Menghan Gao: Refining Next-Generation Cancer Immunotherapies

Abstract

Cancer immunotherapy has revolutionized cancer treatment by harnessing the immune system to eliminate malignant cells. However, durable clinical benefit is achieved in only a subset of patients, with poor responses typically observed in solid tumors characterized by an “immune-cold” tumor microenvironment (TME), such as glioblastoma and pancreatic ductal adenocarcinoma (PDAC). Oncolytic viruses (OVs) offer the dual advantage of direct tumor cell lysis and immune activation, yet their efficacy is often limited by insufficient or transient immune stimulation. Similarly, T cell-based therapies are constrained by functional exhaustion, limited persistence, and immunosuppressive signaling within the TME. This thesis aims to improve the efficacy and durability of next-generation cancer immunotherapies, with a focus on OVs and T cell-based therapies.

Papers I–III focus on improving OV-based immunotherapy through the incorporation of immunomodulatory payloads to amplify antitumor immune responses. In Paper I, we developed a dual-armed oncolytic adenovirus, Ad5f35(OBN), encoding the Th1-polarizing neutrophil-activating protein (NAP) and the co-stimulatory ligand 4-1BBL. This approach reprogrammed the TME toward a T cell-inflamed state and elicited systemic tumor-specific immune responses, which were associated with improved tumor control and survival in glioma and PDAC models.

In Paper II, we developed an oncolytic adenovirus, Ad5f35(OGN), that integrates xenogeneic αGal-mediated hyperacute rejection with Th1-polarizing immune activation to reprogram PDAC cells into an in situ vaccine. In anti-αGal mice, Ad5f35(OGN) treatment induced multifaceted immune activation, including expansion of activated B cells with antigen-presenting features and tumor-specific CD8+ T cells, which was associated with improved survival.

In Paper III, we aimed to potentiate anti-αGal-mediated complement activation in PDAC by incorporating a membrane-anchored properdin (mFP). Ectopic expression of mFP on tumor cells enhanced complement deposition, remodeled the TME, and improved tumor control in anti-αGal mice. Further engineering of an oligomerized mFP construct markedly increased complement activity, offering a strategy to overcome tumor tolerance to complement activation.

Paper IV investigates T cell-intrinsic regulators that govern T cell fitness in the TME. Using an unbiased genome-wide CRISPR-Cas9 loss-of-function screen in an orthotopic glioma model, we identified a translational checkpoint as a previously unrecognized regulator of T cell longevity.