Pharmacological ascorbate improves the response to platinum-based chemotherapy in advanced stage non-small cell lung cancer
Muhammad Furqan,
Taher Abu-Hejleh,
Laura M. Stephens,
Stacey M. Hartwig,
Sarah L. Mott,
Casey F. Pulliam,
Michael Petronek,
John B. Henrich,
Melissa A. Fath,
Jon C. Houtman,
Steven M. Varga,
Kellie L. Bodeker,
Aaron D. Bossler,
Andrew M. Bellizzi,
Jun Zhang,
Varun Monga,
Hariharasudan Mani,
Marina Ivanovic,
Brian J. Smith,
Margaret M. Byrne,
William Zeitler,
Brett A. Wagner,
Garry R. Buettner,
Joseph J. Cullen,
John M. Buatti,
Douglas R. Spitz,
Bryan G. Allen
Affiliations
Muhammad Furqan
Department of Internal Medicine, University of Iowa, 200 Hawkins Dr, Iowa City, IA, 52242, USA; Holden Comprehensive Cancer Center, University of Iowa, 200 Hawkins Dr, Iowa City, IA, 52242, USA; Corresponding author. Department of Internal Medicine, University of Iowa, 200 Hawkins Dr, C21-K GH, Iowa City, IA, 52242, USA.
Taher Abu-Hejleh
Department of Internal Medicine, University of Iowa, 200 Hawkins Dr, Iowa City, IA, 52242, USA; Holden Comprehensive Cancer Center, University of Iowa, 200 Hawkins Dr, Iowa City, IA, 52242, USA
Laura M. Stephens
Interdisciplinary Graduate Program in Immunology, University of Iowa, 200 Hawkins Dr, Iowa City, IA, 52242, USA
Stacey M. Hartwig
Department of Microbiology and Immunology, University of Iowa, 51 Newton Rd., Iowa City, IA, 52242, USA
Sarah L. Mott
Holden Comprehensive Cancer Center, University of Iowa, 200 Hawkins Dr, Iowa City, IA, 52242, USA
Casey F. Pulliam
Holden Comprehensive Cancer Center, University of Iowa, 200 Hawkins Dr, Iowa City, IA, 52242, USA; Department of Radiation Oncology, Free Radical and Radiation Biology Program, University of Iowa, 200 Hawkins Dr, Iowa City, IA, 52242, USA
Michael Petronek
Holden Comprehensive Cancer Center, University of Iowa, 200 Hawkins Dr, Iowa City, IA, 52242, USA; Department of Radiation Oncology, Free Radical and Radiation Biology Program, University of Iowa, 200 Hawkins Dr, Iowa City, IA, 52242, USA
John B. Henrich
Holden Comprehensive Cancer Center, University of Iowa, 200 Hawkins Dr, Iowa City, IA, 52242, USA; Department of Radiation Oncology, Free Radical and Radiation Biology Program, University of Iowa, 200 Hawkins Dr, Iowa City, IA, 52242, USA
Melissa A. Fath
Holden Comprehensive Cancer Center, University of Iowa, 200 Hawkins Dr, Iowa City, IA, 52242, USA; Department of Radiation Oncology, Free Radical and Radiation Biology Program, University of Iowa, 200 Hawkins Dr, Iowa City, IA, 52242, USA
Jon C. Houtman
Holden Comprehensive Cancer Center, University of Iowa, 200 Hawkins Dr, Iowa City, IA, 52242, USA; Interdisciplinary Graduate Program in Immunology, University of Iowa, 200 Hawkins Dr, Iowa City, IA, 52242, USA; Department of Microbiology and Immunology, University of Iowa, 51 Newton Rd., Iowa City, IA, 52242, USA
Steven M. Varga
Holden Comprehensive Cancer Center, University of Iowa, 200 Hawkins Dr, Iowa City, IA, 52242, USA; Interdisciplinary Graduate Program in Immunology, University of Iowa, 200 Hawkins Dr, Iowa City, IA, 52242, USA; Department of Microbiology and Immunology, University of Iowa, 51 Newton Rd., Iowa City, IA, 52242, USA; Department of Pathology, University of Iowa, 200 Hawkins Dr, Iowa City, IA, 52242, USA
Kellie L. Bodeker
Holden Comprehensive Cancer Center, University of Iowa, 200 Hawkins Dr, Iowa City, IA, 52242, USA; Department of Radiation Oncology, Free Radical and Radiation Biology Program, University of Iowa, 200 Hawkins Dr, Iowa City, IA, 52242, USA
Aaron D. Bossler
Department of Pathology, University of Iowa, 200 Hawkins Dr, Iowa City, IA, 52242, USA
Andrew M. Bellizzi
Holden Comprehensive Cancer Center, University of Iowa, 200 Hawkins Dr, Iowa City, IA, 52242, USA; Department of Pathology, University of Iowa, 200 Hawkins Dr, Iowa City, IA, 52242, USA
Jun Zhang
Department of Internal Medicine, University of Iowa, 200 Hawkins Dr, Iowa City, IA, 52242, USA; Holden Comprehensive Cancer Center, University of Iowa, 200 Hawkins Dr, Iowa City, IA, 52242, USA
Varun Monga
Department of Internal Medicine, University of Iowa, 200 Hawkins Dr, Iowa City, IA, 52242, USA; Holden Comprehensive Cancer Center, University of Iowa, 200 Hawkins Dr, Iowa City, IA, 52242, USA
Hariharasudan Mani
