Clinical regressions and broad immune activation following combination therapy targeting human NKT cells in myeloma

Abstract

Key Points• Broad immune activation after a combination of lenalidomide and a-GalCer-loaded dendritic cells.• Proof of principle for harnessing NK T cells to prevent cancer in humans. Natural killer T (iNKT) cells can help IntroductionNatural killer T (NKT) cells are distinct innate CD1d-restricted T cells that recognize lipid antigens. 1 The best-studied subset of NKT cells in both mice and humans are type I NKT cells that express an invariant T-cell receptor. Several studies have described potent antitumor properties of iNKT cells in preclinical models and iNKT cells have also been implicated in immune surveillance against both spontaneous as well as carcinogeninduced murine tumors. 2,3 While iNKT cells can mediate lysis of tumor cells, their antitumor effects likely depend in large part on their ability to activate other immune cells such as NK and dendritic cells (DCs) and recruit adaptive immunity as well as mediate antiangiogenesis. 4-6 ␣-galactosylceramide (␣-GalCer) is a potent prototypic ligand for both human and murine iNKT cells. 7 The availability of clinical-grade ␣-GalCer (KRN7000; KHK) allowed testing of iNKT-targeted approaches in humans. 8 Initial studies with injection of soluble KRN7000 led to only modest effects in humans. [9][10][11] Preclinical studies suggested that targeting ␣-GalCer to DCs led to superior activation of NKT cells in vivo. 12 In a prior study, we have shown that the injection of ␣-GalCer-loaded human DCs led to a clear increase in circulating iNKT cells in vivo. 13 However, these cells were still functionally deficient and, importantly, little activation of downstream innate immune function (including NK cells) was observed.It is now clear that nearly all cases of clinical myeloma (MM) are preceded by an asymptomatic precursor state, including a phase termed as asymptomatic multiple myeloma (AMM). 14 Patients with AMM are currently observed but carry high risk for progression to clinical MM requiring therapy. Strategies to prevent clinical MM may therefore have a major impact on disease-related morbidity and mortality. 14 In prior studies, we have shown that progression from precursor to clinical MM is associated with progressive dysfunction of iNKT cells in vivo. 15 Myeloma is an attractive tumor for NKT-targeted approaches because tumor cells commonly express CD1d and are sensitive to lysis by both NKT as well as NK cells. 15,16 In the past decade, incorporation of immunomodulatory drugs such as lenalidomide (LEN) into clinical care has improved outcome in human MM. 17 An important property of these drugs is providing costimulation of both human T cells as well as NKT cells in culture in an antigen-dependent manner. 18-20 Therefore, we hypothesized that the combination of LEN with ␣-GalCer-loaded DCs will lead to synergistic activation of innate lymphocytes in vivo and mediate antitumor effects in the preventive setting. As LEN alone has some single-agent activity in MM, 21 we chose to test a LEN dose of 10 mg/d, which is lower than the usual starting dose (25 mg/d) in ...

iNKT‐cell help to B cells: A cooperative job between innate and adaptive immune responses

“…In this respect, data obtained in clinical trials for cancer immunotherapy show that administration of αGalCer in humans is safe and does not cause notable side effects [3]. Moreover, the data obtained in cancer patients who received αGalCer-containing vaccines show clear expansion and functional activation of iNKT cells, correlating with the clinical responses, indicating a remarkable responsiveness of these cells to the immunogen in spite of their relatively low frequency in the human immune system [66, 67]. Thus, the possibility to exploit the flexible helper functions of iNKT cells opens the way to the design of a new generation of vaccines.…”

A phase II trial of pan-KIR2D blockade with IPH2101 in smoldering multiple myeloma

“…In vitro studies confirm that IPH2101 enhances NK-cell killing of MM-cell lines, 2 while data from KIR ligand-mismatched allogeneic stem cell transplants (SCT) 3 and infusions of KIR ligand-mismatched allogeneic NK cells prior to autologous SCT 4 suggest a potential therapeutic benefit. Since deteriorated NKcell function tends to occur in later clinical stages of MM, 5 we hypothesized that smoldering multiple myeloma (SMM) may be a unique time point for NK-cell based interventions prior to evasion of host immune system by tumor cells.…”

Natural killer T cell defects in multiple myeloma and the impact of lenalidomide therapy

“…Only two patients with MM were examined in that study, but a more recent analysis of patients with asymptomatic myeloma treated with lenalidomide in combination with αGalCer loaded monocyte-derived dendritic cells (DCs) also identified activated NKT cells and reduced serum paraprotein [20]. Although it was difficult to isolate the impact of the lenalidomide from the transferred DCs in that study, the study speculated that combination therapies targeting NKT cells could help to prevent disease progression in humans.…”

“…The regulatory functions of NKT cells rely upon rapid release of cytokines in response to stimulation; lenalidomide has been proposed as a means of boosting NKT cell function in patients with MM because several studies have demonstrated improved cytokine production by NKT cells in the presence of lenalidomide [18,20,30]. We have reported previously that lenalidomide treatment of patients with MDS did not impact NKT cell frequency or function significantly [29].…”

“…Defective interferon (IFN)-γ production by NKT cells and a trend towards lower NKT cell frequencies reportedly affect patient groups with MM and are also observed in animal models of MM [8,12,17]. As a result, many studies have nominated NKT cells as a potential new target for treatment of MM in humans [12,13,16,[18][19][20].…”