fields beyond oncology. Undoubtedly, there still remains more to learn; new modes of cell death continue to be elucidated with relevance to PDT, and factors that drive PDT innate and adaptive immune responses are not yet fully understood. As research continues to forge a path forward for PDT in the clinic, direction is provided by anchoring new applications in mechanistically grounded protocol design, as was first exemplified in the landmark work conducted by Dougherty and colleagues. See related article by Dougherty and colleagues, Cancer Res 1978;38:2628-35.

Figure 1.. PDT actions.

Mechanisms of action of PDT have been investigated since the first studies of PDT as a cancer treatment. Early observations of PDT-treated tissues included evidence of vascular effects, subsequently identified as vasoconstriction, occlusion, platelet aggregation, which functionally lead to reductions in tissue perfusion and hyperpermeability. Direct cytotoxicity mediated by ¹O₂ (or other PDT-generated reactive species) was first shown to contribute to tumor necrosis and apoptosis, which are now joined by more recently identified cell death pathways such as autophagy and paraptosis. Innate immune response in the form of inflammation was noted early as a characteristic effect of PDT and later accompanied by identification of cytokine and chemokine release, together with local accumulation of innate immune cells such as neutrophils, granulocytic-myeloid derived suppressor cells (G-MDSCs), tissue macrophages, blood monocytes, monocytic-myeloid derived suppressor cells (M-MDSCs), and natural killer (NK) cells. Observations of adaptive antitumor immunity followed, grounded in the response of CD4+ and CD8+ T cells, aided by antigen presentation in the context of major histocompatibility complex (MHC I/II) by dendritic cells in tumor-draining lymph nodes. With an understanding of immunogenic cell death, recognition was given to the immunological contributions of PDT generated tumor-associated antigens and damage associated molecular patterns (DAMPs) released by treated cells. Appreciation also now exists for the role of immune checkpoint modulation in the generation of adaptive immunity in response to PDT; PD-1 on T cells can interact with PD-L1/PD-L2 expressed on tumors or myeloid cells, inhibiting T cell targeting, and similarly, CTLA-4 (inhibitory) and CD28 (stimulatory) on T cells compete for binding with ligands CD80/CD86 on antigen presenting cells. Figure components were adapted from Cramer et al. (2020) Photochemistry and Photobiology 96 (5), 954-961.