Targeted therapy platform for eliciting memory-like NK cell responses

Natural killer (NK) cells are quintessential in the innate immune response, adept at eliminating cells compromised by viral infections. Their coordination with CD8+ T cells of the adaptive immune system is crucial, especially in countering the immunomodulatory strategies employed by pathogens and malignancies, such as the downregulation of MHC class I molecules to evade T cell surveillance. This evasion tactic, however, triggers an enhanced cytotoxic response from NK cells. HLA-E, a non-classical MHC class I molecule, has emerged as a key player in viral contexts by interacting with a specialized subset of NK cells now recognized as adaptive or memory-like NK cells. Despite being part of the innate immunity, these cells display memory-like capabilities, responding specifically to peptides through the NKG2C-HLA-E interaction. This has sparked interest in leveraging NK cell adaptability for cell therapies development. Yet, there are substantial obstacles in the expansion of NK cell-based treatments, notably concerning the NKG2C-HLA-E axis. Culturing NK cells is challenging, and there is a lack of commercially viable methods to consistently expand these cells for research or therapeutic use. At present, researchers use labor-intensive techniques involving stressed cell lines to present peptides on HLA-E, which are not only time-consuming but also suffer from reproducibility issues due to the difficulty in standardizing stress conditions. This limits the feasibility of large-scale peptide screening on HLA-E. To circumvent these limitations, we propose the development of a gold nanoparticle (GNP) platform that would provide a reliable, reproducible, and scalable approach for peptide presentation on HLA-E, adaptable for other targets as well. Our strategy involves using this platform to initially screen peptides related to HIV/SIV, aiming to stimulate and expand a memory-like NK cell population that can specifically recognize these peptides during infection or disease. Project Number: 1R03AI198047-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Daniel Ram (+1 co-PI) | Institution: UNIVERSITY OF CENTRAL FLORIDA, ORLANDO, FL | Award Amount: $146,948 | Activity Code: R03 | Study Section: HIV Immunopathogenesis and Vaccine Development Study Section[HIVD] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R03AI19804701