Virtual Library
Start Your Search
J. Milanowski
Author of
-
+
P2.01 - Poster Session with Presenters Present (ID 461)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
-
+
P2.01-055 - Lymphocytes' Subtypes Differentiation after Stimulation with Synthetic Antigen-Pulsed Dendritic Cells in Lung Adenocarcinoma Patients (ID 5055)
14:30 - 14:30 | Author(s): J. Milanowski
- Abstract
Background:
Immunotherapy in lung cancer is currently experiencing huge interest. The greatest efficacy demonstrated the antibodies against immune checkpoints receptors (PD-L1, CTLA-4 or LAG-3). However, an effective anti-tumor response also required tumor antigen presentation to lymphocytes in peripheral lymph nodes. To enhance this effect, vaccination with synthetic tumor antigen was conducted in many clinical trials using antigen presenting cells (APC). Unfortunately, this type of active immunotherapy has not achieved spectacular success (START or MAGRIT studies). The explanation could lie in distorted presentation of tumor antigens in peripheral lymph nodes or in activation of lymphocytes with strong immunosuppressive properties. In our study, we checked which pathways of T helper differentiation are favored by autologous dendritic cells (DCs) after synthetic tumor antigens stimulation.
Methods:
Peripheral blood was acquired from twenty unresectable and treatment-naïve lung adenocarcinoma patients. Using CD14 magnetic beads, two cell populations were isolated. CD14-negative cells were used for CD3-positive cells isolation, which were frozen until further stimulation. CD14-positive cells were cultured in CellDCGrow medium supplemented with IL-4 and GM-CSF. After TNF-a stimulation, mature DCs were incubated with tumour-specific antigens: MUC1, MAGE-A3, EGFR and CMV (positive stimulator) or only with medium (negative control). Flow cytometry and specific monoclonal antibodies were used to analyse immunophenotype of DCs: CD1a, CD11c, CD83, CD80, CD86, B7-H1 (PD-L1), B7-DC (PD-L2). Mature autologous DCs were cultured with fraction of CD3-positive cells and after 48h of mixed cultures, the expression of intracellular factors specific for different T helper cells subpopulation (T-bet – Th1, STAT-6 – Th2, ROR-gT – Th17, FoxP3 – Treg) and expression of extracellular interleukin receptors (IL-12R, IL-4R, IL-23R, TGF-bR, IL-2R) were analysed.
Results:
Autologous DCs were well generated and showed phenotype specific for fully-mature DCs. In culture with DCs after MUC1 stimulation, we observed in lymphocytes the highest expression of ROR-gT and IL-23R (p<0.05) compared with lymphocytes from cultures with other synthetic tumour antigens. Expression of IL-4R on lymphocytes was also significantly (0<0.05) higher in the culture stimulated with MUC1. The highest expression of intracellular FoxP3 factor, TGF-bR (p<0.05) and IL-2R (p=0.009) on Th cells were observed in mixed culture with DCs after MAGE-A3 stimulation.
Conclusion:
Dendritic cells stimulated with synthetic tumour antigens could activate different T helper cell populations. It could depend on the nature of antigens and could influence the effectiveness of stimulation different lymphocyte subtypes in peripheral lymph nodes. Therefore, our study clarifies some failure reasons of large clinical trials using active antigen-specific immunotherapy.
-
+
P2.03b - Poster Session with Presenters Present (ID 465)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
-
+
P2.03b-011 - Screening for ALK Abnormalities in Central Nervous System Metastases of Non-Small-Cell Lung Cancer (ID 5146)
14:30 - 14:30 | Author(s): J. Milanowski
- Abstract
Background:
Anaplastic lymphoma kinase (ALK) gene rearrangement was reported in 3-7% of primary non-small-cell lung cancer (NSCLC) and its presence is commonly associated with adenocarcinoma (AD) type and non-smoking history. ALK tyrosine kinase inhibitors (TKIs) such as crizotinib, alectinib and ceritinib showed efficiency in patients with primary NSCLC harboring ALK gene rearrangement. Moreover, response to ALK TKIs was observed in central nervous system (CNS) metastatic lesions of NSCLC. Till date there is limited data ALK rearrangement incidence in CNS metastases of NSCLC, which could be considered as a regiment for targeted treatment. For this reason we undertook the present retrospective study to determine the frequency of ALK abnormalities in CNS metastases of NSCLC.
