Combination immunotherapy and photodynamic therapy for cancer

Abstract Cancer is a leading cause of death among modern peoples largely due to metastatic disease. The ideal cancer treatment should target both the primary tumor and the metastases with the minimal toxicity. This is best accomplished by educating the body's immune system to recognize the tumor as foreign so that after the primary tumor is destroyed, distant metastases will also be eradicated. Photodynamic therapy (PDT) involves the IV administration of photosensitizers followed by illumination of the tumor with red light producing reactive oxygen species that eventually cause vascular shutdown and tumor cell apoptosis. Anti-tumor immunity is stimulated after PDT due to the acute inflammatory response, generation of tumor-specific antigens, and induction of heat-shock proteins, while the three commonest cancer therapies (surgery, chemotherapy and radiotherapy) all tend to suppress the immune system. Like many other immunotherapies, the extent of the immune response after PDT tends to depend on the antigenicity of the particular tumor. Combination regimens using PDT and immunostimulating treatments are likely to emerge in the future to even further enhance immunity. These are likely to include the so called biological response modifiers that generally consist of products obtained from pathogenic microorganisms against which mammals have evolved sophisticated defenses involving immune activation. A series of pattern recognition molecules including toll-like receptors have been identified that are activated by products derived from pathogens and lead to upregulation of transcription factors that induce expression of many cytokines and inflammatory mediators, which then cause activation of macrophages, dendritic and natural killer cells. There have been several reports of combinations of PDT with microbial derived products potentiating tumor response and leading to long-term anti-tumor immunity. In recent years the role of regulatory T-cells in suppressing anti-tumor immunity has been identified. Treatments such as low dose cyclophosphamide that selectively reduces T-regulatory cells can also be combined with PDT. Methods may be developed to increase the expression of particular tumor antigens before PDT. Although so far these combination therapies have only been used in animal models, their use in clinical trials should receive careful consideration.