Abstract
Background:
Checkpoint inhibitors revolutionized cancer treatment by potentiating antitumor immune responses. However, many patients do not respond to these therapies, often due to the lack of a pre-existing immune response against cancer cells. Developing immunotherapies that promote cancer-cell antigen recognition, and the initiation of antitumor immune responses could thus improve response rates.
Methods:
We established multimodal nanofilament immunotherapy as an antigen-agnostic in situ cancer vaccine modality. Through genetic engineering of the M13 bacteriophage, nanofilaments displaying combinations of therapeutic agents were generated to guide immune recognition and response against cancer cells. TAT003 is a multimodal nanofilament combining the natural adjuvant properties of M13 with the display of both anti-PD-L1 single-chain antibody fragments (scFvs) and interleukin-2 (IL-2) molecules. It was developed to bind to the surface of cancer cells and transform them into immunological targets. After validation of TAT003's biological activities in vitro and assessment of its biodistribution, its potency was evaluated after intratumoral administration in murine syngeneic tumor models, both as a single agent and in combination with Programmed Death protein 1 (PD-1) blockade therapy. In addition, the mechanism of action of TAT003 was characterized using cytokine and immune profiling and T-cell activation assays.
Results:
TAT003 nanofilaments displayed several copies of biologically active anti-Programmed Death ligand 1 (PD-L1) and IL-2 molecules. On intratumoral injection, TAT003 attached durably to the tumor, thus limiting systemic exposure to the drug. TAT003 profoundly remodeled the tumor microenvironment of injected lesions, where it initiated a robust myeloid-cell infiltrate, and promoted the invasion of non-injected, contralateral lesions by T cells. This translated into potent regression of both injected and non-injected tumors in several cancer models, and potentiated PD-1 blockade therapy. TAT003 treatment induced the expansion of cancer-cell specific effector T cells systemically, providing a long-lasting antitumor vaccine response.
Conclusions:
Multimodal nanofilament immunotherapy is a novel approach to mounting systemic antitumor immune responses in situ by physically attaching large immunostimulatory molecules to cancer cells. TAT003 induced marked tumor regression by leveraging synergies between therapeutic agents displayed on its surface while offering a favorable tolerability profile. The results presented here establish multimodal nanofilaments as an innovative and versatile immunotherapy platform for developing in situ cancer vaccines.