Advances in Hematology

Advances in Hematology / 2012 / Article
Special Issue

Lenalidomide in the Treatment of Lymphoproliferative Disorders and Multiple Myeloma

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Review Article | Open Access

Volume 2012 |Article ID 513702 | 9 pages |

Molecular Action of Lenalidomide in Lymphocytes and Hematologic Malignancies

Academic Editor: Anna Marina Liberati
Received16 Nov 2011
Revised12 May 2012
Accepted18 Jun 2012
Published24 Jul 2012


The immunomodulatory agent, lenalidomide, is a structural analogue of thalidomide approved by the US Food and Drug Administration for the treatment of myelodysplastic syndrome (MDS) and multiple myeloma (MM). This agent is also currently under active investigation for the treatment of chronic lymphocytic leukemia (CLL) and non-Hodgkin’s lymphoma (NHL), as well as in drug combinations for some solid tumors and mantle cell lymphoma (MCL). Although treatment with lenalidomide has translated into a significant extension in overall survival in MM and MDS and has superior safety and efficacy relative to thalidomide, the mechanism of action as it relates to immune modulation remains elusive. Based on preclinical models and clinical trials, lenalidomide, as well as other structural thalidomide derivatives, enhances the proliferative and functional capacity of T-lymphocytes and amplifies costimulatory signaling pathways that activate effector responses and suppress inflammation. This paper summarizes our current understanding of T- and natural killer (NK) cell pathways that are modified by lenalidomide in hematopoietic neoplasms to inform future decisions about potential combination therapies.

1. Introduction

Lenalidomide (Revlimid, CC-5013) is a second-generation synthetic derivative of glutamic acid and thalidomide analogue with antiangiogenic, antitumorigenic, and immunomodulating activity that was realized due to anecdotal immunomodulatory activity in erythema nodosum leprosum (ENL) [1, 2] and in autoimmune disorders [35]. Creation of synthetic modifications to the thalidomide backbone led to the discovery of lenalidomide and pomalidomide with 500-fold greater immunomodulatory potency and safer side effect profile compared to the parent drug [6, 7]. Use of lenalidomide in proliferative neoplasms has recently intensified due to the agent’s success in MM and MDS where it acts to alter immune homeostasis and modulate inflammation within the bone marrow microenvironment. Studies in relapsed and refractory B-cell chronic lymphocytic leukemia (B-CLL) as well as non-Hodgkin’s lymphoma (NHL) solid malignancies such as central nervous system, ovarian, and renal cell carcinoma demonstrate the potential of this drug in diverse neoplastic processes [8, 9]. While the molecular antitumor mechanism and specificity have been extensively studied in preclinical and clinical settings, the future application and design of effective therapeutic combinations with lenalidomide is dependent on understanding the immunomodulatory mechanism and anti-inflammatory properties in the context of the bone marrow milieu, the microenvironmental interactions, and bioactivity within adaptive and innate immune cells.

2. Lenalidomide Augments T-Cell Proliferation and Activation

Immunosurveillance of cancer cells is now a well-established principle thought to contribute not only to the quantity, but also to the quality, or immunogenicity, of a tumor during development [10, 11]. Mechanisms regulating innate and adaptive immune responses are carefully orchestrated to detect and remove infected, transformed, or erratically growing cells within the body. Immune tolerance, induced by changes in the microenvironment and within the tumor cells, contributes to neoplastic expansion. Lenalidomide is able to enhance the proliferative and functional capacity of T cells, which augments immune activity through a variety of mechanisms. Thalidomide was first shown to augment T-cell proliferation and cytokine production in the absence of costimulatory molecules without direct mitogenic activity [12]. Early reports of bone marrow lymphoid aggregates in lenalidomide-responsive MDS patients implicated immune modulation in hematological responses to this agent [13]. When a T-cell encounters cognate tumor antigens presented by antigen presenting cell (APCs), there is an increase in a variety of costimulatory molecules, most importantly CD28, that enables a fully competent signal response by T cells [14]. CD28 binds to B7-1 (CD80) and -2 (CD86) molecules on APCs to generate the appropriate response to antigen stimulation. Absence of CD28-APC interaction (Signal 2) in the presence of T-cell receptor ligation (Signal 1) leads to inactivation or anergy of naïve T cells. Thalidomide, and to a greater extent lenalidomide, induces interleukin-2 (IL-2), interferon-γ (IFN-γ), and TNF-α secretion [12] in the absence of CD28 stimulation, suggesting that the drug somehow activates the costimulatory-dependent signaling cascade initiated by Signal 2 [15].

