Cancer immunotherapy has been the subject of extensive research, but highly effective and broadly applicable methods remain elusive. Moreover, a general approach to engender endogenous patient-specific cellular therapy, without the need for a priori knowledge of tumor antigen, ex vivo cellular manipulation, or cellular manufacture, could dramatically reduce costs and broaden accessibility. Here, we describe a biotechnology based on synthetic, biodegradable nanoparticles that can genetically reprogram cancer cells and their microenvironment in situ so that the cancer cells can act as tumor-associated antigen-presenting cells (tAPCs) by inducing coexpression of a costimulatory molecule (4-1BBL) and immunostimulatory cytokine (IL-12). In B16-F10 melanoma and MC38 colorectal carcinoma mouse models, reprogramming nanoparticles in combination with checkpoint blockade significantly reduced tumor growth over time and, in some cases, cleared the tumor, leading to long-term survivors that were then resistant to the formation of new tumors upon rechallenge at a distant site. In vitro and in vivo analyses confirmed that locally delivered tAPC-reprogramming nanoparticles led to a significant cell-mediated cytotoxic immune response with systemic effects. The systemic tumor-specific and cell-mediated immunotherapy response was achieved without requiring a priori knowledge of tumor-expressed antigens and reflects the translational potential of this nanomedicine.
After ocular surgery, patients routinely receive multiple medications including antibiotics, steroids and ocular hypotensives to ensure optimal surgical outcomes. The current standard of care for postoperative treatment after ocular surgery involves using eye drops daily, which has limited effectiveness mainly due to poor patient adherence. To improve patient experience and outcomes, this article presents the first thermoresponsive hydrogel able to release multiple drug molecules for the application of post-operative treatment following ocular surgery. By varying the parameters such as hydrogel type and polymer hydrophobicity, the drug release profile, duration and dosage can finely be tuned. The approach presented in this article can readily be applied to other applications by simply changing the drug loaded in the drug delivery system.
Introduction: Neuroinflammation has been linked to poor neurologic and functional outcomes in many cerebrovascular disorders. Immune checkpoints are upregulated in the setting of traumatic brain injury, intracerebral hemorrhage, ischemic stroke, central nervous systems vasculitis, and post-hemorrhagic vasospasm, and are potential mediators of pathologic inflammation. Burgeoning evidence suggests that immune checkpoint modulation is a promising treatment strategy to decrease immune cell recruitment, cytokine secretion, brain edema, and neurodegeneration. Areas covered: This review discusses the role of immune checkpoints in neuroinflammation, and the potential for therapeutic immune checkpoint modulation in inflammatory cerebrovascular disorders. A search of Pubmed and clinicaltrials.gov was performed to find relevant literature published within the last 50 years. Expert opinion: The clinical success of immune-activating checkpoint modulators in human cancers has shown the immense clinical potential of checkpoint-based immunotherapy. Given that checkpoint blockade can also precipitate a pathologic pro-inflammatory or autoimmune response, it is plausible that these pathways may also be targeted to quell aberrant inflammation. A limited but growing number of studies suggest that immune checkpoints play a critical role in regulating the immune response in the central nervous system in a variety of contexts, and that immune-deactivating checkpoint modulators may be a promising treatment strategy for acute and chronic neuroinflammation in cerebrovascular disorders.
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