# Project 4: Modulating the natural killer cell response to oHSV1 in recurrent human GBM > **NIH NIH P01** · BRIGHAM AND WOMEN'S HOSPITAL · 2020 · $319,944 ## Abstract PROJECT SUMMARY – PROJECT 4 The ultimate goal of this proposal is to understand the role of innate immunity within the context of oncolytic herpes simplex viral (oHSV) therapy for glioblastoma (GBM), a highly fatal brain tumor. oHSV treatment of GBM relies on cancer-specific replication of the virus leading to tumor destruction with minimal toxicity to adjacent non-neoplastic tissue. Its safety in patients has been proven, yet evidence for significant efficacy remains to be established. Project 4 will focus on the host's natural killer (NK) cell response following oHSV administration. Due to their strong antiviral properties, NK cells represent a potential barrier to oHSV therapy. Alternatively, the anti-tumor NK cell response has the potential of augmenting the tumor clearing properties of oHSV therapy. Our previously published studies demonstrated that: 1) NK cells rapidly respond oHSV and eliminate the virus before it can effectively replicate and disseminate throughout the GBM; 2) transient immune modulation delaying the NK cell response to oHSV, even with a single injection of TGF-beta, significantly enhances oHSV replication, spread and anti-tumor efficacy following inoculation. As a result, we hypothesize that NK cells coordinate a robust inflammatory response following initial oHSV administration that limits oHSV replication, spread, and tumor lysis, thereby creating a barrier to effective oHSV therapy for GBM. A corollary to this hypothesis is that by understanding how NK cells recognize oHSV-infected GBM we can best modulate this process so as to optimize this highly selective therapy for GBM. We therefore recently developed a novel assay whereby we cloned each HSV1 gene into a vector that allowed us to determine its ability to either induce or inhibit NK cell activation. We discovered the mechanism by which NK cells recognize and destroy HSV-infected targets prior to the development of a primary immune response. We term this fundamental, novel discovery passive antibody dependent cellular cytotoxicity or passive ADCC, whereby the Fc fragment of IgG (IgGFc) forms a bridge between the NK cell Fc receptor for IgGFc, called CD16, and the GBM cell expressing HSV Us8, which encodes the Fc binding protein glycoprotein E (gE). The CD16-IgGFc-gE ternary complex activates NK cells to destroy oHSV-infected GBM without the requirement for the antigen-specific Fab portion of IgG. In this proposal, Project 4 will: (1) further investigate passive ADCC to best understand how to modulate the process so as to enhance the efficacy of oHSV therapy for GBM with Project 1; (2) determine the role of TGF-β signaling in regulating the NK cell interaction with oHSV-encoded viral proteins, specifically as relates to passive ADCC and to NOTCH signaling with Project 3; (3) To assess the NK cell immune response in patients with recurrent GBM who will be receiving our oHSV, rQNestin34.5 in Project 2. By elucidating how NK cells recognize and destroy oHSV- infected t... ## Key facts - **NIH application ID:** 10019366 - **Project number:** 5P01CA163205-08 - **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL - **Principal Investigator:** MICHAEL A CALIGIURI - **Activity code:** P01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2020 - **Award amount:** $319,944 - **Award type:** 5 - **Project period:** 2013-02-07 → 2023-08-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10019366 ## Citation > US National Institutes of Health, RePORTER application 10019366, Project 4: Modulating the natural killer cell response to oHSV1 in recurrent human GBM (5P01CA163205-08). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10019366. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*