Optimal Light Dose for hEGFR-Targeted Near-Infrared Photoimmunotherapy.

Abstract

Simple SummaryNear-infrared photoimmunotherapy (NIR-PIT) is a cancer therapy that selectively destroys target cells by first injecting monoclonal antibodies conjugated with a photon absorber (IRDye700DX) into the subject and then activating it at the tumor site by applying nonthermal doses of NIR light at 690 nm. NIR-PIT causes immediate immunogenic cell death but also induces a slightly delayed activation of anti-tumor host immunity which can result in complete responses. The immediate therapeutic effect of NIR-PIT can be enhanced by increasing the dose of near-infrared light irradiation; however, this can cause local side effects such as edema. Since the activation of host immunity also adds to the anti-tumor effect it might be possible to reduce the light dose to avoid immediate side effects while maintaining efficacy of the therapy. In this study, we varied the light dose needed to achieve the maximum therapeutic effect in an immunocompetent mouse model. We show that higher-than-needed light doses caused significant local transient edema that could be avoided with lower but still effective light doses. Here, we present our strategy for optimizing the light dose for NIR-PIT.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.