Background

At therapeutic concentrations, PEGylated IL-10 (AM0010) stimulates the cytotoxicity, survival and proliferation of intratumoral antigen activated CD8+ T cells in pre-clinical cancer models and in patients. AM0010 activates antigen stimulated CD8 T cells while PD-1 inhibits them, providing a rationale for combining AM0010 with PD-1 inhibitors.

Methods

34 NSCLC pts received AM0010 (10-20ug/kg QD, SC) with pembrolizumab (2mg/kg, q3wk IV; n = 5) or nivolumab (3mg/kg, q2wk IV; n = 29). Pts had a median of 2 prior therapies. The median follow-up is 14.9 mo (range 5.6-30.3). Tumor responses were assessed by irRC. 20 patients were analyzed for PD-L1 expression (22C3). Immune responses were measured by analysis of serum cytokines (Luminex), activation of blood derived CD8 T cells (FACS) and peripheral T cell clonality (TCR sequencing). Tumor tissue was analyzed for tumor mutational burden by WES and mRNA expression of IO markers (Nanostring).

Results

AM0010 plus anti-PD-1 was well tolerated. All TrAEs were reversible and transient. G3/4 TrAEs included thrombocytopenia (8), anemia (7), fatigue (6), rash (4), pyrexia (2), hypertriglyceridemia (3) and pneumonitis (1). As of Sept 15, 2017, 27 pts had at least 1 tumor assessment. 10 pts (36.4%) had a partial response (PR) and 12 pts (44.4%) had stable disease (SD). Notably, of five patients with PD-L1 + ≥ 50% NSCLC, four had a PR, 1 had SD with 47% reduction of tumor burden.Table: 9PD

Preliminary response data stratified for PD-L1

The mOS was 19.7 months, 1-year survival was 71%. Biomarker analysis exploring the correlation of the tumor mutational burden, mRNA profiling and the systemic immune response with tumor response and overall survival will be presented.

Conclusions

AM0010 in combination with an anti-PD-1 is well-tolerated in advanced NSCLC pts. The improved efficacy regardless of PD-L1 status and the observed CD8 T cell activation is promising and encourages the continued study of AM0010 in combination with an anti-PD-1.

Clinical trial identification

NCT02009449

Legal entity responsible for the study

ARMO BioSciences

Funding

ARMO BioSciences

Disclosure

N. Ratti, A. Hung, M. Oft: Employee of ARMO BioSciences. P. Van Vlasselaer: Employee and stock owner of ARMO BioSciences. All other authors have declared no conflicts of interest.

Background

Inflammation has a multifaceted role in cancer progression including initiation, promotion and invasion by affecting the immune surveillance and associated signalling pathways. The aim of this study was to measure circulating pro- and anti-inflammatory cytokines (IL 6, TNF-α, and IL10) and their correlation with prognostic factors and progression in breast cancers in Tunisian patients.

Methods

Serum samples were prospectively collected from a cohort of sixty breast cancer patients after surgery. Circulating levels of the pro-inflammatory cytokines TNF-α and IL6 were measured with the technique of a solid-phase, two-site chemo-luminescent enzyme immune-metric assay (Immulite 1000, Simens, USA). Serum levels of the anti-inflammatory cytokine IL10 were measured by the ELISA sandwich method.

Results

The mean age of patients was 47 years (20 – 80 years), 17 patients were metastatic (32% in liver). The mean level of cytokines Il6, IL10 and TNF-α were, respectively, 3.31 +/- 4.07 pg/ml (min 1, max 29.30 pg/ml); 6.560+/- 3.50 pg/ml (min 0.880, max 17.925 pg/ml) and 6.90 +/- 2.99 pg/ml (min 3, max 20.30 pg/ml). We found a significant correlation between high level of IL6 and metastatic disease (p = 0.04) especially with liver metastasis (p = 0.003). We found also a significant correlation between high level of TNF-α and lymph node involvement (p = 0.0011). On the other hand there was a significant correlation between high level of IL10 and high SBR grade (p = 0.01).

Conclusions

Our results highlight the role of circulating cytokines of inflammation IL6, TNF-α and IL10 as a potential prognostic biomarkers in breast cancer patients which could contribute to tumor growth and progression. So there was a rationale for the use of cytokine and chemokine blockade, and further investigation of anti-inflammatory drugs in the chemoprevention and treatment of malignant diseases should be carried out.

Legal entity responsible for the study

Military Hospital

Funding

Military Hospital of Tunis

Disclosure

All authors have declared no conflicts of interest.

Background

Some tumor molecules circulate in the blood, and in some cases, they are used as markers of the disease (CEA, PSA). Several authors have reported the efficacy of some of these molecules for immunotherapy, which is the case of the Autologous Hemoderivative Cancer Vaccine (AHCV) that uses a thermostable molecular fraction of autologous blood as intradermal immunogen, and an intradermal way for immunization. We are searching adjuvant procedures to improve such immunotherapy. In this study, we tested AHCV in human hormone-refractory prostate cancer, and as adjuvant, we used metformin that has been identified as a geroprotector with regenerative activity of immunity, depressed by the immunosenescence phenomenon prevalent in aged patients.