Both Signal 1 (TCR) and Signal 2 (co-stimulation) are necessary for IL-2 production leading to the hypothesis that lenalidomide and the other IMiDs function somewhere within this costimulatory pathway [1618]. Signaling pathways associated with IL-2 transcriptional activation are shown in Figure 1 and recently reviewed by [19]. The exact differential downstream intermediates emanating from the TCR CD28 are difficult to elucidate because the pathways are integrally connected. LeBlanc et al. showed that lenalidomide acts to increase tyrosine-phosphorylation in the intracellular domain of the CD28 receptor in the absence of costimulatory molecules [20]. Although it is not known if lenalidomide acts directly to induce phosphorylation, the presence of downstream signaling events after treatment such as NF-κB p65 translocation to the nucleus, and cytokine production, suggests that this pathway may be important for lenalidomide’s immunomodulatory effect [20]. Others have shown that the activation of PKC-ζ and NFAT-2 are important mediators of cytokine production after IMiD treatment [21]. However, a conflicting report showed that PKC-θ activity and AP-1 DNA binding was increased, without an increase in NF-κB, OCT-1, and NFAT transcription factor binding, which adds to the controversy about lenalidomide’s T-cell-associated molecular mechanism of action [22, 23] (see Figure 1). These controversial results, however, may be attributed to the methods used for T-cell stimulation, namely, TCR stimulation versus calcium channel activation, respectively. Görgün et al. showed that lenalidomide and pomalidomide reduce Suppressor of Cytokine Signaling-1 (SOCS1) expression in T cells, which is an important negative regulator of cytokine signaling [24]. Even when treated with IFN-γ to induce SOCS1 expression, the drug was capable of blocking this inhibitory response and potentiating TCR/anti-CD28 costimulation in effector T cells [24]. Although reduction in a suppressive signal may be important, this would not be expected to generate unique responses, such as IL-2, that specifically require a costimulatory signal.

In addition to the activation of effector T cells and NK cells, there is a valid concern about the potential effect of IMiDs on regulatory T (Treg) cells that may deter antitumor immunity by suppressing immunosurveillance [11, 25]. In this regard, lenalidomide and pomalidomide were shown to inhibit the expansion and function of Tregs by downregulating the expression of forkhead box protein 3 (FOXP3) [26, 27]. The preferential augmentation of CD8+ cytotoxic T cells and inhibition of regulatory T cells makes this drug a very interesting and potentially valuable therapeutic candidate to augment immunotherapy responses in cancer patients.

In addition to the specific effects of lenalidomide on T-cell signaling, our lab and others have shown that the drug alters homeostatic regulation of T cells [28]. In MDS and MM, lenalidomide preferentially acts on specific T-cell memory subsets to reverse immune dysfunction. We found that erythroid responsive MDS patients displayed a greater increase in naïve and central memory T-cell subsets compared to nonresponders. This increase was associated with a concurrent decrease in effector memory subsets, potentially indicating that the drug restores immune homeostasis [28]. A similar increase in central memory T cells was observed by Noonan et al. [29] in MM patients that received lenalidomide in combination with the pneumococcal 7-valent conjugated vaccine (PCV) to establish the principle of vaccine combination therapy. Interestingly, the increase in PCV-specific antibody and cellular responses was specific to the vaccination schedule favoring administration of lenalidomide prior to PCV vaccine. B-CLL, like MDS, is associated with dysfunctional T-cell activity [30, 31] with defects in actin polarization at the immune synapse [32]. Treatment with lenalidomide in CLL restored IL-2 and IFN-γ secreting CD4+ and CD8+ T cells to normal levels [33] and reversed the suppressive signals blocking lytic synapse formation [32].

Antigen-specific effector T-cell activity in vitro and in vivo after lenalidomide was demonstrated after treatment for MM, supporting the idea that T-cell reconstitution may be important for antileukemia effects and eradication of myeloma cells [34]. Our studies have shown that lenalidomide is capable of increasing proliferation and cytokine secretion in anergic MDS T cells and indicate that lenalidomide not only improves healthy T-cell function, but also reverses intrinsic cancer-related immune defects associated with deregulated cancer immunosurveillance.

