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R. Ramlau
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ORAL 01 - Chemotherapy Developments for Lung Cancer (ID 88)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:G. Blumenschein, S. Lee
- Coordinates: 9/07/2015, 10:45 - 12:15, 401-404
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ORAL01.05 - Phase I/II Dose Escalation Study of Immunoconjugate L-DOS47 as a Monotherapy in Non-Squamous Non-Small Cell Lung Cancer Patients (ID 3272)
11:28 - 11:39 | Author(s): R. Ramlau
- Abstract
- Presentation
Background:
L‑DOS47, a cancer therapeutic designed to exploit the acidic tumour extracellular environment, is a protein conjugate consisting of a urease conjugated to a camelid monoclonal antibody (AFAIKL2) that is targeted to the CEACAM6 antigenic tumour marker. The AFAIKL2 antibody serves as a targeting agent to deliver the enzyme to the tumor sites while the urease enzyme converts urea, an abundant natural metabolite, into ammonia and generates a local pH increase. The combined effect of ammonia toxicity and pH increase is cytotoxic to cancer cells in culture and in xenograft models. This first in human study of L‑DOS47 was designed to define the maximum tolerated dose of multiple doses of L-DOS47 administered intravenously to patients with non-squamous NSCLC when given as a monotherapy.
Methods:
Stage IIIb or IV histologically confirmed non-squamous NSCLC patients (aged ≥18 yrs, ECOG PS ≤2) receive multiple cycles of L-DOS47 during the study treatment period. L-DOS47 is administered once weekly over 14 days followed by 7 days rest in each treatment cycle. Patients are recruited into cohorts and received the same dose of L-DOS47 on Days 1 and 8 of each treatment cycle. Dose levels of L-DOS47 are escalated in further cohorts following a review of safety data by the Trial Steering Committee.
Results:
Thirty-three (33) pts (median age 61, 58% male) were enrolled in the first ten cohorts (dose levels: 0.12, 0.21, 0.33, 0.46, 0.59, 0.78, 1.04, 1.38, 1.84, 2.45 µg/kg) in four Polish centers. L-DOS47 was well tolerated at the dose levels reviewed. No DLTs were reported. Adverse events reported to date were expected for the population under study. None of the patients treated to date have had a partial or complete response as defined by RECIST v1.1. Sixteen (16) patients had an overall response of stable disease after completing two cycles of L-DOS47. One patient in cohort 9 was dosed for 9 cycles without disease progression.
Conclusion:
L-DOS47 monotherapy is well tolerated at dose levels up to 2.45 µg/kg. ClinicalTrials.gov identifier: NCT02340208
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P1.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 233)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 2
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.04-054 - Mitochondrial Status in Peripheral Blood Mononuclear Cells in Relation to Cognitive Impairment in Lung Cancer Patients (ID 1435)
09:30 - 09:30 | Author(s): R. Ramlau
- Abstract
Background:
Mitochondrial dysfunction is observed not only in lung cancer cel, but can develop in peripheral tissues. Peripheral blood mononuclear cells (PBMC) represent an available population of cells that can be used for the studies on remote effects of lung cancer. NADH dehydrogenase (ubiquinone) Fe-S protein 1 (Ndufs1) is located at the inner mitochondrial and transfers electrons from NADH to the respiratory system. Mitochondrially encoded cytochrome c oxidase I (MT-CO1) is involved in the coupling between O2 reduction and proton pumping. The changes in both key components of respiratory system reflect mitochodrial status. On the other hand the impairment of mitochondrial function may be crucial among pathomechanisms leading to neurological deficits. The aim of the study was evaluate mitochondrial status in PBMC in relation to the cognition in lung cancer patients.
Methods:
The study included 80 (24 females and 56 males, aged 61.5±6.7 years) consecutive lung cancer patients (5 small-cell lung cancer, 75 non-small cell lung cancer) hospitalized in Clinical Oncology with The Sub-department of Diurnal Chemotherapy Wielkopolska Center of Pulmonology and Thoracosurgery of Eugenia and Janusz Zeyland and Chair and Clinic of Oncology. PBMC were isolated by density gradient centrifugation. The expression Ndufs1 a marker of mitochondrial complex I and MTCO1 a marker of complex IV in PBMC was evaluated by means of ELISA and expressed in pg per mg of protein. Neurological examination, MiniMental State Examination (MMSE), Trail Making Test (TMT) A and B, and Hamilton scale were performed at baseline (time of lung cancer diagnosis) and after 6 months.. Patients serum was tested for the presence of onconeuronal antibodies with indirect immunofluorescence as a screening and Line blot as confirmation test.
