Disease-homing light delivery by engineering bioluminescent immune cells for whole body precision photomedicine

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PROJECT SUMMARY Photodynamic therapy (PDT) offers unique mechanisms of cell death and is used to treat many cancers in the clinic. The principal of phototherapy is that photoactive chemicals delivered to the disease site convert incident photonic energy into local chemical toxicity, avoiding a systemic shock. PDT is agnostic to classical drug- resistance pathways and does not cause critical co-morbidities, making it attractive as a monotherapy or as a component of multi-modal therapy. However, a major criticism of PDT is the need for an external light source, which limits the application of PDT to superficial lesions or those accessible by fiber optics. To overcome this, a paradigm shift in the mechanism of light delivery for PDT has recently emerged: bioluminescence (BL) mediated PDT (BL-PDT), wherein BL enzymes activate spectrally matched, co-localized photosensitizers (PS) within the lesion, eliminating the need for an external light source. Although this overcomes a major hurdle, current methods that leverage semiconductor nanoconstructs for BL enzyme delivery are limited in their ability to localize to the disease. Here, we propose a novel method for BL enzyme delivery and BL-PDT: to genetically engineer ultra-bright bioluminescent immune cells (UBLIs) and exploit their disease-homing capabilities, like chemotaxis, to traffic to and accumulate in sites of disease. This approach eliminates the need for complex and potentially toxic nanoconstructs as a component of drug delivery—only the BL substrate and PS administration (both non-toxic compounds) will be required. Recently, we introduced precision photomedicine using a targeted, activatable PS that exhibited cellular selectivity and reduced off-target toxicity in a metastatic cancer model. We will pair the proposed novel light delivery platform with precision photomedicine for maximal benefit. First, we will optimize the BL-PDT platform in 3D cancer–immune cell co- cultures across biologically and clinically relevant parameter spaces informed by Monte Carlo simulations. Then we will demonstrate the approach in vivo by intravenous injection of UBLIs into an in vivo xenograft model of cancer metastases informed by in vitro results. These proof-of-concept studies will enable comprehensive safety and efficacy studies in multiple disease models in future funding periods. Ultimately, we envision clinical translation involving extraction and engineering of patient immune cells, similar to chimeric antigen redirected (CAR) T cell therapy, followed by reinfusion and administration of photomedicine. This new therapeutic paradigm has potential to benefit many diseases in cancer and beyond, which justifies the high- risk, high-reward nature of the proposal.