Near-infrared (NIR) photothermal therapy (PTT) of solid tumors utilizes localized heat to induce the immunogenic death of tumor cells. The combination of PTT with checkpoint inhibitor therapy can further amplify the immune response and improve the therapeutic outcome in what is known as photothermal immunotherapy. Here, we introduce a triple therapy, where photothermal immunotherapy is further amplified by the pharmacological silencing of tumor-infiltrating sensory neurons, an approach that was recently shown to affect tumor immunosurveillance as a standalone treatment .
For our model, B16F10-OVA melanoma cells were injected subcutaneously in mice. Once the tumors reached approximately 200 mm3, they were treated by NIR laser irradiation, with a local silencing of nociceptors using an lidocaine derivative (QX-314), and immunotherapy alone (aPDL1) or in combination.
We employed mathematical modeling to predict heat distribution and necrotic tissue in mice bearing melanoma tumors. Our model utilized experimentally defined parameters, such as tissue optical properties, tumor size, laser beam size and power, and irradiation time. The model was experimentally validated using data on tumor temperature increases. We found that the tumor size is a key determinant of temperature increase, which underscores the need for personalized treatment conditions . We determined optimal treatment conditions (808 nm, 0.3 W/cm2, 3 min) for mice bearing 200 mm3 tumors.
Laser treatment was subsequently applied either alone (Laser+) or in combination with immunotherapy (aPDL1+) and neuronal silencing (QX-314+). When compared to control groups, the triple therapy (Laser+, QX-314+, and aPDL1+) significantly decreases tumor progression (p=0.0003) and increases survival time. Specifically, it resulted in complete ablation in 42% of the treated mice. Tumor re-growth was observed in only 16% of rechallenged mice, suggesting an immune memory effect.
Our results indicated that triple treatment can lead to a significant reduction in tumor growth and could complete tumor ablation in a significant fraction of the treated mice.