The evidence from in vitro and in vivo experiments to date, therefore, indicates that lenalidomide has multiple effects on T-cell signaling, but the exact molecular target and mechanism remain elusive. Interestingly, the molecular target mediating thalidomide’s teratogenic effects was identified in 2010 by Ito et al. [35]. Using thalidomide-conjugated beads, an E3 ubiquitin ligase, cereblon (CRBN), was shown to directly bind to thalidomide and mediate limb malformation in a zebrafish model. Mutations of two amino acids (Y374A and W376A) in zebrafish CRBN eliminated the drug’s ability to interact with the protein and prevented its effects on limb formation. Decreased cereblon expression in MM cells was also recently found to be associated with lenalidomide and pomalidomide resistance [36]. CRBN functions within an E3 complex containing several components including DDB1 and Cullin 4 (Cul4A or Cul4B) that polyubiquitinate (Ub) substrate proteins and mediate their degradation [35]. CRBN and other members of this E3 complex play no known role in T-cell signaling. However, increased Cul4A expression was recently linked to thalidomide response in prostate cancer [37]. Lenalidomide was shown recently by our group to stabilize mouse double minute 2 protein (MDM2) by blocking its autoubiquitination [38]. Since MDM2, like CRBN, is a RING finger E3 ubiquitin ligase, it is possible that IMiDs mediate a class-selective suppressive action against Ub-ligating enzymes, potentially mediating the increase in T-cell signaling.

3. Lenalidomide in B-CLL and MM

Lenalidomide has proven efficacy in several hematologic malignancies, including MDS, B-CLL, MM, and even some solid tumors attributed to T-cell and NK cell functional reconstitution. B-CLL is the most common leukemia in the United States, and although treatment with nucleoside analog-based chemoimmunotherapies has significantly enhanced outcomes in patients, nearly all of the patients ultimately relapse [39]. Lenalidomide combination treatments for patients with relapsed, refractory, and primary CLL, have resulted in durable hematologic improvement [4042]. Exposure of primary CLL cells to lenalidomide in vitro leads to the induction of costimulatory molecules like CD80, CD86, and FASL on the tumor cells [43], restoring immunological synapse formation and improving autologous tumor cell recognition by T cells [44, 45] (Figure 2). The improved immune synapse formation between T cells and tumor cells was also evident in vitro when studied in NHL [46].

The ability of lenalidomide to augment IL-2, IFN-γ, and TNF-α production from T cells in vitro has been described extensively. Similar increases in TNF-α production in CLL have been confirmed [47]. Cytokine production and increased T-cell function in CLL is thought to contribute to the tumor flare response (TFR), which is an adverse side effect of lenalidomide treatment that is positively associated with hematologic improvement when properly managed [48]. Since TFR occurs in association with an increase in circulating CD8+ T cells and NK cells, and release of proinflammatory cytokines, it suggests that immunomodulation is important for success of the drug clinically by enhancing the reactivation of immune effector responses against the tumor [47, 48]. Continuous treatment of relapsed refractory CLL patients with lenalidomide was associated with a stable increase in T-cell number in the peripheral blood, which was indicative of a sustained immune response [42]. In B-CLL, both thalidomide and lenalidomide lead to improved tumor recognition. The drug-induced induction of costimulatory molecules on the B-cell tumor cells in CLL resulting in enhanced immune-mediated killing, and decreased tumor burden.

Impaired differentiation and activation of T and B-cells, as well as NK and dendritic cells, is an important mediator of disease progression in MM [49, 50]. MM is, at present, an incurable B-cell malignancy with abnormal cells accumulating in bone and the bone marrow, which suppress normal hematopoiesis and disrupt the bone marrow microenvironment [51]. Lenalidomide is known in MM to disrupt cellular interactions and adherence of MM to stromal constitutions, decrease growth factors such as IL-6, and induce apoptosis of the neoplastic cells, therefore blocking disease progression [5254]. The dysregulation of hematopoiesis and increased inflammatory cytokine milieu within the bone marrow microenvironment also contributes to impaired immune effector cell function. Lenalidomide treatment in MM, similar to B-CLL and MDS, reverses T-cell defects directly, but also reverses dendritic cell (DC) dysfunction. DCs from patients with MM have reduced expression, or even absence, of costimulatory molecules [55] and this, along with high levels of IL-6, IL-10, and TGF-β within the bone marrow microenvironment, contributes to impaired T-cell costimulation and activation [55, 56].

