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Generation of Epigenetically-modified Autologous Tumor Cell Lines for Vaccines Targeting Cancer-testis Antigens in Thoracic Malignancies
David S. Schrump, Julie A. Hong, Mary Zhang, Yuwei Zhang, Tricia F. Kunst, Ana Hancox, Leandro Mercedes, King Kwong; Thoracic Oncology Section, NCI, Bethesda, MD
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Objective: Cancer-testis antigens (CTA) are highly diverse immunogenic proteins encoded by germ cell restricted genes, which are aberrantly activated by epigenetic mechanisms in human cancers. One potential strategy to target CTAs in thoracic malignancies involves utilization of epigenetically-modified autologous tumor lines to immunize patients against multiple CTAs that can be up-regulated in primary cancers by systemic gene induction regimens. The present study was undertaken to 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 thoracic malignancies including 10 NSCLC, 2 SCLC, 4 EsC, 3 MPM, and 2 sarcomas, and processed 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 or without the DNA demethylating agent, Decitabine (DAC), the histone deacetylase inhibitor, Depsipeptide (DP), or sequential DAC/DP. Cytokine release assays were used to assess recognition of tumor lines by MAGE-A3 and NY-ESO-1-specific cytolytic T lymphocytes (CTL) before and after drug exposure.
Results: Primary tumor lines were successfully generated and continuously propagated 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 revealed heterogeneous, time- and dose-dependent gene induction profiles in cell lines following treatment with DAC, DP, or sequential DAC/DP under exposure conditions greatly exceeding those achievable in clinical settings. Induction levels of cancer-testis genes 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 lines from thoracic oncology patients is feasible. These data support phase I evaluation of epigenetically- modified autologous tumor cell vaccination as a means to broadly immunize thoracic oncology patients against a variety of potentially relevant CTAs that can be targeted using gene induction protocols.
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