Patients with peripheral T- cell lymphoma (PTCL) constitute approximately 12-15% of all lymphoma cases and PTCL patients typically have a poor outcome. Patients with PTCL typically respond to initial combination chemotherapy, but most patients subsequently progress and require additional therapy. Treatments such as romidepsin and belinostat have been approved for patients with PTCL, but their efficacy has been limited. There is therefore clearly a need for additional new therapies to treat patients with PTCL.
Multiple mechanisms account for the lack of durable benefit with current treatment, but the inability of tumor-specific immune cells to eradicate the lymphoma is a central issue. A novel mechanism used by cancer cells to inhibit the immune response, however, is overexpression of programmed death ligand 1 or 2 (PD-L1 or PD-L2). These proteins interact with the programmed death-1 (PD-1) receptor expressed on intratumoral T-cells and provide an inhibitory signal thereby suppressing anti-tumor immunity. In previous work, we have shown that PD-1/PD-1 ligand interactions are critically important in PTCL and have found that PD-1 is expressed both on malignant cells and in the tumor microenvironment. Similarly, we have found that PD-L1 is highly expressed by malignant T-cells and intratumoral monocytes, and have shown that tumor-associated PD-L1 suppresses T-cell immunity.
Monoclonal antibodies that block PD-1 signaling can prevent T-cell suppression and promote an anti-lymphoma immune response. Antibodies, directed against PD-1 or PD-L1, are currently being tested in clinical trials and have shown remarkable efficacy in some hematologic malignancies. Despite broad clinical use of PD-1 directed therapy, very little is known about the immunology of PD-1 signaling in hematological malignancies. In PTCL in particular, PD-1/PD-L1/2 signaling is complicated by the fact that the receptor and ligands can both be expressed on the cancer cell. Furthermore, initial clinical trials have included very few patients with PTCL; however, in 5 patients receiving nivolumab, an antibody that blocks PD-1 signaling, 2 patients had an objective response, suggesting possible efficacy of PD-1 blockade in PTCL.
In this application, therefore, we propose to 1) measure the immune consequences of inhibiting PD-1/PD-1 ligand signaling, 2) determine the clinical efficacy of PD-1 blockade alone, and in combination with romidepsin, in patients with relapsed and refractory PTCL, and 3) determine the immunological predictors of clinical response to PD-1 therapy in patients with PTCL. In the proposed aims, we will determine how well PD-1 blockade works in PTCL, the specific mechanism of action of PD-1 blockade in PTCL, and in which subgroup of PTCL patients PD-1 blockade is predicted to have clinical benefit. Successful completion of this project is likely to have a major impact on clinical practice by potentially leading to an effective new therapy for patients with PTCL.