Although an increase in immune activation is associated with drug response and a decrease in tumor burden in CLL, efficacy of the drug has not been definitively shown to be mediated by a direct cytotoxic effect of T cells against the malignant B-cells. Christensen et al. first demonstrated such activity in MM, as lenalidomide treatment in patients in vivo increased the killing of HM1.24+ myeloma cells by MART-1 specific T cells [34, 57]. Lenalidomide’s action on T-cell cytokine secretion, specific tumor cell recognition, and ability to enhance costimulation derived from dendritic cells may all participate in lenalidomide’s efficacy for the treatment of MM.

4. Immunomodulatory Drugs Increase Natural Killer Cell Recognition and Cytotoxicity of Leukemia Cells

In addition to the potentiating effect on T and B cells, immunomodulatory drugs have a profound effect on the innate immune response, namely, natural killer (NK) cells. NK cells are an important component of the innate immune system where they play major roles in tumor rejection, viral clearance, and DC regulation [5860]. Thalidomide was shown to enhance the cytotoxic effects of NK cells, as well as increase their cell numbers in MM patients [61]. This enhanced killing effect requires cytokine support from accessory lymphocytes, like T cells, as there is no measurable increase in direct killing of the K562 human leukemia cell line by purified NK cells in the presence of high doses of lenalidomide or pomalidomide [62]. PBMCs depleted of NK cells were not able to kill K562 at all, nor were PBMCs in a transwell experiment, suggesting that NK cells and their contact with the tumor cell is a necessary component of lenalidomide-mediated tumor cell apoptosis [62]. Support from T cells, in the form of IL-2 secretion, is extremely important for NK-cell-mediated cytotoxicity of MM after lenalidomide treatment [21]. Although the combination of lenalidomide with dexamethasone has been shown to have significant activity, IL-2 production was abrogated in vivo when MM patients received this combination simultaneously [63]. Hsu et al. demonstrated that dexamethasone treatment suppressed IL-2 production from CD4+ helper T cells, impaired NK cell-mediated cytotoxicity, and countered the immunostimulatory effects of lenalidomide in MM patients. Pharmacodynamic studies may maximize the efficacy of this combination therapy in MM.

There are multiple mechanisms postulated for increased NK cell killing in the various disease settings. Both pomalidomide and lenalidomide upregulate the expression of CD56, which normally decreases NK killing capacity, but in this setting had no detriment to NK cell killing [62]. Carbone et al. showed that the expression of natural cytotoxic receptors (NCR) and NK receptor member D of the lectin-like receptor family (NKG2D) is necessary for myeloma cell recognition [64] and NKG2D blockade abrogated the effect of lenalidomide in solid tumors [65]. It was recently shown by Benson et al. that the addition of a murine anti-inhibitory killer immunoglobulin receptor (KIR) antibody with concurrent lenalidomide therapy mediated rejection of lenalidomide-resistant tumors in a mouse model [66]. This is similar to their IPH2101 human anti-inhibitory KIR antibody that also increases in vitro NK cell cytotoxicity specifically against MM cell targets, but not normal cells, suggesting that clinical testing in combination with lenalidomide is warranted [66].

A schematic of the various mechanisms of NK cell-mediated killing in MM after lenalidomide treatment in combination with various monoclonal antibodies is shown in Figure 3. MM cells, like most tumor cells, express the programmed death receptor-1 ligand (PD-L1) which downregulates the immune response against malignant cells through programmed death receptor-1 interactions on T cells [67, 68]. Recently, it was shown that NK cells from MM patients express PD-1, and the PD-1/PD-L1 interaction decreased NK cell-mediated killing [69]. A novel anti-PD-1 antibody, CT-011, can increase NK cell-mediated killing of autologous MM cells from patients, without effecting normal cells [69]. This new monoclonal therapy, along with lenalidomide’s action of decreasing PD-L1 on MM cells, may improve response rates to this combination therapy.

