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

Background

IL-10 is regarded as an anti-inflammatory cytokine but it is also essential for 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.

Methods

Pts with advanced renal cell cancer (RCC) were treated with AM0010 alone (daily SC) or in combination with pembrolizumab (q3wk IV). Tumor responses were monitored following irRC. Immune responses were measured by analysis of serum cytokines, activation of blood derived T cells, peripheral T cell clonality.

Results

Nineteen pts. with RCC (15 evaluable), were treated with AMO010 alone (20 mg/kg) and eight were treated in combination with pembrolizumab (2mg/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. Objective responses (PR/CR) were observed in 4 of 15 evaluable RCC pts. in monotherapy (27%) and in 4 of 8 patients in AM0010 /pembrolizumab (50%). Progression free survival (PFS) was 3 and 9.4 months, respectively. AM0010 alone and in combination with anti-PD1 increased Th1 cytokines (IL-18, IFNg, IL-7) as well as the number and proliferation of PD1+ activated CD8 T cells while decreasing the proliferation of FoxP3+ Tregs and TGFb in the blood. AM0010 / anti-PD1 induced de-novo oligoclonal expansion of T cell clones in the blood without affecting total lymphocyte counts.

Conclusions

AM0010 alone or in combination with anti-PD1 is well-tolerated. The clinical activity and the observed CD8 T cell activation encourages the continued exploration of AM0010 in combination with anti-PD1.

Clinical trial identification

Clinicaltrials.gov NCT02009449

Legal entity responsible for the study

ARMO Bioscience - Martin Oft

Funding

ARMO Biosciences

Disclosure

All authors have declared no conflicts of interest.