NK cell activation and recovery of NK cell subsets in lymphoma patients after obinutuzumab and lenalidomide treatment

Abstract

Obinutuzumab (OBZ) shows stronger antibody-dependent cell cytotoxicity (ADCC) compared to rituximab and improved clinical activity for treating certain CD20 C neoplasia. However, the efficacy of monoclonal antibody (mAb) as a monotherapy is limited. Natural Killer (NK) cells are mediators of ADCC. Hematological cancer patients possess antitumor NK cells that are unable to control disease, possibly because they are dysfunctional. The immunomodulatory drug lenalidomide (LEN) could be a treatment to restore exhausted NK cell cytotoxic functions. The clinical trial GALEN is a Phase Ib/II study of OBZ combined with LEN for the treatment of relapsed/refractory follicular and aggressive (DLBCL and MCL) B-cell Lymphoma. During treatment, we analyzed specific aspects of NK cell biology. Treatment reversed the immature NK phenotype of patients and increased expression of NK activating receptors. Inhibitory receptors were either unchanged or decreased. There was a strong NK response at the end of the 1st cycle: NK number and intracellular granzyme B (GrzB) expression decreased, degranulation increased and NK responded better to allogeneic target challenge. Moreover, the interaction of NK cells with B cell targets, measured by trogocytosis, decreased during treatment. At the end of treatment, when target cells had been wiped out, the proportion of reactive NK cells (CD69 C , CD45RARO C , CD107a C , CD19 C) strongly decreased. Because all patients received LEN and OBZ, it was uncertain which drug was responsible of our observations, or even if a combination of both products was necessary for the described effects on this lymphocyte lineage.

Unleashing Natural Killer Cells in the Tumor Microenvironment–The Next Generation of Immunotherapy?

“…As additional means to augment NK-mediated anti-CD20 therapy (apart from glyco-optimization), combination with cytokines such as IL-15/21 was shown to increase the efficacy of anti-CD20 treatment (226)(227)(228). Lenalidomide, an immunomodulatory drug commonly used for multiple myeloma also enhances the effect of anti-CD20 administration on NK cell effector function, in part by promoting nanoscale reorganization of the cytoskeleton at the immunological synapse (229)(230)(231). Moreover, a recent study revealed a CD56 hi CD16 − PD-1 hi NK population in HL patients.…”

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

“…These findings support early results of a phase 3 trial of R 2 in relapsed/refractory FL, in which patients with double‐refractory FL have achieved 1‐year PFS rates of 66% and CR/CRu rates of 21% (Andorsky et al , ). Lenalidomide has also demonstrated immune stimulatory activity in combination with the type II anti‐CD20 antibody obinutuzumab, as recently reported by Morschhauser et al from their phase 1b (GALEN) study, where they are assessing the combination in patients with relapsed/refractory FL (Morschhauser et al , ; Vo et al , ). Their analysis showed that lenalidomide monotherapy prior to the first infusion of obinutuzumab resulted in reactivation of peripheral blood T cells (Menard et al , ).…”

“…Their analysis showed that lenalidomide monotherapy prior to the first infusion of obinutuzumab resulted in reactivation of peripheral blood T cells (Menard et al , ). Moreover, lenalidomide in combination with obinutuzumab reversed an immature NK phenotype and induced activation of circulating NK cells (Vo et al , ). These findings are similar to the effects we observed when NK cells from FL patients were treated with combination lenalidomide‐rituximab ex vivo .…”

Non-Genetically Improving the Natural Cytotoxicity of Natural Killer (NK) Cells

“…Interestingly, recent clinical data also in myeloma suggest that such antibodies can modify the endogenous NK repertoire and make them further hyporeactive (19). Other clinical attempts to activate endogenous NK cells include the use of lenalidomide [LEN; (20,21)]. Biological results from the Phase Ib/II clinical trial GALEN suggest that LEN could facilitate obinutuzumab (OBZ)-mediated NK cell activation (21), as was observed with rituximab (RTX) (22).…”

“…Other clinical attempts to activate endogenous NK cells include the use of lenalidomide [LEN; (20,21)]. Biological results from the Phase Ib/II clinical trial GALEN suggest that LEN could facilitate obinutuzumab (OBZ)-mediated NK cell activation (21), as was observed with rituximab (RTX) (22). In fact cancer patients, at least those with hematological cancers, already possess NK cells, which recognize and kill tumor cells, but are unable to control the disease (21,23,24).…”