Combination lenalidomide‐rituximab immunotherapy activates anti‐tumour immunity and induces tumour cell death by complementary mechanisms of action in follicular lymphoma

Abstract

Summary Chemotherapy plus rituximab has been the mainstay of treatment for follicular lymphoma ( FL ) for two decades but is associated with immunosuppression and relapse. In phase 2 studies, lenalidomide combined with rituximab (R 2 ) has shown clinical synergy in front‐line and relapsed/refractory FL . Here, we show that lenalidomide reactivated dysfunctional T and Natural Killer ( NK ) cells ex vivo from FL patients by enhancing proliferative capacity and T‐helper cell type 1 (Th1) cytokine release. In combination with rituximab, lenalidomide improved antibody‐dependent cellular cytotoxicity in sensitive and chemo‐resistant FL cells, via a cereblon‐dependent mechanism. While single‐agent lenalidomide and rituximab increased formation of lytic NK cell immunological synapses with primary FL tumour cells, the combination was superior and correlated with enhanced cytotoxicity. Immunophenotyping of FL patient samples from a phase 3 trial revealed that R 2 treatment increased circulating T‐ and NK ‐cell counts, while R‐chemotherapy was associated with reduced cell numbers. Finally, using an in vitro model of myeloid differentiation, we demonstrated that lenalidomide caused a reversible arrest in neutrophil maturation that was distinct from a cytotoxic chemotherapeutic agent, which may help explain the lower rates of neutropenia observed with R 2 versus R‐chemotherapy. Taken together, we believe these data support a paradigm shift in the treatment of FL – moving from combination immunochemotherapy to chemotherapy‐free immunotherapy.

Prognostic implications of the microenvironment for follicular lymphoma under immunomodulation therapy

“…We substantiate the selective influence of this immunomodulatory agent to potentially restore this immune synapsis, corroborating in vitro and in vivo experiments in different settings of haematological diseases (Gorgun et al , ; Balaian et al , ; Grygorowicz et al , ). Along these lines, using samples of the RELEVANCE trial, Chiu et al , () could demonstrate by analysis of peripheral blood patient samples and in vitro that lenalidomide can reactivate anergic/silenced natural killer (NK) cells and T cells and that patients receiving R 2 therapy had higher circulating amounts of T and NK cells in comparison to patients of the R arm (Chiu et al , ). Lenalidomide was shown to be capable of (re)activating the interaction of these T and NK cells with lymphoma cells.…”

Avadomide monotherapy in relapsed/refractory DLBCL: safety, efficacy, and a predictive gene classifier

“…The 5/7-day schedule was introduced based on preclinical data from an in vitro assay of neutrophil differentiation. 52 In these experiments, continuous treatment of bone marrow precursor cells with avadomide led to an arrest in myeloid maturation at a promyelocyte stage with a 90% decrease in mature neutrophil counts compared with vehicle control (supplemental Figure 4). Shifting to a 5/7-day treatment schedule partially relieved the arrest and allowed mature neutrophil populations in the cultures to expand.…”

“…We recently reported that lenalidomide-mediated degradation of Ikaros in an in vitro model of myeloid differentiation results in a reversible arrest in neutrophil maturation, which is released upon removal of the drug, without any loss of cell viability. 52 Using a similar preclinical model, we demonstrated that treatment of human bone marrow precursor cells with avadomide on a novel 5/7-day schedule allowed Ikaros to be resynthesized during the 2-day drug holiday, enabling mature neutrophils to repopulate after a transient arrest. 57 Our data demonstrate the potent immunomodulatory activity of avadomide, including positive effects on T-cell activation and a broad expansion of T-cell populations, as defined by an increase in richness of the peripheral T-cell repertoire.…”

Mechanisms of Resistance to NK Cell Immunotherapy

“…Indeed, lenalidomide markedly increases NK cell activation and proliferation through the induction of IL-2 production by CD4 T cells in chronic lymphocytic leukemia (CLL) [46,47]. Also, lenalidomide increases NK cell numbers, promotes the expression of activating receptors, such as CD16, and reduces that of checkpoint receptors, thus enhancing NK cell-mediated cytotoxicity and ADCC [45,46,[48][49][50]. Moreover, lenalidomide increases the expression of NKG2D and DNAM-1 ligands (MICA and PVR) in multiple myeloma [51].…”