Near-infrared photoimmunotherapy (NIR-PIT) is a newly developed cancer therapy that targets cancer cells using a monoclonal antibody-photon absorber conjugate (APC) that is bound to the target cell surface. Subsequent application of low levels of NIR light results in immediate cancer cell death. The anti-tumor effect of NIR-PIT in immunocompromised mice depends on immediate cancer cell death; therefore, the efficacy increases in a light-dose-dependent manner. However, NIR-PIT also induces a strong anti-tumor immune activation in immunocompetent mice that begins soon after therapy. Thus, it may be possible to reduce the light dose, which might otherwise cause local edema while maintaining therapeutic efficacy. In this study, we determined the optimal dose of NIR light in NIR-PIT based on a comparison of the therapeutic and adverse effects. Either one of two monoclonal antibodies (mAbs) against human epidermal growth factor receptor (hEGFR), Cetuximab or Panitumumab, were conjugated with a photo-absorbing chemical, IRDye700DX (IR700), and then injected in hEGFR-expressing mEERL (mEERL-hEGFR) tumor-bearing C57BL/6 immunocompetent mice or A431-GFP-luc tumor-bearing athymic immunocompromised mice. NIR light was varied between 0 to 100 J/cm² one day after administration of APC. In an immunocompromised mouse model, tumor growth was inhibited in a light-dose-dependent manner, yet extensive local edema and weight loss were observed at 100 J/cm². On the other hand, in an immunocompetent mouse model using the mEERL-hEGFR cell line, maximal tumor response was achieved at 50 J/cm², with a commensurate decrease in local edema. In this study, we show that a relatively low dose of NIR light is sufficient in an immunocompetent mouse model and avoids side effects seen with higher light doses required in immunocompetent mice. Thus, light dosing can be optimized in NIR-PIT based on the expected immune response.

Disialoganglioside (GD2) is a subtype of glycolipids that is highly expressed in tumors of neuroectodermal origins, such as neuroblastoma and osteosarcoma. Its limited expression in normal tissues makes GD2 a potential target for precision therapy. Several anti-GD2 monoclonal antibodies are currently in clinical use and have had moderate success. Near-infrared photoimmunotherapy (NIR-PIT) is a cancer therapy that arms antibodies with IRDye700DX (IR700) and then exposes this antibody–dye conjugate (ADC) to NIR light at a wavelength of 690 nm. NIR light irradiation induces a profound photochemical response in IR700, resulting in protein aggregates that lead to cell membrane damage and death. In this study, we examined the feasibility of GD2-targeted NIR-PIT. Although GD2, like other glycolipids, is only located in the outer leaflet of the cell membrane, the aggregates formation exerted sufficient physical force to disrupt the cell membrane and kill target cells in vitro. In in vivo studies, tumor growth was significantly inhibited after GD2-targeted NIR-PIT, resulting in prolonged survival. Following GD2-targeted NIR-PIT, activation of host immunity was observed. In conclusion, GD2-targeted NIR-PIT was similarly effective to the conventional protein-targeted NIR-PIT. This study demonstrates that membrane glycolipid can be a new target of NIR-PIT.

Near-infrared photoimmunotherapy (NIR-PIT) is a newly developed and promising therapy that specifically destroys target cells by irradiating antibody-photo-absorber conjugates (APCs) with NIR light. APCs bind to target molecules on the cell surface, and when exposed to NIR light, cause disruption of the cell membrane due to the ligand release reaction and dye aggregation. This leads to rapid cell swelling, blebbing, and rupture, which leads to immunogenic cell death (ICD). ICD activates host antitumor immunity, which assists in killing still viable cancer cells in the treated lesion but is also capable of producing responses in untreated lesions. In September 2020, an APC and laser system were conditionally approved for clinical use in unresectable advanced head and neck cancer in Japan, and are now routine in appropriate patients. However, most tumors have been relatively accessible in the oral cavity or neck. Endoscopes offer the opportunity to deliver light deeper within hollow organs of the body. In recent years, the application of endoscopic therapy as an alternative to surgery for the treatment of cancer has expanded, providing significant benefits to inoperable patients. In this review, we will discuss the potential applications of endoscopic NIR-PIT, especially in thoracic and gastrointestinal cancers.