Lenalidomide enhances antitumor functions of chimeric antigen receptor modified T cells

Abstract

Tumor immunotherapy based on the use of chimeric antigen receptor modified T cells (CAR T cells) is a promising approach for the treatment of refractory hematological malignancies. However, a robust response mediated by CAR T cells is observed only in a minority of patients and the expansion and persistence of CAR T cells in vivo is mostly unpredictable.Lenalidomide (LEN) is an immunomodulatory drug currently approved for the treatment of multiple myeloma (MM) and mantle cell lymphoma, while it is clinically tested in the therapy of diffuse large B-cell lymphoma of activated B cell immunophenotype. LEN was shown to increase antitumor immune responses at least partially by modulating the activity of E3 ubiquitin ligase Cereblon, which leads to increased ubiquitinylation of Ikaros and Aiolos transcription factors, which in turn results in changed expression of various receptors on the surface of tumor cells. In order to enhance the effectiveness of CAR-based immunotherapy, we assessed the anti-lymphoma efficacy of LEN in combination with CAR19 T cells or CAR20 T cells in vitro and in vivo using various murine models of aggressive B-cell non-Hodgkin lymphomas (B-NHL).Immunodeficient NSG mice were transplanted with various human B-NHL cells followed by treatment with CAR19 or CAR20 T cells with or without LEN. Next, CAR19 T cells were subjected to series of tests in vitro to evaluate their response and signaling capacity following recognition of B cell in the presence or absence of LEN.Our data shows that LEN significantly enhances antitumor functions of CAR19 and CAR20 T cells in vivo. Additionally, it enhances production of interferon gamma by CAR19 T cells and augments cell signaling via CAR19 protein in T cells in vitro. Our data further suggests that LEN works through direct effects on T cells but not on B-NHL cells. The biochemical events underlying this costimulatory effect of LEN are currently being investigated. In summary, our data supports the use of LEN for augmentation of CAR-based immunotherapy in the clinical grounds.

Advances of CD19-directed chimeric antigen receptor-modified T cells in refractory/relapsed acute lymphoblastic leukemia

“…One study found that lenalidomide has synergistic anti-tumor effects with CD19 CAR-T cells and CD20 CAR-T cells in treating B-Non Hodgkin’s lymphoma (B-NHL) [46]. …”

A review of chimeric antigen receptor T-cells in lymphoma

“…Proposed mechanisms for this observation include of mobilization of malignant cells into blood by ibrutinib and/or reduction of expression of inhibitory receptors such as PD-1 [34]. Similar synergistic response is seen in models with the use of lenolidomide and CAR-T possibly via improved co-stimulation of CAR and/or favorable cytokine expression of IL2 and TNF gamma [39]. Large multi-center clinical trials with the use of CAR-T in MCL are currently underway including the TRANSCEND (NCT02631044) and ZUMA-2 (NCT02601313) trials.…”

Redirecting T cells with Chimeric Antigen Receptor (CAR) for the treatment of childhood acute lymphoblastic leukemia

“…Moreover, pembrolizumab proved to be safe and well tolerated, and only a slight fever was reported in 2 of the patients and no autoimmune toxicities were observed [93]. Other innovative approaches have been investigated such as the combination with lenalidomide [94], or indoleamine 2,3dioxygenase (IDO) inhibitors [95], highlighting how this field of research is continuously raising the bar moving toward a more personalized medicine.…”