Anti-tumor activity of PEGylated human IL-10 (AM0010) in renal cancer alone and in combination with anti-PD1

Abstract

Immunotherapy as well as anti-inflammatory molecules (TOR inhibitors) have antitumor activity in kidney cancer. AM0010 is a PEGylated human Interleukin 10 (IL- 10). IL-10 is regarded as an anti-inflammatory cytokine but it enhances also the cytotoxicity and proliferation of antigen activated CD8 T cells. Activation of the T cell receptor induces the expression of IL- 10 receptors and PD-1 on CD8 T cells. This provides the mechanistic rationale for combining AM0010 and anti-PD1 for the treatment of cancer pts. Tolerability and anti-tumor activity of AM0010 alone and in combination with chemotherapies or immune checkpoint inhibitors was explored in a multi-basket phase 1 clinical trial. Nineteen pts. with RCC (15 evaluable), were treated with AMO010 alone (20 mg/kg) and eight were treated in combination with pembrolizumab (2 mg/kg). Both regimens were tolerated well (observation period 15 months). All TrAEs were transient and TrAEs leading to study discontinuation were not observed. There was no colitis, pneumonitis, or endocrine disruptions. G3/4 TrAEs in monotherapy included anemia (9), hypertriglyceridemia (3), thrombocytopenia (2), ALT/AST increase (2) and fatigue (2). AM0010 combination with pembrolizumab did not increase TrAEs. Four RCC patients treated with AM0010 monotherapy (n = 15) had a tumor response (Naing et al., JCO 2016). Four RCC patients treated with AM0010 and pembrolizumab (n = 8) had a tumor response (Naing et al., ASCO 2016). Median progression free survival (mPFS) was 3 months on AM0010 monotherapy and 9.4 months on AM0010 plus pembrolizumab. CD8+ T cells analysis in patients on AM0010 monotherapy showed an increase in activation markers, including PD-1 and Lag-3 as well as an increase of proliferating PD1+ Lag-3+ CD8 T cells. Several hundred rare, previously not detectable T cell clones were found expanded more than 10 fold in patients treated with AM0010 monotherapy or AM0010 and pembrolizumab.