PDE Inhibitors in Immunotherapy

Case ID:
C04580
Disclosure Date:
11/29/2004
Description:
Unmet Need
Tumors have the ability to interfere with the adaptive immune response by recruiting myeloid-derived suppressor cells (MDSCs), blocking antigen-presenting dendritic cell (DC) function and altering normal T-cell signal transduction and function. Such immunosuppressive mechanisms allow tumor cells to avoid immune recognition and eradication.  The use of phosphodiesterase-5 (PDE5) inhibitors (sildenafil, tadalafil, and vardenafil; currently used to treat erectile dysfunction) are proposed as modulators of MDSC function to restore antitumor immune response.
 
Technology Overview
Extensive mouse model data correlates tumor progression with the accumulation of MDSCs, dendritic cells and macrophages which induce local and possibly systemic immunosuppression.  In vitro experiments treating immune-compromised mice with PDE5 demonstrated no antitumor efficacy because these mice lack T and B lymphocytes, but had normal or enhanced natural killer (NK) and natural killer T (NKT) cell activity. These results strongly suggested that the antitumor activity of PDE5 inhibition in mouse models is primarily caused by an adaptive immune response.
 
Clinical Phase II data from multiple myeloma and head and neck cancer patients suggest that the same mechanisms found in mice are also present in human patients.  PDE5 inhibition down-regulates MDSC suppressive pathways and restores antitumor immunity.
 
Stage of Development
Randomized, prospective, double-blinded, placebo-controlled, phase II clinical trial data is available.
 
Publications
Califano, JA, et al., Clin Cancer Res. 2015 Jan 1; 21(1): 30–38.
Noonan, KA, et al., Cancer Immunol Res. 2014 Aug; 2(8): 725–731.
Serafini, P, et al., J Exp Med. 2006 Nov 27; 203(12): 2691–2702.
Patent Information:
Title App Type Country Serial No. Patent No. File Date Issued Date Expire Date Patent Status
PDE Inhibitor Compositions and Methods for Immunotherapy PCT: Patent Cooperation Treaty European Patent Office 06733655.2 1838319 1/9/2006 3/7/2018   Granted
PDE5 Inhibitor Compositions and Methods for Immunotherapy CON: Continuation United States 14/281,363 9,468,643 5/19/2014 10/18/2016 1/9/2026 Granted
Inventors:
Category(s):
For Information, Contact:
Jeanine Pennington
jpennin5@jhmi.edu
410-614-0300
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