Enhanced antibody-dependent cytotoxicity (ADCC) by NK cells is also an extremely important mechanism in IMiD function in CLL, MM, and even solid tumors [21, 65, 70]. ADCC is a process where antibodies bind to their ligand antigens on target cells, which then bind to FcR-γ receptors on NK cells, and trigger cell lysis through perforin and granzyme-dependent pathways [71]. Lenalidomide- and pomalidomide-induced killing correlates with an increase in Fas ligand (FasL) and granzyme B expression in NK cells, leading to increased ADCC in multiple tumor settings [70]. Thalidomide plus rituximab (RTX), an anti-CD20 monoclonal antibody commonly used in CLL, was found to increase complete response rates in relapsed and refractory MCL patients [72]. Further study of the mechanism showed that the drug-antibody combination increased growth arrest of MCL cell lines, as well as primary cells, compared to RTX alone [73]. Mechanistically, they discovered that lenalidomide enhanced CD20-mAb-dependent apoptosis of the MCL cells by upregulating activation of caspase-3, -8, -9 and the cleavage of PARP, as well as enhanced ADCC by CD16 induction on NK cells [73]. An increase in NK-mediated ADCC is also implicated in the success of RTX and lenalidomide combination therapy in CLL and NHL, although unproven in vivo [74, 75]. Ofatumumab, another anti-CD20 monoclonal antibody, binds to a different epitope and induces greater complement-dependent cytotoxicity and has shown evidence of activity in fludarabine and rituximab-refractory CLL [76, 77]. Another CD20 mAb, the glycoengineered GA-101 antibody, induces greater ADCC in vitro than RTX and has shown promising preclinical activity in animal models of NHL and B-CLL [7882]. Lenalidomide therapy is currently being tested with ofatumumab [83] and elotuzumab [84] in advanced, relapsed or refractory patients and has shown therapeutic potential. Therefore, concurrent lenalidomide therapy with these antibodies may prove beneficial in refractory patients to augment antitumorigenic activity through NK cell potentiating effects.

As an immunomodulatory agent in solid tumors, lenalidomide has been used to reverse tolerance to tumor antigens [85, 86]. As such, lenalidomide may prove beneficial as an adjuvant to vaccine therapies. Wu et al. demonstrated that lenalidomide enhances NK cell killing in a variety of solid tumor cell lines (breast, colorectal cancer, ovary, head and neck, lung cancer, bone sarcoma) treated with cetuximab or trastuzumab [65]. The treatment of hematologic and solid tumors with specific monoclonal antibody therapy concurrently with lenalidomide could potently increase NK cell-mediated tumor lysis and enhance response rates. Lenalidomide induces NK cells to produce granulocyte-macrophage colony-stimulating factor (GM-CSF), TNF-α, and various immune recruiting chemokines including RANTES, IL-8, MCP-1, and MIP-1α/β in response to antibody-coated tumor cell lines, which contributes to a more effective immune response [65]. The IMiDs enhance immunosurveillance in solid and liquid tumor settings through recruiting and activating T and NK cells to suppress malignant growth.

5. Summary

This paper summarizes the current information about lenalidomide in proliferative neoplasms and describes our understanding of the molecular mechanism of action in lymphocytes. Based on the overwhelming success of lenalidomide for the treatment of several hematologic malignancies, there is potential for therapies that augment host immune responses to be extended from the relapsed and refractory setting, to primary therapy. Studies over several decades have elucidated the importance of immunosurveillance in malignancy. The seminal discoveries that lenalidomide can potently augment T-cell cytokine secretion and activation in the absence of a secondary signal and augment NK-mediated ADCC in the presence of antibody therapy have only begun to shed light on the mechanism of lenalidomide immune modulating activity. The potential in furthering lenalidomide in combination therapy with therapeutic antibodies, vaccines, and chemotherapy depends on improving our understanding of the molecular mechanism of the drug.

The mechanism of action and the important molecular and cellular determinants that mediate the immunomodulatory function are poorly understood, yet many cancer patients have benefited from this therapy. T cells and NK cells are rendered anergic or ignorant by the tumor cells through multiple mechanisms related to the lack of costimulation and immunosuppressive signals within the tumor microenvironment. Because of the importance of costimulation in determining the immune response, therapeutic manipulation with lenalidomide has generated particular interest. The mechanism of action is clearly linked to changes in the bone marrow microenvironment, cytokine secretion, regulation of angiogenesis and host antitumor immunity. Since this agent has significant activity in MM, MDS, CLL, NHL, and MCL, a better understanding of the leukemia biology and the molecular targets that mediate the immunomodulatory activity is needed to harness the full potential of this agent in combination therapies.


Investigators contributing to this work were supported by NIH R01 CA129952.


