Effect of dual PI3K-δ,γ inhibitor duvelisib on immunosuppressive Tregs and myeloid cells to enhance efficacy of checkpoint and co-stimulatory antibodies in a B cell lymphoma model.

Abstract

33 Background: Duvelisib is a dual inhibitor of PI3K-δ and PI3K-γ which has shown clinical activity as monotherapy in CLL/SLL, FL and T cell lymphoma (O’Brien; Flinn; Horwitz, ASH 2014). Recent publications have demonstrated that PI3K-δ inhibition reduces immunosuppressive Tregs (Ali, Nature, 2014) whereas PI3K-γ inhibition reduces immunosuppressive myeloid cells (Kaneda, Nature, 2016; De Henau, Nature, 2016). Hence, we postulated that duvelisib may augment the efficacy of immune checkpoint or co-stimulatory antibodies. Methods: Mice bearing syngeneic A20 B cell lymphoma tumors (60-90 mm3) were treated with vehicle, duvelisib, anti-PD1, anti-PD1 + duvelisib, anti-OX40, or anti-OX40 + duvelisib. Tumor volumes were measured by caliper. Tregs, macrophages and MDSCs were quantified by flow cytometry from mice bearing A20 tumors after 8 days of treatment. Results: In the A20 model, duvelisib, anti-PD-1 and anti-OX40 treatments each induced tumor growth delay. When duvelisib and anti-PD-1 were combined in mice with pre-existing A20 tumors, strong anti-tumor synergy was observed. When anti-OX40 and duvelisib were combined, tumor regression was observed which correlated with strong reduction of tumor Tregs, M2 macrophages and MDSCs. To assess immune memory, tumor-free mice following anti-OX40 alone or anti-OX40 + duvelisib were injected with A20 cells in the contralateral flank with no further treatment. Whereas mice that had received anti-OX40 alone grew new tumors upon A20 re-challenge, all tumor-free mice that had received anti-OX40 + duvelisib did not grow tumors upon re-challenge and showed elevated memory T cells in blood and spleen. These findings indicate that anti-OX40 + duvelisib treatment established immune memory. Conclusions: The dual inhibition of PI3K-δ and PI3K-γ appears to make duvelisib especially effective in reducing both lymphoid and myeloid immuno-suppressive populations, enhancing the anti-tumor efficacy of immune checkpoint and co-stimulatory antibodies. These data support potential clinical exploration of duvelisib in combination with checkpoint or co-stimulatory antibodies.