Citations 2
Abstract 1860: DNA-PK-mediated transcriptional regulation drives tumor progression and metastasis
Goodwin, Jonathan F., Zhao, Shuang , Dylgjeri, Emanuela , Dean, Jeffry L. , Graham, Nicholas , Vashisht, Ajay A., Karnes, R. Jeffrey , Takhar, Mandeep, Tomlins, Scott A. , Sharifi, Nima , Witte, Owen N. , Feng, Felix Y. , Kothari, Vishal , Drake, Justin M , Schiewer, Matthew J. , McNair, Christopher M. , Magee, Michael S. , Den, Robert B. , Zhu, Ziqi , Wohlschlegel, James Akira , Graeber, Thomas G. , Davicioni, Elai , Knudsen, Karen E.
Cancer Research | August 5, 2015 | Volume: 75 | Issue: 15_Supplement | Pages: 1860-1860
Abstract Emerging evidence demonstrates that the DNA repair kinase DNA-PK exerts divergent roles in transcriptional regulation of unsolved consequence. Here, in vitro and in vivo interrogation demonstrate that DNA-PK functions as a selective modulator of transcriptional networks that induce cell migration, invasion, and metastasis. Accordingly, suppression of DNA-PK inhibits tumor metastases. Clinical assessment revealed that DNA-PK is significantly elevated in advanced disease, and independently predicts for metastases, recurrence, and reduced overall survival. Further investigation demonstrated that DNA-PK in advanced tumors is highly activated, independently of DNA damage indicators. Combined, these findings put forth new paradigms for DNA-PK function, identify DNA-PK as a potent driver of tumor progression and metastases, and nominate DNA-PK as a therapeutic target for advanced malignancies. Citation Format: Jonathan F. Goodwin, Vishal Kothari, Justin M. Drake, Shuang Zhao, Emanuela Dylgjeri, Jeffry L. Dean, Matthew J. Schiewer, Christopher McNair, Michael S. Magee, Robert B. Den, Ziqi Zhu, Nicholas A. Graham, Ajay A. Vashisht, James A. Wohlschlegel, Thomas G. Graeber, R Jeffrey Karnes, Mandeep Takhar, Elai Davicioni, Scott A. Tomlins, Nima Sharifi, Owen N. Witte, Felix Y. Feng, Karen E. Knudsen. DNA-PK-mediated transcriptional regulation drives tumor progression and metastasis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1860. doi:10.1158/1538-7445.AM2015-1860
Adoptive Transfer of MART-1 T-Cell Receptor Transgenic Lymphocytes and Dendritic Cell Vaccination in Patients with Metastatic Melanoma
Comı́n-Anduix, Begoña , Chmielowski, Bartosz , Koya, Richard C. , Wu, Zhongqi , Auerbach, Martin, Ng, Charles, Avramis, Earl , Seja, Elizabeth, Villanueva, Arturo, McCannel, Tara A. , Czernin, Johannes, Radu, Caius G. , Wang, Xiaoyan , Gjertson, David W., Cochran, Alistair J., Cornetta, Kenneth , Wong, Deborah Jean Lee, Kaplan‐Lefko, Paula , Hamid, Omid , Cohen, Peter A. , Daniels, Gregory A. , Mukherji, Bijay, Yang, Lili , Zack, Jerome A. , Kohn, Donald B. , Glaspy, John A. , Witte, Owen N. , Baltimore, David , Economou, James S., Ribas, Antoni , Chodon, Thinle, Chodon, Thinle , Ishiyama, Akira , Samlowski, Wolfram E. , Heath, James R. , Chmielowski, Bartosz , Kohn, Donald B
Clinical Cancer Research | March 14, 2014 | Volume: 20 | Issue: 9 | Pages: 2457-2465
Abstract Purpose: It has been demonstrated that large numbers of tumor-specific T cells for adoptive cell transfer (ACT) can be manufactured by retroviral genetic engineering of autologous peripheral blood lymphocytes and expanding them over several weeks. In mouse models, this therapy is optimized when administered with dendritic cell (DC) vaccination. We developed a short 1-week manufacture protocol to determine the feasibility, safety, and antitumor efficacy of this double cell therapy. Experimental Design: A clinical trial (NCT00910650) adoptively transferring MART-1 T-cell receptor (TCR) transgenic lymphocytes together with MART-1 peptide-pulsed DC vaccination in HLA-A2.1 patients with metastatic melanoma. Autologous TCR transgenic cells were manufactured in 6 to 7 days using retroviral vector gene transfer, and reinfused with (n = 10) or without (n = 3) prior cryopreservation. Results: A total of 14 patients with metastatic melanoma were enrolled and 9 of 13 treated patients (69%) showed evidence of tumor regression. Peripheral blood reconstitution with MART-1–specific T cells peaked within 2 weeks of ACT, indicating rapid in vivo expansion. Administration of freshly manufactured TCR transgenic T cells resulted in a higher persistence of MART-1–specific T cells in the blood as compared with cryopreserved. Evidence that DC vaccination could cause further in vivo expansion was only observed with ACT using noncryopreserved T cells. Conclusion: Double cell therapy with ACT of TCR-engineered T cells with a very short ex vivo manipulation and DC vaccines is feasible and results in antitumor activity, but improvements are needed to maintain tumor responses. Clin Cancer Res; 20(9); 2457–65. ©2014 AACR.