  1. C. G. Iyer, J. Languillon, K. Ramanujam et al., “WHO co-ordinated short-term double-blind trial with thalidomide in the treatment of acute lepra reactions in male lepromatous patients,” Bulletin of the World Health Organization, vol. 45, no. 6, pp. 719–732, 1971. View at: Google Scholar
  2. J. Sheskin, “The treatment of lepra reaction in lepromatous leprosy. Fifteen years' experience with thalidomide,” International Journal of Dermatology, vol. 19, no. 6, pp. 318–322, 1980. View at: Google Scholar
  3. O. Gutierrez-Rodriguez, “Thalidomide: a promising new treatment for rheumatoid arthritis,” Arthritis and Rheumatism, vol. 27, no. 10, pp. 1118–1121, 1984. View at: Google Scholar
  4. E. Atra and E. I. Sato, “Treatment of the cutaneous lesions of systemic lupus erythematosus with thalidomide,” Clinical and Experimental Rheumatology, vol. 11, no. 5, pp. 487–493, 1993. View at: Google Scholar
  5. M. H. Hamza, “Treatment of Behcet's disease with thalidomide,” Clinical Rheumatology, vol. 5, no. 3, pp. 365–371, 1986. View at: Google Scholar
  6. G. W. Muller, L. G. Corral, M. G. Shire et al., “Structural modifications of thalidomide produce analogs with enhanced tumor necrosis factor inhibitory activity,” Journal of Medicinal Chemistry, vol. 39, no. 17, pp. 3238–3240, 1996. View at: Publisher Site | Google Scholar
  7. V. Kotla, S. Goel, S. Nischal et al., “Mechanism of action of lenalidomide in hematological malignancies,” Journal of Hematology and Oncology, vol. 2, article 36, 2009. View at: Publisher Site | Google Scholar
  8. V. Saloura and P. D. Grivas, “Lenalidomide: a synthetic compound with an evolving role in cancer management,” Hematology, vol. 15, no. 5, pp. 318–331, 2010. View at: Publisher Site | Google Scholar
  9. E. Carballido, M. Veliz, R. Komrokji, and J. Pinilla-Ibarz, “Immunomodulatory drugs and active immunotherapy for chronic lymphocytic leukemia,” Cancer Control, vol. 19, no. 1, pp. 54–67, 2012. View at: Google Scholar
  10. G. P. Dunn, A. T. Bruce, H. Ikeda, L. J. Old, and R. D. Schreiber, “Cancer immunoediting: from immunosurveillance to tumor escape,” Nature Immunology, vol. 3, no. 11, pp. 991–998, 2002. View at: Publisher Site | Google Scholar
  11. V. Shankaran, H. Ikeda, A. T. Bruce et al., “IFNγ, and lymphocytes prevent primary tumour development and shape tumour immunogenicity,” Nature, vol. 410, no. 6832, pp. 1107–1111, 2001. View at: Publisher Site | Google Scholar
  12. P. A. J. Haslett, L. G. Corral, M. Albert, and G. Kaplan, “Thalidomide costimulates primary human t lymphocytes, preferentially inducing proliferation, cytokine production, and cytotoxic responses in the CD8+ subset,” Journal of Experimental Medicine, vol. 187, no. 11, pp. 1885–1892, 1998. View at: Publisher Site | Google Scholar
  13. A. List, S. Kurtin, D. J. Roe et al., “Efficacy of lenalidomide in myelodysplastic syndromes,” The New England Journal of Medicine, vol. 352, no. 6, pp. 549–557, 2005. View at: Publisher Site | Google Scholar
  14. P. S. Linsley, J. L. Greene, W. Brady, J. Bajorath, J. A. Ledbetter, and R. Peach, “Human B7-1 (CD80) and B7-2 (CD86) bind with similar avidities but distinct kinetics to CD28 and CTLA-4 receptors,” Immunity, vol. 1, no. 9, pp. 793–801, 1994. View at: Google Scholar
  15. P. A. Bretscher, “A two-step, two-signal model for the primary activation of precursor helper T cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 1, pp. 185–190, 1999. View at: Publisher Site | Google Scholar
  16. J. A. Keene and J. Forman, “Helper activity is required for the in vivo generation of cytotoxic T lymphocytes,” Journal of Experimental Medicine, vol. 155, no. 3, pp. 768–782, 1982. View at: Google Scholar
  17. T. Mustelin and K. Taskén, “Positive and negative regulation of T-cell activation through kinases and phosphatases,” Biochemical Journal, vol. 371, part 1, pp. 15–27, 2003. View at: Publisher Site | Google Scholar
