Nanoparticle-based Photothermal Therapy to Treat Solid Tumors
Open AccessStandard-of-care therapies against aggressive solid tumors can yield promising response, but recurrence and therapy-related side effects are common. One reason for recurrence is that cancer undergoes immunoediting to express markers that can suppress immune activity to allow for tumor escape and progression. Nanoparticle-based photothermal therapy (PTT) rapidly debulks tumors while generating immunogenic cell death, a type of cell death where damage-associated molecular patterns are expressed to initiate an immune response. Yet, as monotherapy, PTT commonly exhibits recurrence, limiting its clinical potential. Immunotherapies can significantly enhance PTT-induced tumor control and generate a systemic response. I hypothesized that introducing strategies to eliminate post-PTT treatment recurrence, by combining with immunoepigenetic therapy or enhancing PTT ablation, could boost antitumor response and immunity. In Chapter 2 of my dissertation, I evaluated a nanoengineered approach that combined PTT and Histone deacetylase 6 inhibitor (HDAC6i) agents in a single nanoparticle to eliminate melanoma tumors. Combination therapy marginally increased median survival in vivo, with sustained HDAC6 reducing the tumor growth rate. Interestingly, combination therapy in vitro exhibited synergy in upregulating MHC-I expression. In Chapter 3, Prussian blue nanoparticles (PBNPs) conjugated to anti-Fn14 antibody demonstrated high retention of PBNPs on Fn14-expressing glioblastoma cells in vitro as a proof-of-concept nanotherapeutic for targeted PBNP-PTT. For Chapter 4, PBNPs injected into neuroblastoma were interstitially illuminated to assess interstitial-PTT (I-PTT). I-PTT generated higher heating efficiency and expanded the treatment zone, reducing recurrence with tumor-dependent long-term tumor protection. Lastly, Chapter 5 evaluates the immune response after PBNP-PTT and associated with long-term tumor protection. More CD8 T cells were in circulation after treatment. Successful long-term protection demonstrated baseline T cell levels, whereas lymphatic NK cells were higher. TLR9-agonist CpG in CpG-PBNP-PTT induced DC levels in distant lymph nodes and were associated with T cell expansion. This dissertation details nanoparticle-based approaches to improve PTT against solid tumors and presents a preclinical strategy for interstitial laser ablation. Altogether, my results suggest that enhancing the PTT ablation improves local tumor control, while the long-term tumor protection has a promising immune response that could benefit from immunotherapies to immunologically target and regress distant tumors. PTT, with complementary adjuvants, could effectively harness local and immune-driven systemic tumor control, supporting its translation for immune-oncology.
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