Results:
Ndufs 1 expression in PBMC was lower in patient with peripheral nervous system involvement (0.00; 0.0-3.6218 ; median; minimum-maximum) than in subjects without neurological deficit (0.0; 0.0-8.61; median; minimum-maximum; P= 0,024). Up-regulated expression of Ndufs 1 in PBMC is associated with worse TMT- A (13.61±3.13s) than in patients with down-regulated complex I marker (8.60±4.51s; P=0.003). Similarly TMT- B results were worse in patients with higher Ndufs 1 expression (162.48±46.40s) than in cases with inhibited Ndufs1 (124.78±51.77s; P<0,05). Ndufs1 expression correlated negatively with MMSE 6 months after lung cancer diagnosis (Kendall tau =-0.310; P=0.0236), and positively with Hamilton scale score after 6 months (Kendall tau=0.288; P=0.0428), TMT-A (Kendall tau=0.301; P=0.0001) and TMT-B (Kendall tau=0.199; P=0.0120) at baseline. Up-regulated expression of MTCO1 was associated with worse TMT-A results (11.05±5.81s) compared to down-regulated marker of mitochondrial complex IV (8.52±4.14s; P=0.048). MTCO1 expression correlated positively with TMT-A results (Kendall tau=0.167; P=0.0344) at baseline. In 12 patients onconeuronal antibodies were identified (Ma/Ta, Yo, Ri). No differences in Ndufs1 and MTCO1 expression were found between patients with onconeronal antibodies and seronegative subjects.
Conclusion:
Up-regulation of mitochondrial complex I and IV in PBMC of lung cancer patients is associated with cognitive decline. Stimulation of mitochondria status in PBMC may indicate cytotoxic response leading to cognitive impairement.
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P1.04-075 - Kynurenine Pathway Activity in Peripheral Blood Mononuclear Cells and Cognitive Functions in Lung Cancer Patients (ID 1440)
09:30 - 09:30 | Author(s): R. Ramlau
- Abstract
Background:
The kynurenine pathway is crucial for tryptophan metabolism, which has been shown to be active both in macrophages and microglial cells. L-Kynurenine (L-KYN) is transported across the blood-brain barrier and serves as a source for the synthesis of all the other metabolites of the kynurenine pathway. Glial cells have the enzymatic capability for the biosynthesis of brain kynurenines as kynurenine aminotransferase (KAT). KAT converts L-KYN to kynurenic acid, which is an inhibitor of glutamate neurotransmission. The lowered KAT activity was observed in the plasma and brains of patients with neurodegenerative disorders followed by a tendency to a decrease KYNA in plasma and brains. Peripheral blood mononuclear cells (PBMC) can be considered as representative for metabolic changes in peripheral tisues during the course of lung cancer. With this background in mind we have undertaken the evaluation of translocator protein 18 kDa (TSPO), which reflects microglia activation, G Protein-coupled Receptor (GPR35), a KYNA receptor and kynurenine aminotransferase II (KAT) in PBMC and serum L-KYN concentration in relations to cognitive functions in lung cancer patients.
Methods:
We included in the study 80 consecutive lung cancer patients (5 small-cell lung cancer, 75 non-small cel lung cancer, 24 females and 56 males, aged 61.5±6.7 years) hospitalized in Clinical Oncology with The Sub-department of Diurnal Chemotherapy Wielkopolska Center of Pulmonology and Thoracosurgery of Eugenia and Janusz Zeyland and Chair and Clinic of Oncology. PBMC were isolated by density gradient centrifugation. The expression of TSPO, GPR35 KAT in PBMC was evaluated with ELISA. Serum L-KYN concentration was measured by means of spectrofotometric method. Neurological examination, MiniMental State Examination (MMSE), Trail Making Test (TMT) A and B, and Hamilton scale were performed at baseline (time of lung cancer diagnosis) and after 6 months.
Results:
Decreased TSPO expression in PBMC was associated with better results of MMSE evaluation (29.00; 28.0–29.0; median, interquartile range) than in lung cancer patients with up-regulated TPSO (28.0; 26.0–28.7; P=0.016). Also, TMT-A results were better in lung cancer patients with down-regulated TPSO (8.41±3.68s) compared to the subject with stimulated TPSO (12.92±7.30s; P=0.002). TSPO expression in PBMC negatively correlated with MMSE score (Kendall’s tau = -0.182; P=0.0178) and positively with TMT-A (Kendall’s tau = 0.168; P=0.0309) evaluated at baseline. The up-regulation of KAT expression in PBMC was associated with better cognitive functions measured with MMSE 6 months after baseline (28.4±0.7) comparing to lung cancer patients with inhibited KAT (27.1±1.8). KAT correlated positively with MMSE scoring 6 months after baseline (Kendall’s tau= 0.308; P=0.0234).The expression of GPR35 in PBMC did not correlated with cognitive measures. Serum L-KYN concentration correlated negatively with TMT-A evaluated 6 months after baseline (Kendall’s tau= -0.586; P=0.0141). Moreover, TPSO expression correlated positively with KAT (Kendall’s tau= 0.253, P=0.0009) and negatively with GPR35 (Kendall’s tau= -0.173, P=0.0491), but no correlation with L-KYN was found.
Conclusion:
Stimulation of kynurenine pathway in PBMC seems to be protective against cognitive decline during the course of lung cancer. Microglial activation can be independent pathomechanism leading to cognitive impairement in lung cancer patients.
