Phosphodiesterase Inhibitors: Increasing Immunity and Improving Antitumor Therapies
A group of researchers led by Kimberly A. Noonan and Ivan Borrello of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University have demonstrated the success of a novel method to combat immune suppression and improve antitumor therapies. The research, published in Cancer Immunology Research, focuses on targeting myeloid-derived suppressor cells (MDSC) to overcome tumor-induced immune suppression. The researchers had previously demonstrated the ability of phosphodiesterase-5 (PDE5) inhibitors to augment antitumor immunity by reducing MDSC function in murine tumor models and they have now demonstrated similar success in a human patient with end-stage multiple myeloma. The research suggests that targeting MDSC function with PDE5 inhibitors may be a novel approach to increasing the efficacy of tumor-directed therapies.
One of the greatest impediments to effective cancer immunotherapy is the inability of the host to overcome the immunosuppressive mechanisms associated with tumor growth. Myeloid-derived suppressor cells (MDSC) play a central role in mediating tumor-induced immunosuppressive mechanisms. MDSCs induce immune suppression in two primary ways: upregulation of inducible nitric oxide synthase (iNOS,) and overexpression of arginase-1 (Arg-1). Thus, therapies that inhibit iNOS and Arg-1 production have been suggested as a way to enhance antitumor immunity.
The researchers had previously reported that PDE5 inhibitors were capable of downregulating MDSC-dependent iNOS and Arg-1 activity in murine models. In several mouse tumor models, they demonstrated the ability of PDE5 inhibitors to reverse tumor-induced immune suppression and enable a measurable antitumor immune response thus delaying tumor progression.
Aware of their prior work in mouse models, the patient requested that the PDE5 inhibtor, tadalafil, be added to his existing lenalidomide-based therapy. A 50 year old male with end-stage multiple myeloma, the patient had previously been refractory to lenalidomide. However upon the addition of tadalafil, responsiveness to lenalidomide-based therapy was restored. While tadalafil alone is unlikely to generate a measurable clinical response, the results suggest that the immune-mediated efficacy of lenalidomide was augmented by tadalafil inhibition of MDSC function; the researchers observedreduced expression of both Arg-1 and iNOS.
This is the first demonstration in humans suggesting that PDE5 inhibitors can effectively block MDSC function and restore immune responsiveness. The results suggest that the addition of PDE5 inhibitors may increase the efficacy of existing cancer therapies. A clinical trial in myeloma is under way examining the therapeutic efficacy of PDE5 inhibitors in conjunction with a lenalidomide-based regimen.
