A now well established approach to cancer immunotherapy is using antibodies that are directed against substance (antigen) on a cancer cell surface. A fully human monoclonal antibody directed against the negative immunoregulatory human cell surface receptor PD-1 (programmed death-1 or programmed cell death-1/PCD-1) with immunopotentiation activity. Put simply, it activates T cells and produces cell-mediated immune responses against tumor cells or pathogens. In vitro cytotoxicity and in vivo inhibition of growth can be restored by anti-PD-L1 antibodies or by genetic ablation of PD-1. First use in humans was published by Berger et al in 2008 and showed that a single administration of 0.2 to 6.0 mg/kg of CT-011 is safe and well tolerated in patients with advanced hematologic malignancies. A more recent report in 2012 in the prestigious New England Journal of Medicine in 296 patients found cumulative response rates (all doses) of 18% among patients with non–small-cell lung cancer (14 of 76 patients), 28% among patients with melanoma (26 of 94 patients), and 27% among patients with renal-cell cancer (9 of 33 patients). On the other hand, Grade 3 or 4 drug-related adverse events occurred in 14% of patients; there were three deaths from pulmonary toxicity. Ongoing studies should bring more clarity to how this agent can contribute to treating cancer.
Raanan Berger et al, Phase I Safety and Pharmacokinetic Study of CT-011, a Humanized Antibody Interacting with PD-1, in Patients with Advanced Hematologic Malignancies Clinical Cancer Research 14, 3044-3051, May 15, 2008.
Mohamed Elrefaei, Chris A. R. Baker, Norman G. Jones, David R. Bangsberg and Huyen Cao. Presence of Suppressor HIV-Specific CD8+ T Cells Is Associated with Increased PD-1 Expression on Effector CD8+ T Cells. The Journal of Immunology, 2008, 180: 7757-7763
Suzanne L. Topalian, M.D., F. Stephen Hodi, M.D., Julie R. Brahmer, M.D., Scott N. Gettinger, M.D., David C. Smith, M.D., David F. McDermott, M.D., John D. Powderly, M.D., Richard D. Carvajal, M.D., Jeffrey A. Sosman, M.D., Michael B. Atkins, M.D., Philip D. Leming, M.D., David R. Spigel, M.D., Scott J. Antonia, M.D., Ph.D., Leora Horn, M.D., Charles G. Drake, M.D., Ph.D., Drew M. Pardoll, M.D., Ph.D., Lieping Chen, M.D., Ph.D., William H. Sharfman, M.D., Robert A. Anders, M.D., Ph.D., Janis M. Taube, M.D., Tracee L. McMiller, M.S., Haiying Xu, B.A., Alan J. Korman, Ph.D., Maria Jure-Kunkel, Ph.D., Shruti Agrawal, Ph.D., Daniel McDonald, M.B.A., Georgia D. Kollia, Ph.D., Ashok Gupta, M.D., Ph.D., Jon M. Wigginton, M.D., and Mario Sznol, M.D.Safety, Activity, and Immune Correlates of Anti–PD-1 Antibody in Cancer N Engl J Med 2012; 366:2443-2454June 28, 2012
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