Data from Lenalidomide Enhances Immune Checkpoint Blockade-Induced Immune Response in Multiple Myeloma

Julie E Anderson,Shohei Kikuchi,Randie E White,Rikio Suzuki,Teru Hideshima,Hiroto Ohguchi,Giada Bianchi,Florence Magrangeas,David M Dorfman,Nikhil C Munshi,Ahaana Singh,Güllü Görgün,Steven Paula,Noopur Raje,Jacob P Laubach,Mehmet K Samur,Paul G Richardson,Kenneth C Anderson,Taishi Harada ,Yu‐Tzu Tai ,Hervé Avet‐Loiseau ,Kristen Cowens ,Stéphane Minvielle

doi:10.1158/1078-0432.c.6524619.v1

Abstract

<div>AbstractPurpose: PD-1/PD-L1 signaling promotes tumor growth while inhibiting effector cell–mediated antitumor immune responses. Here, we assessed the impact of single and dual blockade of PD-1/PD-L1, alone or in combination with lenalidomide, on accessory and immune cell function as well as multiple myeloma cell growth in the bone marrow (BM) milieu.Experimental Design: Surface expression of PD-1 on immune effector cells, and PD-L1 expression on CD138+ multiple myeloma cells and myeloid-derived suppressor cells (MDSC) were determined in BM from newly diagnosed (ND) multiple myeloma and relapsed/refractory (RR) multiple myeloma versus healthy donor (HD). We defined the impact of single and dual blockade of PD-1/PD-L1, alone and with lenalidomide, on autologous anti–multiple myeloma immune response and tumor cell growth.Results: Both ND and RR patient multiple myeloma cells have increased PD-L1 mRNA and surface expression compared with HD. There is also a significant increase in PD-1 expression on effector cells in multiple myeloma. Importantly, PD-1/PD-L1 blockade abrogates BM stromal cell (BMSC)-induced multiple myeloma growth, and combined blockade of PD-1/PD-L1 with lenalidomide further inhibits BMSC-induced tumor growth. These effects are associated with induction of intracellular expression of IFNγ and granzyme B in effector cells. Importantly, PD-L1 expression in multiple myeloma is higher on MDSC than on antigen-presenting cells, and PD-1/PD-L1 blockade inhibits MDSC-mediated multiple myeloma growth. Finally, lenalidomide with PD-1/PD-L1 blockade inhibits MDSC-mediated immune suppression.Conclusions: Our data therefore demonstrate that checkpoint signaling plays an important role in providing the tumor-promoting, immune-suppressive microenvironment in multiple myeloma, and that PD-1/PD-L1 blockade induces anti–multiple myeloma immune response that can be enhanced by lenalidomide, providing the framework for clinical evaluation of combination therapy. Clin Cancer Res; 21(20); 4607–18. ©2015 AACR.</div>

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