Targeted, conditionally active interferons, interleukins and CD8 T cell engagers for novel cancer immunotherapies

Cytokines, including interferons (IFNs) and various interleukins (ILs) such as IL-2 and IL-1, play major roles in the regulation of innate/adaptive immune responses and the emergence and progression of multiple cancer types. This involves both immune and cancer cell intrinsic signaling pathways. For example, IFNs and ILs are potent stimulators of tumor neoantigen processing and presentation by antigen presenting cells, activation of CD8 T and NK cells, and modulation of immune suppressive components of tumor microenvironments (e.g., MDSCs, TAMs). Repression of cancer cell intrinsic IFN signaling is implicated in mechanisms whereby oncogenic signals (e.g., KRAS mutations, MYC overexpression, p53 loss of function) contribute to establishment and maintenance of an immune-suppressive tumor microenvironment. We have established a multifaceted technology foundation for the engineering of vectorized, on-target, conditionally active cytokines to exploit their therapeutic potential and simultaneously avoid systemic toxicities associated with traditional cytokine-based therapies. We will describe applications of our technology innovations for the development of targeted cDC1 dendritic cell activators, immune checkpoint regulatory cell engagers, and potent CD8 T cell-selective engagers with broad spectrum cancer application potential. Examples of these we have recently advanced into clinical trials.