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
