Synergistic Anti-Tumor Efficacy Of The Dual Pi3k-Delta/Pi3k-Gamma Inhibitor Duvelisib With Pd-1 Blockade In Solid Tumor And Lymphoma Models

Blockade of immune checkpoints, such as PD-1, has provided meaningful clinical benefit for patients with a broad range of malignancies. However, limited response rates and resistance after initial response suggest a need for additional strategies. Duvelisib is an oral, dual PI3K-δ,γ inhibitor that is FDA-approved as monotherapy for chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) and follicular lymphoma (FL) after ≥2 prior systemic therapies. In addition to targeting malignant B cells, duvelisib regulates key immune cells in the tumor microenvironment, making it a promising candidate for combination with PD-1 blockade. Using T cells from human donors or CLL patients, we now show that duvelisib induced a 3 to 4-fold increase in T cell expansion ex vivo, and that dual PI3K-δ,γ inhibition was necessary for maximal effect. Furthermore, duvelisib reduced expression of T cell exhaustion markers (Tim-3, Lag-3) and enriched early memory T cell populations. We have previously shown that duvelisib is more effective than inhibitors of only PI3K-δ or PI3K-γ in reducing Tregs and immunosuppressive myeloid cells when combined with an OX40 agonist antibody in a syngeneic tumor model. Accordingly, dual PI3K-δ,γ inhibition may represent an advantage over agents that inhibit only PI3K-δ or PI3K-γ for combination with PD-1 blockade. We next investigated whether duvelisib augments the efficacy of a PD-1 antibody (anti-PD-1) in solid tumor and lymphoma syngeneic models. In mice bearing CT26 colorectal tumors, duvelisib or anti-PD-1 alone induced tumor growth inhibition (TGI) of 59 and 49%, respectively, whereas duvelisib plus anti-PD-1 resulted in enhanced TGI (81%) and survival. Sixty percent of mice treated with duvelisib plus anti-PD-1 were tumor free, whereas only 10% of the mice treated with anti-PD-1 alone were tumor free by 60 days after tumor inoculation. In the A20 B-cell lymphoma model, reductions in tumor volume were observed with duvelisib or anti-PD-1 alone (TGI = 50 and 54%, respectively). Duvelisib plus anti-PD-1 was associated with enhanced antitumor activity (TGI = 85%) and survival (median survival of 37 days for the combination group compared to 16.5 and 18 days for duvelisib or anti-PD-1 monotherapy groups, respectively). Reductions in Tregs, M2 macrophages, and M-MDSCs in tumors were observed in the duvelisib plus anti-PD-1 combination group compared to anti-PD-1 alone. Taken together, these data indicate the value of dual PI3K-δ,γ inhibition for combination with PD-1 blockade and support clinical evaluation of duvelisib with anti-PD-1 in patients with solid tumors or hematologic malignancies. Clinical studies are underway investigating the combination of duvelisib plus nivolumab in aggressive lymphomas (Richter9s transformation or transformed FL; NCT03892044) and duvelisib plus pembrolizumab in head and neck squamous cell carcinoma. Citation Format: Silvia Coma, Christopher R. Funk, Shuhua Wang, Edmund K. Waller, David T. Weaver, Jonathan A. Pachter. Synergistic anti-tumor efficacy of the dual PI3K-δ/PI3K-γ inhibitor duvelisib with PD-1 blockade in solid tumor and lymphoma models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT045.