  18. M. A. Williams, A. J. Tyznik, and M. J. Bevan, “Interleukin-2 signals during priming are required for secondary expansion of CD8+ memory T cells,” Nature, vol. 441, no. 7095, pp. 890–893, 2006. View at: Publisher Site | Google Scholar
  19. T. Nakayama and M. Yamashita, “The TCR-mediated signaling pathways that control the direction of helper T cell differentiation,” Seminars in Immunology, vol. 22, no. 5, pp. 303–309, 2010. View at: Publisher Site | Google Scholar
  20. R. LeBlanc, T. Hideshima, L. P. Catley et al., “Immunomodulatory drug costimulates T cells via the B7-CD28 pathway,” Blood, vol. 103, no. 5, pp. 1787–1790, 2004. View at: Publisher Site | Google Scholar
  21. T. Hayashi, T. Hideshima, M. Akiyama et al., “Molecular mechanisms whereby immunomodulatory drugs activate natural killer cells: clinical application,” British Journal of Haematology, vol. 128, no. 2, pp. 192–203, 2005. View at: Publisher Site | Google Scholar
  22. F. Payvandi, L. Wu, S. D. Naziruddin et al., “Immunomodulatory drugs (IMiDs) increase the production of IL-2 from stimulated T cells by increasing PKC-θ activation and enhancing the DNA-binding activity of AP-1 but not NF-κB, OCT-1, or NF-AT,” Journal of Interferon and Cytokine Research, vol. 25, no. 10, pp. 604–616, 2005. View at: Publisher Site | Google Scholar
  23. P. H. Schafer, A. K. Gandhi, M. A. Loveland et al., “Enhancement of cytokine production and AP-1 transcriptional activity in T cells by thalidomide-related immunomodulatory drugs,” Journal of Pharmacology and Experimental Therapeutics, vol. 305, no. 3, pp. 1222–1232, 2003. View at: Publisher Site | Google Scholar
  24. G. Görgün, E. Calabrese, E. Soydan et al., “Immunomodulatory effects of lenalidomide and pomalidomide on interaction of tumor and bone marrow accessory cells in multiple myeloma,” Blood, vol. 116, no. 17, pp. 3227–3237, 2010. View at: Publisher Site | Google Scholar
  25. M. J. Smyth, D. I. Godfrey, and J. A. Trapani, “A fresh look at tumor immunosurveillance and immunotherapy,” Nature Immunology, vol. 2, no. 4, pp. 293–299, 2001. View at: Publisher Site | Google Scholar
  26. C. Galustian, B. Meyer, M. C. Labarthe et al., “The anti-cancer agents lenalidomide and pomalidomide inhibit the proliferation and function of T regulatory cells,” Cancer Immunology, Immunotherapy, vol. 58, no. 7, pp. 1033–1045, 2009. View at: Publisher Site | Google Scholar
  27. K. Giannopoulos, M. Schmitt, P. Własiuk et al., “The high frequency of T regulatory cells in patients with B-cell chronic lymphocytic leukemia is diminished through treatment with thalidomide,” Leukemia, vol. 22, no. 1, pp. 222–224, 2008. View at: Publisher Site | Google Scholar
  28. J. M. McDaniel, J. X. Zou, W. Fulp, D.-T. Chen, A. F. List, and P. K. Epling-Burnette, “Reversal of T-cell tolerance in myelodysplastic syndrome through lenalidomide immune modulation,” Leukemia, vol. 26, no. 6, pp. 1425–1429, 2012. View at: Publisher Site | Google Scholar
  29. K. Noonan, L. Rudraraju, A. Ferguson et al., “Lenalidomide-induced immunomodulation in multiple myeloma: impact on vaccines and antitumor responses,” Clinical Cancer Research, vol. 18, no. 5, pp. 1426–1434, 2012. View at: Publisher Site | Google Scholar
  30. S. Scrivener, R. V. Goddard, E. R. Kaminski, and A. G. Prentice, “Abnormal T-cell function in B-cell chronic lymphocytic leukaemia,” Leukemia and Lymphoma, vol. 44, no. 3, pp. 383–389, 2003. View at: Publisher Site | Google Scholar
  31. S. Kiaii, A. Choudhury, F. Mozaffari, E. Kimby, A. Österborg, and H. Mellstedt, “Signaling molecules and cytokine production in T cells of patients with B-cell chronic lymphocytic leukemia (B-CLL): comparison of indolent and progressive disease,” Medical Oncology, vol. 22, no. 3, pp. 291–302, 2005. View at: Publisher Site | Google Scholar
  32. A. G. Ramsay, A. J. Clear, and R. Fatah, “Multiple inhibitory ligands induce impaired T cell immunological synapse function in chronic lymphocytic leukemia that can be blocked with lenalidomide,” Blood. In press. View at: Google Scholar