Methods

From the data included in published trials that tested AHCV, 45 records were reviewed for this analysis, all patients with hormone-resistant prostate cancer in PSA progression, 60-85 years old, diabetes type 2, treated with metformin. These were divided into3 groups of 15 records each, patients receiving 0, 5 and 10 months of metformin 850 to 1000 mg/day, respectively. All groups had received monthly for one year vaccination with AHCV as was reported. Follow-up of records was for 12 months. Assessments: At the beginning and at the end of the 1-yr follow-up, evaluations were performed: PSA in blood by standard immunochemical method, glycosylated hemoglobin and ferritin, two biomarkers of aging mechanisms (glycation and inflammation), and diameter of intradermal papular response to vaccination measured 48 hours after inoculation. The variations of such assessments were registered.

Results

Shown in Table.Table: 78P

Conclusions

In hormone-resistant prostate cancer, the previously reported immunogenic activity of AHCV increases with metformin pretreatment in association with geroprotection, as estimated by biomarkers of aging.

Clinical trial identification

Records review.

Legal entity responsible for the study

Cooperative Research Group Interdoctors-Telemedical Organization

Funding

None

Disclosure

All authors have declared no conflicts of interest.

Background

TP53 somatic mutations have been suspected to induce an autoantibody immune response against p53. The aim of this study was to determine if a specific TP53 tumor mutational status, is associated with the presence of circulating p53-autoantibodies (p53-AAbs) in patients with advanced high grade ovarian cancer (HGOC).

Methods

A retrospective study was carried out in 117 patients with stage III-IV and high grade (G2-G3) tumors, who were enrolled at CRO Institute and provided adequate tissue sample. All patients underwent surgical debulking and received platinum-based regimen. Matched tumor and blood DNA samples were analyzed for TP53 genetic mutations using a MiSeq platform. Commercially available ELISA kit was used to detect p53-AAbs in plasma or serum.

Results

Median age of the patients was 58 years (range 31-82). Median follow-up time was 40 months (IQ range 20-67). TP53 somatic mutations were found in 74,4% (87/117) of HGOC patients and 26,5% (31/117) were positive for p53-AAbs. Among mutated patients, 28.7% (25/87) was tested positive for presence of p53-AAbs and 71.3% (62/87) was p53-AAbs negative (Fisher’s exact test; p=0.473). In p53-AAbs positive patients with at least a TP53 mutation in matched tumor (81%, 25/31), missense mutations were strongly associated with the presence of p53-AAbs while insertion/deletion, splice/intronic and nonsense variants were associated with p53-AAbs negative patients (p<0.001). Gain of function (GOF) missense mutations were prevalent in p53-AAbs positive patients, while insertion/deletion mutations with loss of function (LOF) properties prevailed in p53-AAbs negative patients (p=0.0162).

Conclusions

This study for the first time compared data from the genetic TP53 tumor status through an NGS approach with the presence of circulating p53-AAbs. In most of HGOC, the presence of p53-AAbs was associated with tumors harboring TP53 missense mutations that share GOF effects. These new findings suggest that a specific mutational status in the HGOC tumor is associated with presence of p53-AAbs, but not completely explain the amount of p53-AAbs appearance. Both markers should be further explored and evaluated for impact on clinical outcome.

Legal entity responsible for the study

CRO-National Cancer Institute

Funding

None

Disclosure

All authors have declared no conflicts of interest.

Background

Checkpoint inhibitors including the CTLA-4 blocking antibody ipilimumab have become the new standard therapy of many metastatic cancers. Development of anti-drug antibodies (ADAs) after treatment with other biopharmaceuticals has been thoroughly investigated, but induction of ADAs after treatment with checkpoint inhibitors is poorly investigated. In this retrospective study, we measured ipilimumab serum levels and anti-ipilimumab antibody levels in patients with unresectable or metastatic melanoma (MM), and related the findings to clinical outcome.

Methods

Serum samples from 31 patients with MM were analyzed for ADAs against ipilimumab and serum levels of ipilimumab at baseline, after 1^st infusion and 3^rd infusion using an in-house developed bead-based assay. Data were correlated with progression-free survival (PFS) and overall survival (OS).

Results

Low serum levels of ipilimumab after 1^st infusion correlated significantly to a shorter OS (p = 0.024) but not PFS, and this correlation was not observed after 3^rd infusion. Seven patients (23%) were ADA-positive after 1^st infusion, three of whom were excluded before the 3^rd infusion due to disease progression. Five patients (19%) were ADA-positive after the 3^rd infusion. Patients with a positive ADA status after 1^st infusion had shorter PFS (p = 0.0186) and OS (p = 0.0143) than ADA-negative patients, while ADA-positivity after the 3^rd infusion did not correlate significantly with PFS or OS. ADA status did not correlate with serum levels of ipilimumab.

Conclusions

Low serum levels of ipilimumab after 1^st infusion is correlated with shorter OS, while ADA-positivity is associated with shorter OS as well as PFS in patients with MM.

Legal entity responsible for the study

Inge Marie Svane

Funding

None

Disclosure

All authors have declared no conflicts of interest.