Enhancing Immunogenicity in Metastatic Melanoma: Adjuvant Therapies to Promote the Anti-Tumor Immune Response.

Advanced melanoma is an aggressive form of skin cancer characterized by low survival rates. Less than 50% of advanced melanoma patients respond to current therapies, and of those patients that do respond, many present with tumor recurrence due to resistance. The immunosuppressive tumor-immune microenvironment (TIME) remains a major obstacle in melanoma therapy. Adjuvant treatment modalities that enhance anti-tumor immune cell function are associated with improved patient response. One potential mechanism to stimulate the anti-tumor immune response is by inducing immunogenic cell death (ICD) in tumors. ICD leads to the release of damage-associated molecular patterns within the TIME, subsequently promoting antigen presentation and anti-tumor immunity. This review summarizes relevant concepts and mechanisms underlying ICD and introduces the potential of non-ablative low-intensity focused ultrasound (LOFU) as an immune-priming therapy that can be combined with ICD-inducing focal ablative therapies to promote an anti-melanoma immune response.

Surface-Modified Shortwave-Infrared-Emitting Nanophotonic Reporters for Gene-Therapy Applications.

Gene therapy is emerging as the next generation of therapeutic modality with United States Food and Drug Administration approved gene-engineered therapy for cancer and a rare eye-related disorder, but the challenge of real-time monitoring of on-target therapy response remains. In this study, we have designed a theranostic nanoparticle composed of shortwave-infrared-emitting rare-earth-doped nanoparticles (RENPs) capable of delivering genetic cargo and of real-time response monitoring. We showed that the cationic coating of RENPs with branched polyethylenimine (PEI) does not have a significant impact on cellular toxicity, which can be further reduced by selectively modifying the surface characteristics of the PEI coating using counter-ions and expanding their potential applications in photothermal therapy. We showed the tolerability and clearance of a bolus dose of RENPs@PEI in mice up to 7 days after particle injection in addition to the RENPs@PEI ability to distinctively discern lung tumor lesions in a breast cancer mouse model with an excellent signal-to-noise ratio. We also showed the availability of amine functional groups in the collapsed PEI chain conformation on RENPs, which facilitates the loading of genetic cargo that hybridizes with target gene in an in vitro cancer model. The real-time monitoring and delivery of gene therapy at on-target sites will enable the success of an increased number of gene- and cell-therapy products in clinical trials.

Engineering Lineage Potency and Plasticity of Stem Cells using Epigenetic Molecules.

Stem cells are considered as a multipotent regenerative source for diseased and dysfunctional tissues. Despite the promise of stem cells, the inherent capacity of stem cells to convert to tissue-specific lineages can present a major challenge to the use of stem cells for regenerative medicine. We hypothesized that epigenetic regulating molecules can modulate the stem cell's developmental program, and thus potentially overcome the limited lineage differentiation that human stem cells exhibit based on the source and processing of stem cells. In this study, we screened a library of 84 small molecule pharmacological agents indicated in nucleosomal modification and identified a sub-set of specific molecules that influenced osteogenesis in human mesenchymal stem cells (hMSCs) while maintaining cell viability in-vitro. Pre-treatment with five candidate hits, Gemcitabine, Decitabine, I-CBP112, Chidamide, and SIRT1/2 inhibitor IV, maximally enhanced osteogenesis in-vitro. In contrast, five distinct molecules, 4-Iodo-SAHA, Scriptaid, AGK2, CI-amidine and Delphidine Chloride maximally inhibited osteogenesis. We then tested the role of these molecules on hMSCs derived from aged human donors and report that small epigenetic molecules, namely Gemcitabine and Chidamide, can significantly promote osteogenic differentiation by 5.9- and 2.3-fold, respectively. Taken together, this study demonstrates new applications of identified small molecule drugs for sensitively regulating the lineage plasticity fates of bone-marrow derived mesenchymal stem cells through modulating the epigenetic profile of the cells.