Methods:
The studied group included 145 patients (45 females, 100 males, median age 60 years ±8) with CNS metastases of NSCLC. The studied group was heterogeneous in terms of histology (80 adenocarcinoma, 29 squamous-cell carcinoma, 22 large-cell carcinoma, 14 not otherwise specific) and smoking status. ALK abnormalities were screened in sections obtained from formalin fixed paraffin embedded (FFPE) tissue samples. NSCLC using immunohistochemical (IHC) automated staining (BenchMark GX, Ventana, USA) and fluorescence in situ hybridization (FISH) technique (Abbot Molecular, USA).
Results:
ALK abnormalities were detected in 4.8% (7/145) of CNS metastases of NSCLC. ALK abnormalities were observed in AD and squamous-cell carcinoma (SqCC) patients (7.5%; 6/80 vs. 3.4%; 1/29, respectively). Analysis of clinical and demographic factors indicated that expression of abnormal ALK was significantly more frequently observed (p=0.0002; χ[2]=16.783) in former-smokers. Comparison of IHC and FISH results showed some discrepancies, which were caused by unspecific staining of macrophages and glial/nerve cells, which constitute the background of CNS tissues.
Conclusion:
In this retrospective study we evaluated the expression of ALK abnormal protein and ALK gene rearrangement in extremely unique material which are CNS metastatic lesions of NSCLC. The frequency of ALK abnormalities in this material could be higher or comparable to frequency of ALK gene rearrangement in primary NSCLC tumors. However, the comparison of IHC and FISH results showed discrepancies that arose from unspecific background, which was made by cells with nonmalignant origin. For this reason assessment of ALK gene rearrangement in CNS tissues require additional standardizations.
-
+
P2.05 - Poster Session with Presenters Present (ID 463)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Radiotherapy
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
-
+
P2.05-030 - WBRT Prior EGFR TKIs is Effective Treatment Option for NSCLC Patients with CNS Metastases Harboring EGFR Mutation (ID 5151)
14:30 - 14:30 | Author(s): J. Milanowski
- Abstract
Background:
Central nervous system (CNS) metastases are considered as a common cause of morbidity and mortality in advanced non-small-cell lung cancer (NSCLC). It is estimated that 20–40% of NSCLC develop CNS metastases during their disease course. Sensitivity of chemotherapy is limited in CNS metastases of NSCLC, because of restrict transit function of blood-brain barrier. The main treatment options based on whole brain radiation therapy (WBRT), stereotactic radiosurgery, neurosurgery or combination of them. Median overall survival (mOS) achieved in NSCLC with CNS metastases treated with irradiation methods is 6.5-7.5 months. Introduction of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) – gefitinib, erlotinib, afatinib – improved the treatment possibilities in selected group of NSCLC patients harboring EGFR gene mutations. Also CNS metastatic lesions of NSCLC showed sensitivity to EGFR-TKIs (mOS to 15-17 months). Moreover, concurrent EGFR TKIs and WBRT may be used synergistic because potentially improve survival and delays intracranial progression. The main aim of the study was evaluation weather implementation of WBRT prior EGFR TKIs in NSCLC patients with CNS metastases might influence on their survival in comparison to patients without CNS metastases treated with EGFR TKIs monotherapy.
Methods:
The studied group included 178 NSCLC patients harboring EGFR gene mutation. 160 (110 female, 50 male; median age 67 years) patients with primary NSCLC received EGFR TKIs in first or second line of treatment. 18 patients (16 female, 2 male; median age 69 years), who had diagnosed CNS metastases, received WBRT prior administration of EGFR TKIs.
