Activity of lenalidomide in mantle cell lymphoma can be explained by NK cell‐mediated cytotoxicity

Abstract

Lenalidomide is an immunomodulatory agent that has demonstrated clinical benefit for patients with relapsed or refractory mantle cell lymphoma (MCL); however, despite this observed clinical activity, the mechanism of action (MOA) of lenalidomide has not been characterized in this setting. We investigated the MOA of lenalidomide in clinical samples from patients enrolled in the CC-5013-MCL-002 trial (NCT00875667) comparing single-agent lenalidomide versus investigator's choice single-agent therapy and validated our findings in pre-clinical models of MCL. Our results revealed a significant increase in natural killer (NK) cells relative to total lymphocytes in lenalidomide responders compared to non-responders that was associated with a trend towards prolonged progression-free survival and overall survival. Clinical response to lenalidomide was independent of baseline tumour microenvironment expression of its molecular target, cereblon, as well as genetic mutations reported to impact clinical response to the Bruton tyrosine kinase inhibitor ibrutinib. Preclinical experiments revealed lenalidomide enhanced NK cell-mediated cytotoxicity against MCL cells via increased lytic immunological synapse formation and secretion of granzyme B. In contrast, lenalidomide exhibited minimal direct cytotoxic effects against MCL cells. Taken together, these data provide the first insight into the clinical activity of lenalidomide against MCL, revealing a predominately immune-mediated MOA.

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

“…These results support recent findings from two clinical studies. One study noted early T‐cell activation in patients with relapsed FL or DLBCL in response to lenalidomide monotherapy (Menard et al , ), and another revealed lenalidomide‐mediated enhancement of NK cell proliferation in patients with MCL (Hagner et al , ). Results of our analysis of patient samples from the phase 3 RELEVANCE trial (Morschhauser et al , ) are consistent with those from a phase 2 trial of R 2 in FL, where increased numbers of memory T cells, NK cells, and other immune cell populations were detected in peripheral blood of patients, starting from cycle 2 day 1 of therapy (Fowler et al , ; Morschhauser et al , ).…”

“…In neoplastic B cells, degradation of these substrates causes apoptosis, whereas in T cells the result is enhanced co-stimulation signalling and increased interleukin 2 (IL2) production (Gandhi et al, 2014). As a single agent, lenalidomide restores the ability of tumourinfiltrating T cells from patients with B-cell lymphoma to form functional immune synapses with autologous malignant B cells (Ramsay et al, 2008(Ramsay et al, , 2009Hagner et al, 2017). Lenalidomide in combination with rituximab (R 2 ) has been shown to enhance activation of healthy donor NK cells and increase ADCC of various NHL cell lines (Wu et al, 2008;Zhang et al, 2009;Lagrue et al, 2015).…”

A clearer light on the role of NK cells in haematological malignancies

“…Given that a benefit in progression‐free survival (PFS) was observed in the lenalidomide arm, this would seem to be a fitting setting to evaluate its mode of action. Fortunately, cell material from a number of participating patients was available, and in a paper in this issue (Hagner et al , ) several of the above mentioned mechanisms of action are addressed in a longitudinal fashion.…”

“…Notably, the effect could be shown as significant increases in the number of circulating CD56 + NK cells in responders, but not in non‐responders (with a trend towards increased PFS and overall survival). In addition, in an in vitro setting analysing NK cytotoxicity of MCL cell lines, lenalidomide was shown to act primarily by enhancing the NK synapse formation and secretion of granzyme B (Hagner et al , ).…”

“…The latter highlights another feature of this company‐sponsored trial, namely the addition of banked material. At the end of the day, it might be argued that the value of the clinical study, on which the study by Hagner et al () is based, is related to these para‐clinical findings rather than the single agent therapy approach to patients with end‐stage MCL.…”