Near-infrared photoimmunotherapy (NIR-PIT) is a recently developed hybrid cancer therapy that directly kills cancer cells as well as producing a therapeutic host immune response. Conventional immunotherapies, such as immune-activating cytokine therapy, checkpoint inhibition, engineered T cells and suppressor cell depletion, do not directly destroy cancer cells, but rely exclusively on activating the immune system. NIR-PIT selectively destroys cancer cells, leading to immunogenic cell death that initiates local immune reactions to released cancer antigens from dying cancer cells. These are characterized by rapid maturation of dendritic cells and priming of multi-clonal cancer-specific cytotoxic T cells that kill cells that escaped the initial direct effects of NIR-PIT. The NIR-PIT can be applied to a wide variety of cancers either as monotherapy or in combination with conventional immune therapies to further activate anti-cancer immunity. A global Phase 3 clinical trial (https://clinicaltrials.gov/ct2/show/NCT03769506) of NIR-PIT targeting the epidermal growth factor receptor (EGFR) in patients with recurrent head and neck cancer is underway, employing RM1929/ASP1929, a conjugate of anti-EGFR antibody (cetuximab) plus the photo-absorber IRDye700DX (IR700). NIR-PIT has been given fast-track recognition by regulators in the USA and Japan. A variety of imaging methods, including direct IR700 fluorescence imaging, can be used to monitor NIR-PIT. As experience with NIR-PIT grows, additional antibodies will be employed to target additional antigens on other cancers or to target immune-suppressor cells to enhance host immunity. NIR-PIT will be particularly important in patients with localized and locally advanced cancers and may help such patients avoid side-effects associated with surgery, radiation and chemotherapy.

Near-infrared photoimmunotherapy (NIR-PIT), a newly developed cancer-cell-specific therapy, relies on a monoclonal antibody−photoabsorber conjugate (APC) and is based on a photoinduced ligand release reaction. Local exposure of the tumor to NIR light induces rapid immunogenic necrotic cell death. The molecular properties of APCs, including their stability and aggregation properties, have important implications for the longterm stability and shelf life. In this study, panitumumab was conjugated with IRDye700DX (IR700) as a model for other NIR-PIT agents. Higher IR700-to-mAb conjugation ratios correlated with increased in vitro cell death up to a ratio of 2.5 dye molecules per antibody. Conjugation ratios higher than 2.5 did not improve cell killing activity. APC aggregation was induced in a light-dosedependent manner. A near-room-level light dose was sufficient to induce aggregation of APCs. Solvent pH lower than 4 induced aggregation, but higher pH did not induce aggregation. The IR700-to-mAb conjugation ratio, light irradiation dose, and solvent pH affect the APC stability and efficacy.