Anti–B-cell Maturation Antigen Chimeric Antigen Receptor T cell Function against Multiple Myeloma Is Enhanced in the Presence of Lenalidomide

Abstract

Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cells have shown promising clinical responses in patients with relapsed/refractory multiple myeloma. Lenalidomide, an immunomodulatory drug, potentiates T cell functionality, drives antimyeloma activity, and alters the suppressive microenvironment; these properties may effectively combine with anti-BCMA CAR T cells to enhance function. Using an anti-BCMA CAR T, we demonstrated that lenalidomide enhances CAR T cell function in a concentration-dependent manner. Lenalidomide increased CAR T effector cytokine production, particularly under low CAR stimulation or in the presence of inhibitory ligand programmed cell death 1 ligand 1. Notably, lenalidomide also enhanced CAR T cytokine production, cytolytic activity, and activation profile relative to untreated CAR T cells in chronic stimulation assays. This unique potentiation of both short-term CAR T activity and long-term functionality during chronic stimulation prompted investigation of the molecular profile of lenalidomide-treated CAR T cells. Signatures from RNA sequencing and assay for transposase-accessible chromatin using sequencing indicated that pathways associated with T-helper 1 response, cytokine production, T cell activation, cell-cycle control, and cytoskeletal remodeling were altered with lenalidomide. Finally, study of lenalidomide and anti-BCMA CAR T cells in a murine, disseminated, multiple myeloma model indicated that lenalidomide increased CAR T cell counts in blood and significantly prolonged animal survival. In summary, preclinical studies demonstrated that lenalidomide potentiated CAR T activity in vivo in low-antigen or suppressive environments and delayed onset of functional exhaustion. These results support further investigation of lenalidomide and anti-BCMA CAR T cells in the clinic.

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

“…IMiDs costimulate immune effector cells (T, NK) and block immunosuppressive BM accessory cells, that is, myeloid suppressor cells, regulatory T (Treg) and regulatory B (Breg) cells, via cell-cell contact and cytokinemediated mechanisms. 4,[36][37][38][39][40][41][42] In recent preclinical studies, IMiDs coupled with CAR T cells had increased anticancer activity compared with CAR T cells alone, [43][44][45] suggesting that the combination of IMiDs with other novel immunotherapeutic modalities may show enhanced antitumor activity. Until now, the combination of IMiDs with BiTE molecule treatment has not been investigated in MM.…”

CAR T-Cell Therapy for B-Cell non-Hodgkin Lymphoma and Chronic Lymphocytic Leukemia: Clinical Trials and Real-World Experiences

“…Lenalidomide and other immunomodulatory drugs (IMIDs) can also be used to recover T-cell exhaustion. Preclinical data have demonstrated that lenalidomide enhances the anti-tumor activity and persistence of CAR T cells in different NHL and multiple myeloma models ( 141 – 143 ). Of note, the already mentioned PLATFORM trial also includes an arm in which patients will receive CC-122, a novel IMID, and the phase 1/2 ZUMA-11 trial (NCT03704298) is investigating the safety and efficacy of axi-cel in combination with utomilumab, a monoclonal antibody that binds 4-1BB and stimulates immune cells, in patients with refractory DLBCL.…”

Befriending the Hostile Tumor Microenvironment in CAR T-Cell Therapy

“…Recently, considerable work has been done to study how lenalidomide, an immune-modulatory drug, can be used to potentiate CAR T-cells. Indeed several studies have shown that treatment of CAR T-cells with lenalidomide improved CAR T-cell cytokine release and cytotoxicity in vitro , and improved tumor clearance in mouse models of multiple myeloma and lymphoma ( 124 – 126 ). In another murine model of CRS, Ruella et al.…”