Safety, Antitumor Activity, and Immune Activation of Pegylated Recombinant Human Interleukin-10 (AM0010) in Patients With Advanced Solid Tumors

Abstract

Interleukin-10 (IL-10) stimulates the expansion and cytotoxicity of tumor-infiltrating CD8+ T cells and inhibits inflammatory CD4+ T cells. Pegylation prolongs the serum concentration of IL-10 without changing the immunologic profile. This phase I study sought to determine the safety and antitumor activity of AM0010. Patients and MethodsPatients with selected advanced solid tumors were treated with AM0010 in a dose-escalation study, which was followed by a renal cell cancer (RCC) dose-expansion cohort. AM0010 was selfadministered subcutaneously at doses of 1 to 40 mg/kg once per day. Primary end points were safety and tolerability; clinical activity and immune activation were secondary end points. ResultsIn the dose-escalation and -expansion cohorts, 33 and 18 patients, respectively, were treated with daily subcutaneous injection of AM0010. AM0010 was tolerated in a heavily pretreated patient population. Treatment-related adverse events (AEs) included anemia, fatigue, thrombocytopenia, fever, and injection site reactions. Grade 3 to 4 nonhematopoietic treatment-related AEs, including rash (n = 2) and transaminitis (n = 1), were observed in five of 33 patients. Grade 3 to 4 anemia or thrombocytopenia was observed in five patients. Most treatment-related AEs were transient or reversible. AM0010 led to systemic immune activation with elevated immune-stimulatory cytokines and reduced transforming growth factor beta in the serum. Partial responses were observed in one patient with uveal melanoma and four of 15 evaluable patients with RCC treated at 20 mg/kg (overall response rate, 27%). Prolonged stable disease of at least 4 months was observed in four patients, including one with colorectal cancer with disease stabilization for 20 months. ConclusionAM0010 has an acceptable toxicity profile with early evidence of antitumor activity, particularly in RCC. These data support the further evaluation of AM0010 both alone and in combination with other immune therapies and chemotherapies.

The biology of uveal melanoma

“…Similarly, immune checkpoint blockade therapy using antibodies directed against immunomodulatory receptors and ligands induces long-term survival in a considerable portion of CM patients [73] but shows only limited activity in metastatic UM patients with extended responses in some patients [74–83]. A recent phase I trial with AM0010, a pegylated recombinant IL-10, showed responses of solid tumors with BRCA1-associated protein 1 (BAP1) mutations, among which is a UM [84]. …”

“…Gene expression data from 79 cases of primary UM from the TCGA cohort were used for the identification of genes that are differentially expressed in cases that yielded distant metastases later on as compared to cases without progression to metastatic disease. Statistically significant gene expression differences were obtained by analysis using the bootstrapping algorithm significance analysis of microarrays as described [84]. Expression values over the mean value are indicated in red , values below the mean in blue , and values at the mean in white ; the intensity of the color corresponds to the distances from the mean as indicated in the red-blue bar on top of the diagram .…”

“…Expression values over the mean value are indicated in red , values below the mean in blue , and values at the mean in white ; the intensity of the color corresponds to the distances from the mean as indicated in the red-blue bar on top of the diagram . Differentially expressed genes were used for hierarchical clustering performed as described [84]. The dendrograms on top of the gene expression panel show the relationship of single samples and their agglomeration in clusters.…”

Cytokines as potential combination agents with PD‐1/PD‐L1 blockade for cancer treatment

“…In this expansion cohort, patients were treated with daily AM0010 in the dose‐escalation and illustrated the drug is well tolerated. Also, the authors observed drug‐related grade 3 and 4 adverse events) in 15% of patients (NCT02009449) (Naing et al, 2016). More recently, a Phase 1b clinical trial was reported on the antitumor activity of AM0010 in combination with nivolumab or pembrolizumab in RCC patients ( n = 38).…”

Targeting Immunotherapy to the Tumor Microenvironment

“…TNFα has high systemic toxicity, but can be administered to isolated limbs containing melanoma or sarcoma with reasonable safety and high rates of complete response [Lienard et al, ]. Systemic versions of IL‐15, IL‐18, and IL‐10 have all met with acceptable safety profiles in phase I trials, although it is not clear yet that they will be effective at tumor control in humans [Robertson et al, ; Conlon et al, ; Naing et al, ; Rosario et al, ]. Overall, systemic administration of defined cytokines is associated with significant side effects caused by overwhelming immune activation.…”