Department of Internal Medicine, University of Iowa, 200 Hawkins Dr, Iowa City, IA, 52242, USA
Marina Ivanovic
Holden Comprehensive Cancer Center, University of Iowa, 200 Hawkins Dr, Iowa City, IA, 52242, USA; Department of Pathology, University of Iowa, 200 Hawkins Dr, Iowa City, IA, 52242, USA
Brian J. Smith
Holden Comprehensive Cancer Center, University of Iowa, 200 Hawkins Dr, Iowa City, IA, 52242, USA; Department of Biostatistics, College of Public Health, University of Iowa, 145 N. Riverside Dr, Iowa City, IA, 52242, USA
Margaret M. Byrne
Department of Internal Medicine, University of Iowa, 200 Hawkins Dr, Iowa City, IA, 52242, USA; Holden Comprehensive Cancer Center, University of Iowa, 200 Hawkins Dr, Iowa City, IA, 52242, USA
William Zeitler
Department of Internal Medicine, University of Iowa, 200 Hawkins Dr, Iowa City, IA, 52242, USA; Holden Comprehensive Cancer Center, University of Iowa, 200 Hawkins Dr, Iowa City, IA, 52242, USA
Brett A. Wagner
Holden Comprehensive Cancer Center, University of Iowa, 200 Hawkins Dr, Iowa City, IA, 52242, USA; Department of Radiation Oncology, Free Radical and Radiation Biology Program, University of Iowa, 200 Hawkins Dr, Iowa City, IA, 52242, USA
Garry R. Buettner
Holden Comprehensive Cancer Center, University of Iowa, 200 Hawkins Dr, Iowa City, IA, 52242, USA; Department of Radiation Oncology, Free Radical and Radiation Biology Program, University of Iowa, 200 Hawkins Dr, Iowa City, IA, 52242, USA
Joseph J. Cullen
Holden Comprehensive Cancer Center, University of Iowa, 200 Hawkins Dr, Iowa City, IA, 52242, USA; Department of Radiation Oncology, Free Radical and Radiation Biology Program, University of Iowa, 200 Hawkins Dr, Iowa City, IA, 52242, USA
John M. Buatti
Holden Comprehensive Cancer Center, University of Iowa, 200 Hawkins Dr, Iowa City, IA, 52242, USA; Department of Radiation Oncology, Free Radical and Radiation Biology Program, University of Iowa, 200 Hawkins Dr, Iowa City, IA, 52242, USA
Douglas R. Spitz
Holden Comprehensive Cancer Center, University of Iowa, 200 Hawkins Dr, Iowa City, IA, 52242, USA; Department of Radiation Oncology, Free Radical and Radiation Biology Program, University of Iowa, 200 Hawkins Dr, Iowa City, IA, 52242, USA
Bryan G. Allen
Holden Comprehensive Cancer Center, University of Iowa, 200 Hawkins Dr, Iowa City, IA, 52242, USA; Department of Radiation Oncology, Free Radical and Radiation Biology Program, University of Iowa, 200 Hawkins Dr, Iowa City, IA, 52242, USA
Purpose: Platinum-based chemotherapy with or without immunotherapy is the mainstay of treatment for advanced stage non-small cell lung cancer (NSCLC) lacking a molecular driver alteration. Pre-clinical studies have reported that pharmacological ascorbate (P-AscH-) enhances NSCLC response to platinum-based therapy. We conducted a phase II clinical trial combining P-AscH- with carboplatin-paclitaxel chemotherapy. Experimental design: Chemotherapy naïve advanced stage NSCLC patients received 75 g ascorbate twice per week intravenously with carboplatin and paclitaxel every three weeks for four cycles. The primary endpoint was to improve tumor response per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 compared to the historical control of 20%. The trial was conducted as an optimal Simon's two-stage design. Blood samples were collected for exploratory analyses. Results: The study enrolled 38 patients and met its primary endpoint with an objective response rate of 34.2% (p = 0.03). All were confirmed partial responses (cPR). The disease control rate was 84.2% (stable disease + cPR). Median progression-free and overall survival were 5.7 months and 12.8 months, respectively. Treatment-related adverse events (TRAE) included one grade 5 (neutropenic fever) and five grade 4 events (cytopenias). Cytokine and chemokine data suggest that the combination elicits an immune response. Immunophenotyping of peripheral blood mononuclear cells demonstrated an increase in effector CD8 T-cells in patients with a progression-free survival (PFS) ≥ 6 months. Conclusions: The addition of P-AscH- to platinum-based chemotherapy improved tumor response in advanced stage NSCLC. P-AscH- appears to alter the host immune response and needs further investigation as a potential adjuvant to immunotherapy.
