Browsing by Author "Aghlara-Fotovat, Samira"

Now showing 1 - 3 of 3
  • Thumbnail Image
    Item
    Activation of Adaptive and Innate Immune Cells via Localized IL2 Cytokine Factories Eradicates Mesothelioma Tumors
    (AACR, 2022) Nash, Amanda M.; Aghlara-Fotovat, Samira; Castillio, Bertha; Hernandez, Andrea; Pugazenthi, Aarthi; Lee, Hyun-Sung; Jang, Hee-Jin; Nguyen, Annie; Lu, Alexander; Burt, Bryan M.; Ghanta, Ravi K.; Veiseh, Omid
    IL2 immunotherapy has the potential to elicit immune-mediated tumor lysis via activation of effector immune cells, but clinical utility is limited due to pharmacokinetic challenges as well as vascular leak syndrome and other life-threatening toxicities experienced by patients. We developed a safe and clinically translatable localized IL2 delivery system to boost the potency of therapy while minimizing systemic cytokine exposure.We evaluated the therapeutic efficacy of IL2 cytokine factories in a mouse model of malignant mesothelioma. Changes in immune populations were analyzed using time-of-flight mass cytometry (CyTOF), and the safety and translatability of the platform were evaluated using complete blood counts and serum chemistry analysis.IL2 cytokine factories enabled 150× higher IL2 concentrations in the local compartment with limited leakage into the systemic circulation. AB1 tumor burden was reduced by 80% after 1 week of monotherapy treatment, and 7 of 7 of animals exhibited tumor eradication without recurrence when IL2 cytokine factories were combined with anti–programmed cell death protein 1 (aPD1). Furthermore, CyTOF analysis showed an increase in CD69+CD44+ and CD69−CD44+CD62L− T cells, reduction of CD86−PD-L1− M2-like macrophages, and a corresponding increase in CD86+PD-L1+ M1-like macrophages and MHC-II+ dendritic cells after treatment. Finally, blood chemistry ranges in rodents demonstrated the safety of cytokine factory treatment and reinforced its potential for clinical use.IL2 cytokine factories led to the eradication of aggressive mouse malignant mesothelioma tumors and protection from tumor recurrence, and increased the therapeutic efficacy of aPD1 checkpoint therapy. This study provides support for the clinical evaluation of this IL2-based delivery system.See related commentary by Palanki et al., p. 5010
  • Thumbnail Image
    Item
    Assessing Gq-GPCR–induced human astrocyte reactivity using bioengineered neural organoids
    (Rockefeller University Press, 2022) Cvetkovic, Caroline; Patel, Rajan; Shetty, Arya; Hogan, Matthew K.; Anderson, Morgan; Basu, Nupur; Aghlara-Fotovat, Samira; Ramesh, Srivathsan; Sardar, Debosmita; Veiseh, Omid; Ward, Michael E.; Deneen, Benjamin; Horner, Philip J.; Krencik, Robert
    Astrocyte reactivity can directly modulate nervous system function and immune responses during disease and injury. However, the consequence of human astrocyte reactivity in response to specific contexts and within neural networks is obscure. Here, we devised a straightforward bioengineered neural organoid culture approach entailing transcription factor–driven direct differentiation of neurons and astrocytes from human pluripotent stem cells combined with genetically encoded tools for dual cell-selective activation. This strategy revealed that Gq-GPCR activation via chemogenetics in astrocytes promotes a rise in intracellular calcium followed by induction of immediate early genes and thrombospondin 1. However, astrocytes also undergo NF-κB nuclear translocation and secretion of inflammatory proteins, correlating with a decreased evoked firing rate of cocultured optogenetic neurons in suboptimal conditions, without overt neurotoxicity. Altogether, this study clarifies the intrinsic reactivity of human astrocytes in response to targeting GPCRs and delivers a bioengineered approach for organoid-based disease modeling and preclinical drug testing.
  • Thumbnail Image
    ItemEmbargo
    Encapsulated Cell Systems for Treating Inflammatory Diseases
    (2024-04-19) Aghlara-Fotovat, Samira; Veiseh, Omid; Ghanta, Ravi K
    In response to pathogens and trauma, host immune cells interact bi-directionally with their local environment to receive and deposit molecular signals, which orchestrate cellular activation, proliferation, differentiation, and function to maintain healthy tissue homeostasis. While our immune system functions as a vigilant safeguard against environmental threats, instances of immune dysregulation may occur, leading to uncontrolled responses. In these conditions, it is essential to restore balance to the body through modulation of the immune system and the ECM. Cell-based therapeutics have significant potential in locally monitoring and treating inflammatory diseases, however, their widespread use is hindered by recognition and elimination by the host. Thus, novel technologies that can improve the viability and function of cell-based therapies have significant potential in improving translation. Here, we aim to utilize biomaterial encapsulation as a tool for improving the delivery of cell-based therapeutics for local immunomodulation in various inflammatory diseases including myocardial infarct, acute respiratory distress syndrome, neural inflammation, inflammatory bowel disease.