Boston - American Association for Thoracic Surgery

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89 TH ANNUAL MEETING MAY 9–MAY 13, 2009BOSTON, MASSACHUSETTSF15. Generation of Epigenetically-Modified Autologous Tumor CellLines for Vaccines Targeting Cancer-Testis Antigens inThoracic MalignanciesDavid S. Schrump, * Julie A. Hong, Mary Zhang, Yuwei Zhang, Tricia F. Kunst,Ana Hancox, Leandro Mercedes, King Kwong †Thoracic Oncology Section, NCI, Bethesda, MD, USAInvited Discussant: Stephen G. SwisherOBJECTIVE: Cancer-testis antigens (CTA) are highly diverse immunogenic proteinsencoded by germ cell restricted genes, which are aberrantly activated by epigeneticmechanisms in human cancers. One potential strategy to target CTAs in thoracicmalignancies involves utilization of epigenetically-modified autologous tumorlines to immunize patients against multiple CTAs that can be up-regulated in primarycancers by systemic gene induction regimens. The present study was undertakento assess the feasibility of this approach as a prelude to a phase I clinical trial.METHODS: Primary tumor tissues were harvested from 21 patients with thoracicmalignancies including 10 NSCLC, 2 SCLC, 4 EsC, 3 MPM, and 2 sarcomas, andprocessed for cell culture. Quantitative RT-PCR, western blot, and immunohistochemistry(IHC) techniques were used to assess BORIS variant, MAGE-A1,-A3,NY-ESO-1, and CT-45 expression in cell lines cultured in normal media with orwithout the DNA demethylating agent, Decitabine (DAC), the histone deacetylaseinhibitor, Depsipeptide (DP), or sequential DAC/DP. Cytokine release assays wereused to assess recognition of tumor lines by MAGE-A3 and NY-ESO-1-specificcytolytic T lymphocytes (CTL) before and after drug exposure.RESULTS: Primary tumor lines were successfully generated and continuouslypropagated from 12 of 21 individuals (57%), including 3 NSCLC, 2 SCLC, 3 EsC,2 MPM, and 2 sarcoma patients. Quantitative RT-PCR and IHC analysis revealedheterogeneous, time- and dose-dependent gene induction profiles in cell lines followingtreatment with DAC, DP, or sequential DAC/DP under exposure conditionsgreatly exceeding those achievable in clinical settings. Induction levels of cancertestisgenes frequently approximated or exceeded those observed in control testes,as well as thresholds for CTL recognition in cultured cancer lines.CONCLUSION: Generation of autologous epigenetically-modified cancer linesfrom thoracic oncology patients is feasible. These data support phase I evaluationof epigenetically-modified autologous tumor cell vaccination as a means to broadlyimmunize thoracic oncology patients against a variety of potentially relevant CTAsthat can be targeted using gene induction protocols.* AATS Member† Second John Alexander Research Scholarship 2004144
AMERICAN ASSOCIATION FOR THORACIC SURGERYF16. Atrial Natriuretic Peptide Extends Lung PreservationAttenuating Ischemia-Reperfusion Lung Injury ThroughPhospholipase A2 InhibitionYury A. Bellido Reyes, Prudencio Díaz-Agero, Joaquin García S. GirónThoracic Surgery, La Paz Hospital, Madrid, SpainInvited Discussant: Dirk E. Van RaemdonckOBJECTIVE: Phospholipase A2 (PLA2), a key enzyme in the regulation of thearachidonic acid metabolism, is potentially involved in the physiopathology ofischemia-reperfusion (IR) injury. In the present study, we hypothesized thatsupplementation of low potassium dextram (LPD) solution with atrial natriureticpeptide (ANP) extends lung preservation attenuating IR lung injury through inhibitionof the PLA2 cascade.METHODS: To test the hypothesis, we examined the effects of ANP in an isolatedrat lung model. Three groups were defined (n = 6, each): in the vehicle group,lungs were perfused for 2 hours without an ischemic period. In two ischemicgroups, lungs were flushed with low potassium dextram solution (LPD group) orLPD containing 10 nM of ANP (LPD+ANP group), cold-stored 18 hours, andreperfused for 2 hours.TUESDAYMorningEdema Formation, Neutrophil Extravasation, and Phospholipase A2 MetabolismAfter Ischemia-ReperfusionVehiclegroupLPDgroupLPD+ANPgroupWet-to-DryRatioProteinsBALFmg/mLMPOActivityOD/mg/mincPLA2Activitynmol/mg/minsPLA2ActivityThromboxan LeukotrieneA2 B4nmol/mg/min pg/mL pg/mL6.22 ± 0.37 § 0.17 ± 0.07 § 0.44 ± 0.06 § 1.15 ± 0.14 § 171.8 ± 38.2 § 203.3 ± 70.9 § 132.4 ± 68.8 §10.97 ± 1.40 1.01 ± 0.15 1.21 ± 0.15 1.63 ± 0.18 350.3 ± 84.3 826.1 ± 213.0 392.3 ± 77.36.62 ± 1.24 § 0.38 ± 0.09 0.62 ± 0.05 § 1.12 ± 0.21 § 239.3 ± 62.0 § 495.5 ± 97.9 §, 253.6 ± 63.0 §,Values are mean ± SEM (n = 6, per group). BALF, bronchoalveolar lavage fluid; MPO, myeloperoxidase;cPLA2, cytosolic phospholipase A2; sPLA2, soluble phospholipase A2. (§) p < 0.01 vs LPD group,() p < 0.05 vs vehicle group.RESULTS: Isquemia-reperfusion reduced PO2 from 615.7 ± 28.5 to 452.1 ± 28.2mmHg (p < 0.001), at the end of reperfusion in the LPD group. Compared to thevehicle group the pulmonary artery pressure, airway pressure, wet-to-dry ratio,proteins in BAL, and myeloperoxidase activity increased significantly in the LPDgroup, (p < 0.05) respectively. In addition, IR increased significantly cytosolic andsoluble phospholipase A2 activity together with thromboxane and leukotrieneformation in the LPD group compare to vehicle; while supplementation of the145
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AATS FUTURE MEETINGSMay 1-5, 2010Me
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