Results:
The treatment response was showed in both studied group. We did not observed a significant differences in survival in both studied groups. The progression free survival (PFS) in patients with primary NSCLC treated with EGFR TKIs and in patients with CNS lesions treated with WBRT prior EGFR TKIs was 10 vs. 9 months (p=0.785; HR=1.07; 95% CI=0,618-1.866), respectively. Also mOS did not show significance discrepancies in both studied group (26 vs. 32 months, respectively; p=0.32; HR=0.639; 95% CI=0.301-1.356). Implementation of WBRT prior TKIs did not lead to additional neurotoxicity.
Conclusion:
The following study showed that combination of WBRT prior TKIs in NSCLC patients with CNS metastases achieves similar benefit like treatment of primary NSCLC (without CNS metastases) with EGFR TKIs monotherapy. Based on overall data, patients with CNS metastases achieved better response rate when EGFR TKIs are administrated prior WBRT. It may be caused by EGFR TKIs feature which possess CNS penetrability for radiation.
-
+
P3.02b - Poster Session with Presenters Present (ID 494)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
-
+
P3.02b-048 - Oral Vinorelbine Monotherapy in Patients with EGFR+ NSCLC after Failure of EGFR-TKI in First Line: A Prospective Study (ID 4315)
14:30 - 14:30 | Author(s): J. Milanowski
- Abstract
Background:
In advanced/metastatic EGFR+ NSCLC patients (pts) progressing after EGFR-TKIs failure in first line, single-agent chemotherapy (CT) may be offered in pts who are unfit for a platinum combination. In this study (NAVoTRIAL 2), oral vinorelbine (NVBo) was evaluated as monotherapy in advanced NSCLC EGFR+ pts who failed to EGFR-TKIs in first line.
Methods:
Phase II, prospective, multicentre, open-label, international study. Main eligibility criteria: stage IIIB/IV NSCLC, EGFR+, prior EGFR-TKI treatment failure, Karnofsky PS ≥70, no prior CT or immunotherapy. Study treatment until progression or unacceptable toxicity: NVBo 60 mg/m[2] weekly for 3 weeks (first cycle), followed by 80 mg/m[2] weekly for subsequent cycles in absence of grade 3/4 toxicity. The primary endpoint was the disease control rate (DCR = CR + PR + SD, RECIST 1.1).
Results:
Final results: 30 pts included (March 2013 - November 2014). Main pts characteristics: median age: 66.8 years (60% ≥65 years); median Karnofsky PS 90%. Adenocarcinoma 96.7%. ≥3 organs involved (53.3%). All pts harboured EGFR mutation and received prior EGFR-TKI therapy: Gefitinib 73.3%, Erlotinib 16.7%, Afatinib 10%; 33.3% of pts had ≥2 comorbidities; Total number of cycles: 166 (443 doses administered); median number of cycles: 3.5 (range 1-20); median relative dose intensity: 77.6% (range 46.8-105); dose escalation was performed in 76.7 % of pts; Disease control rate 63.3% (95% CI [43.8-80]) and 23.3% of patients with stable disease ≥6 months. Median time to treatment failure: 2.7 months (range 0.4-13.6). Median PFS of 3.3 months (95% CI [1.6-5.4]) and OS of 13.1 months (95% CI [6.1-15.8]). Grade 3/4 toxicities per pt: neutropenia 53.3%, anemia 6.7%, leukopenia 26.7%, fatigue 16.7%, nausea 3.3% and vomiting 6.7%. Three cases of febrile neutropenia reported. No grade 3/4 diarrhoea, constipation, peripheral neuropathies or alopecia.
Conclusion:
NVBo as single-agent CT is a well-tolerated option in advanced EGFR+ NSCLC pts beyond failure of EGFR-TKI in first line. Its favourable tolerability profile allows a prolonged disease control in non-progressing pts.
