NL-201 is a stable IL-2/IL-15 mimetic that does not bind the high-affinity α receptor subunit, to prevent activation of Tregs, and is pegylated to improve pharmacokinetic half-life. Mortales et al. showed that NL-201 induced antitumor immunity in immune-cold mouse tumors. This effect was associated with increased tumoral MHC-I and PD-L1 expression, which depended on effector cell IFNγ production. Combination treatment with anti-PD-1 in several cold murine tumor models revealed synergistic antitumor efficacy. Treatment increased the clonal diversity of tumoral T cells and increased the number of IFNγ-producing CD8+ and CD4+ Th1 cells, but not Tregs.
Contributed by Maartje Wouters
ABSTRACT: Cytokine engineering has shown promise as a means to create novel immunomodulatory agents or to improve upon the therapeutic potential of natural cytokines. NL-201, a de novo, hyperstable, interleukin-2 receptor alpha (IL-2R_)-independent agonist of the receptors for IL-2 and IL-15, elicits robust preclinical activity in syngeneic murine cancer models, including those resistant to immune checkpoint inhibitors (ICIs). Here, we report that NL-201 monotherapy converts 'cold' tumor microenvironments to immunologically 'hot' states by driving pro-inflammatory gene expression, enhancing IFN_-dependent MHC-I expression, and expanding both T-cell number and clonal diversity. Additionally, the combination of NL-201 and anti-PD-1 resulted in complementary antitumor activity in the immunologically 'cold' and ICI resistant B16F10, EMT6, and Renca syngeneic models. In the B16F10 model, treatment with NL-201 plus anti-PD-1 increased the abundance of CD4+ and CD8+ effector T cells in the tumor microenvironment. These findings reveal an important mechanistic basis for the antitumor activity of NL-201 both as a monotherapy and in combination with PD-1 antagonists, and provide further context for the role of IL2R_-based signaling in ICI-resistant tumors.
Author Info: (1) Neoleukin Therapeutics, Inc., Seattle, United States. (2) Neoleukin Therapeutics, Inc., Seattle, United States. (3) Neoleukin Therapeutics, Inc., Seattle, United States. (4) Ne
Author Info: (1) Neoleukin Therapeutics, Inc., Seattle, United States. (2) Neoleukin Therapeutics, Inc., Seattle, United States. (3) Neoleukin Therapeutics, Inc., Seattle, United States. (4) Neoleukin Therapeutics, Inc., Seattle, United States. (5) Neoleukin Therapeutics, Inc., Seattle, United States. (6) Neoleukin Therapeutics, Inc., Seattle, United States. (7) A-Alpha Bio, Seattle, United States.
