Homogeneous drug delivery to solid tumors is difficult to achieve because of biological barriers in the tumor and of its elevated interstitial fluid pressure. We investigated the distribution of a photosensitizer (redaporfin) in orthotopic 4T1 and subcutaneous CT26 tumors using photoacoustic tomography. Redaporfin has a distinct photoacoustic spectrum that allows for its localization and relative quantification. Whereas CT26 tumors uptake a large amount of redaporfin, 4T1 tumors have redaporfin mostly in their periphery. We exposed 4T1 tumors to high-intensity, broadband photoacoustic waves and show that the amount of redaporfin in 4T1 tumors increases after 5 minutes of exposure. Photoacoustic waves are a promising non-invasive method to increase drug delivery to solid tumors.
Vascular photodynamic therapy (PDT) with redaporfin was shown to destroy the primary tumor and to reduce the development of distant cancer lesions in animal models, thus suggesting anti-tumor immunity.
Vascular-PDT with redaporfin triggers an acute local inflammation, neutrophilia and leads to an increase in CD4+/CD8+ T cells ratio, which has been correlated with increased survival rates in cancer patients, and further corroborates the activation of the adaptive immune system a few hours post-PDT. Previous experiments also confirmed the importance of some cell populations that are increased in response to PDT (CD4+ and CD8+ T cells expressing IFNγ,). Specific inhibition with monoclonal antibodies revealed significant decreases in percentage of survival of CD8+ T cells depleted animals, in comparison with PDT alone.
To evaluate if combinatorial therapies in animal model would led to synergies between PDT and immunotherapy, we evaluated the therapeutic outcome of the combination between redaporfin-PDT and immune checkpoint blockers (ICB). ICB’s function as boosters of tumor immunity through reversing T-cell exhaustion and are an emerging immunotherapeutic modality. Our experiments with mice bearing CT26WT tumors revealed an improvement of redaporfin-PDT outcome when combined with anti-CTLA-4 antibody therapy, but no significant differences were observed with anti-PD-1.
On-going experiments intend to clarify about the immune infiltrates variations in the tumor bed after combinatorial approaches, as well as to validate these results in a second animal model.
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