The immunomodulatory drugs lenalidomide and pomalidomide enhance the potency of AMG 701 in multiple myeloma preclinical models

Shih Feng Cho, Liang Lin, Lijie Xing, Yuyin Li, Kenneth Wen, Tengteng Yu, Phillip A. Hsieh, Nikhil Munshi, Joachim Wahl, Katja Matthes, Matthias Friedrich, Tara Arvedson, Kenneth C. Anderson, Yu Tzu Tai

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

We investigated here the novel immunomodulation and anti–multiple myeloma (MM) function of T cells engaged by the bispecific T-cell engager molecule AMG 701, and further examined the impact of AMG 701 in combination with immunomodulatory drugs (IMiDs; lenalidomide and pomalidomide). AMG 701 potently induced T-cell–dependent cellular cytotoxicity (TDCC) against MM cells expressing B-cell maturation antigen, including autologous cells from patients with relapsed and refractory MM (RRMM) (half maximal effective concentration, ,46.6 pM). Besides inducing T-cell proliferation and cytolytic activity, AMG 701 also promoted differentiation of patient T cells to central memory, effector memory, and stem cell–like memory (scm) phenotypes, more so in CD8 vs CD4 T subsets, resulting in increased CD8/CD4 ratios in 7-day ex vivo cocultures. IMiDs and AMG 701 synergistically induced TDCC againstMMcell lines and autologous RRMM patient cells, even in the presence of immunosuppressive bone marrow stromal cells or osteoclasts. IMiDs further upregulated AMG 701–induced patient T-cell differentiation toward memory phenotypes, associated with increased CD8/CD4 ratios, increased Tscm, and decreased interleukin 10–positive T and T regulatory cells (CD25highFOXP3high), which may downregulate T effector cells. Importantly, the combination of AMG 701 with lenalidomide induced sustained inhibition of MM cell growth in SCID mice reconstituted with human T cells; tumor regrowth was eventually observed in cohorts treated with either agent alone (P , .001). These results strongly support AMG 701 clinical studies as monotherapy in patients with RRMM (NCT03287908) and the combination with IMiDs to improve patient outcomes in MM.

Original languageEnglish (US)
Pages (from-to)4195-4207
Number of pages13
JournalBlood Advances
Volume4
Issue number17
DOIs
StatePublished - Sep 8 2020

ASJC Scopus subject areas

  • Hematology

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