No abstract

Dendritic cells (DCs) of the cDC2 lineage are necessary for the initiation of the allergic immune response and in the dermis are marked by their expression of CD301b.CD301b + dermal DCs respond to allergens encountered in vivo, but not in vitro. This suggests that another cell in the dermis may sense allergens and relay that information 5 to activate and induce the migration of CD301b + DCs to the draining lymph node. Using a model of cutaneous allergen exposure, we show that allergens directly activate TRPV1 + sensory neurons leading to itch and pain behaviors. Allergen-activated sensory neurons release the neuropeptide Substance P, which stimulates proximally located CD301b + DCs through MRGPRA1. Substance P induces CD301b + DC migration to the 10 draining lymph node where they initiate Th2 differentiation. Thus, sensory neurons act as primary sensors of allergens, linking exposure to activation of allergic-skewing DCs and the initiation of the allergic immune response. 15

In the past decade, great strides have been made in the development of novel immunotherapies, such as immune checkpoint inhibitors (ICI) to treat cancer. However, despite these improvements, subsets of patients do not respond to ICI, highlighting an unmet need for alternative immunotherapies. As potent immunomodulators, cytokines have been explored as treatments for cancer but have been limited due to toxicity and poor pharmacokinetics (PK). One of these key cytokines, interleukin 21 (IL-21), is a pluripotent cytokine that activates anti-tumor T cell responses, induces B cell activation, and promotes generation and maintenance of germinal centers and tertiary lymphoid structures. A member of the common γ-chain family of cytokines, IL-21 acts on a broader range of cells than IL-2 and does not induce vascular leak syndrome. Despite being a potent inducer of immune activation, clinical activity of IL-21 has been hampered by poor PK and adverse events at dose levels associated with efficacy. To explore the potential therapeutic benefits of IL-21 as a treatment for cancer, Werewolf Therapeutics has developed different formats of IL-21 INDUKINETM polypeptides containing native human IL-21, an inactivation domain and a half-life extension domain tethered together by protease sensitive linkers. IL-21 INDUKINETM polypeptides are peripherally inactive, but due to dysregulation of the protease milieu in the tumor microenvironment, upon dosing and distribution to the tumor, the linkers are cleaved and IL-21 is released intratumorally. We will present data demonstrating that IL-21 INDUKINETM polypeptides showed in vitro and in vivo inducibility and activity. In mouse syngeneic tumor models, the IL-21 INDUKINETM polypeptides showed improved tolerability and therapeutic window compared to equal molar dosing of a half-life extended IL-21 protein (IL-21-HLE). Mechanistically, IL-21 triggered a pronounced activation of the adaptive immunity in the tumor. Efficacy in these tumor models was linked to expansion and activation of tumor infiltrating T cells, increased polyfunctionality in CD8+ T cells, as well as signs of increased activation of B cells. Together, these data support continued exploration of an IL-21 INDUKINETM polypeptide as a therapy for cancer. Citation Format: Jenna M. Sullivan, Pamela A. Aderhold, Heather R. Brodkin, Kyriakos Economides, Daniel J. Hicklin, Nesreen Ismail, Yuka Lewis, Cynthia Seidel-Dugan, Cierra Spencer, William M. Winston, Andres Salmeron. Generation of IL-21 INDUKINETM molecules for the treatment of cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1829.