Tumor-targeted immunotherapy using an engineered adenoviral vector platform

In spite of clinical success, cancer immunotherapy still fails to evoke durable tumor rejection in the vast majority of patients. While the current treatment modalities are predominantly T cell-centric, leaving aside the impact of innate immunity, recent evidence has highlighted the fundamental role of innate immune cells in orchestrating cancer immunity. In this work, I present how enhanced anti-cancer immunity can be achieved by rationally engaging key cellular interplays of both adaptive and innate immunity utilizing adenoviral vectors: First, I introduce a modular assembly system for the efficient generation and production of high-capacity adenoviral vectors as a platform for tumor-targeted cancer immunotherapy. As proof of concept, we show that a single HCAdV encoding the cytokines IL-2, IL-12, as well as an anti-PD-1 antibody, yielded comparable amounts of payloads produced by a mixture of single-payload HCAdVs, and resulted in equal tumor regression and prolonged survival in tumor mouse models. Second, I present work which aims to assess the potential of these vectors to improve cancer immunotherapy by augmenting anti-tumorigenic T cell- NK cell- DC crosstalk. In detail, I here describe the following major findings: (1) IL-12, induced by an engineered viral vector for tumor-targeting, enforces a tumor-eliminating positive feedback loop, enhances CD8 T cell-DC interactions and achieves protective immunity, (2) intra-tumoral NK cells producing cDC1 attractants such as CCL5 are required for IL-12-mediated tumor rejection, and (3) attraction of cDC1s by local delivery of CCL5 can compensate for the lack of NK cell function and boost responses to IFNγ-inducing therapies, such as IL-12 and immune checkpoint inhibition (ICI). This work provides evidence that lack of intra-tumoral cDC1 recruitment by NK cells represents a major barrier for T cell-based therapies. It will be exciting to determine if and which tumor-derived factors might mediate resistance by limiting functionality of DCs and NK cells within the tumor microenvironment. In addition, identifying such factors will help to define predictive markers for T cell-focused therapies, such as ICI and provide new avenues beyond CCL5 to improve their efficacy by rationally designing combinatorial therapies