PEGylated IL-10 (Pegilodecakin) Induces Systemic Immune Activation, CD8+ T Cell Invigoration and Polyclonal T Cell Expansion in Cancer Patients

Abstract

Graphical Abstract Highlights d Pegilodecakin induces systemic and intratumoral CD8 + T cell activation in patients d PD-1 + Lag3 + CD8 + T cells and previously undetected T cell clones are expanded d IFN-g, IL-18, GranzymeB, and FasL are elevated across tumor types d The magnitude of systemic immune activation correlates with tumor response SUMMARYTumor-reactive T cell exhaustion prevents the success of immune therapies. Pegilodecakin activates intratumoral CD8 + T cells in mice and induces objective tumor responses in patients. Here we report that pegilodecakin induces hallmarks of CD8 + T cell immunity in cancer patients, including elevation of interferon-g and GranzymeB, expansion and activation of intratumoral CD8 + T cells, and proliferation and expansion of LAG-3 + PD-1 + CD8 + T cells. On pegilodecakin, newly expanded T cell clones, undetectable at baseline, become 1%-10% of the total T cell repertoire in the blood. Elevation of interleukin-18, expansion of LAG-3 + PD-1 + T cells and novel T cell clones each correlated with objective tumor responses. Combined pegilodecakin with anti-PD-1 increased the expansion of LAG-3 + PD-1 + CD8 + T cells.

Immune regulation and cytotoxic T cell activation of IL-10 agonists – Preclinical and clinical experience

“…CD8 + T cell mediated tumor responses were also observed in endogenous tumors in a Her2 transgenic tumor model, which generally have a strongly reduced number of somatic mutations and accordingly a low infiltration by T cells [15,51]. Moreover, patients on Pegilodecakin monotherapy had an increase in the number of activated, tumor infiltrating CD8 + T cells in tumors with low T cell infiltration prior to therapy [52].…”

“…CD8 + T cell activation by TCR stimulation leads to an upregulation of the IL-10Ra and IL-10Rb [51,52]. This increases the sensitivity of TCR stimulated CD8 + T cells to STAT3 induction by IL-10 and may selectively deliver anti-apoptotic signals to TCR stimulated CD8 + T cells [52].…”

“…CD8 + T cell activation by TCR stimulation leads to an upregulation of the IL-10Ra and IL-10Rb [51,52]. This increases the sensitivity of TCR stimulated CD8 + T cells to STAT3 induction by IL-10 and may selectively deliver anti-apoptotic signals to TCR stimulated CD8 + T cells [52]. Simultaneously, activation of CD8 + T cell leads to a temporary induction of immune checkpoint receptors such as PD-1 and Lag-3, and this activation signature is stabilized by the treatment with IL-10 [52].…”

“…Simultaneously, activation of CD8 + T cell leads to a temporary induction of immune checkpoint receptors such as PD-1 and Lag-3, and this activation signature is stabilized by the treatment with IL-10 [52]. IL-10 also directly induces GranzymeB expression in activated CD8 + T cells, leading to a higher antigen specific cytotoxicity of those cells on target cells [15,52].…”

“…Pegilodecakin (AM0010) was well tolerated at escalating doses from 1μg/ kg to 40μg/kg. This resulted in a sustained, meaningfully elevated serum concentration of IL-10 between 1 and 40 ng/ml [81], since the half maximal effective concentration (EC50) of pegilodecakin in cellbased in vitro assays was approximately 8 ng/mL and the serum concentration of IL-10 in cancer patients prior to dosing averaged at 3 pg/ mL [52]. The DLT was not determined and adverse events (AE) included anemia, thrombocytopenia, fever and fatigue, while hypotension or durable auto-immune related adverse events were not recorded.…”