  33. B. N. Lee, H. Gao, E. N. Cohen et al., “Treatment with lenalidomide modulates T-cell immunophenotype and cytokine production in patients with chronic lymphocytic leukemia,” Cancer, vol. 117, no. 17, pp. 3999–4008, 2011. View at: Publisher Site | Google Scholar
  34. B. Neuber, I. Herth, C. Tolliver et al., “Lenalidomide enhances antigen-specific activity and decreases CD45RA expression of T cells from patients with multiple myeloma,” The Journal of Immunology, vol. 187, no. 2, pp. 1047–1056, 2011. View at: Publisher Site | Google Scholar
  35. T. Ito, H. Ando, T. Suzuki et al., “Identification of a primary target of thalidomide teratogenicity,” Science, vol. 327, no. 5971, pp. 1345–1350, 2010. View at: Publisher Site | Google Scholar
  36. Y. X. Zhu, E. Braggio, C.-X. Shi et al., “Cereblon expression is required for the antimyeloma activity of lenalidomide and pomalidomide,” Blood, vol. 118, no. 18, pp. 4771–4779, 2011. View at: Publisher Site | Google Scholar
  37. S. Ren, C. Xu, Z. Cui et al., “Oncogenic CUL4A determines the response to thalidomide treatment in prostate cancer,” Journal of Molecular Medicine. In press. View at: Google Scholar
  38. S. Wei, X. Chen, K. McGraw et al., “Lenalidomide promotes p53 degradation by inhibiting MDM2 auto-ubiquitination in myelodysplastic syndrome with chromosome 5q deletion,” Oncogene. In press. View at: Google Scholar
  39. F. T. Awan, A. J. Johnson, R. Lapalombella et al., “Thalidomide and lenalidomide as new therapeutics for the treatment of chronic lymphocytic leukemia,” Leukemia and Lymphoma, vol. 51, no. 1, pp. 27–38, 2010. View at: Publisher Site | Google Scholar
  40. A. Chanan-Khan, K. C. Miller, L. Musial et al., “Clinical efficacy of lenalidomide in patients with relapsed or refractory chronic lymphocytic leukemia: results of a phase II study,” Journal of Clinical Oncology, vol. 24, no. 34, pp. 5343–5349, 2006. View at: Publisher Site | Google Scholar
  41. C. I. Chen, P. L. Bergsagel, H. Paul et al., “Single-agent lenalidomide in the treatment of previously untreated chronic lymphocytic leukemia,” Journal of Clinical Oncology, vol. 29, no. 9, pp. 1175–1181, 2011. View at: Publisher Site | Google Scholar
  42. A. Ferrajoli, B. N. Lee, E. J. Schlette et al., “Lenalidomide induces complete and partial remissions in patients with relapsed and refractory chronic lymphocytic leukemia,” Blood, vol. 111, no. 11, pp. 5291–5297, 2008. View at: Publisher Site | Google Scholar
  43. A. Chanan-Khan and C. W. Porter, “Immunomodulating drugs for chronic lymphocytic leukaemia,” The Lancet Oncology, vol. 7, no. 6, pp. 480–488, 2006. View at: Publisher Site | Google Scholar
  44. A. G. Ramsay, A. J. Johnson, A. M. Lee et al., “Chronic lymphocytic leukemia T cells show impaired immunological synapse formation that can be reversed with an immunomodulating drug,” The Journal of Clinical Investigation, vol. 118, no. 7, pp. 2427–2437, 2008. View at: Publisher Site | Google Scholar
  45. G. Gorgun, A. G. Ramsay, T. A. W. Holderried et al., “Eμ- TCL1 mice represent a model for immunotherapeutic reversal of chronic lymphocytic leukemia-induced T-cell dysfunction,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 15, pp. 6250–6255, 2009. View at: Publisher Site | Google Scholar
  46. A. G. Ramsay, A. J. Clear, R. Fatah, and J. G. Gribben, “Lenalidomide repairs suppressed T cell immunological synapse formation in follicular lymphoma,” Blood, vol. 112, 2008, Abstract no. 885. View at: Google Scholar
  47. A. A. Chanan-Khan, K. Chitta, N. Ersing et al., “Biological effects and clinical significance of lenalidomide-induced tumour flare reaction in patients with chronic lymphocytic leukaemia: in vivo evidence of immune activation and antitumour response,” British Journal of Haematology, vol. 155, no. 4, pp. 457–467, 2011. View at: Publisher Site | Google Scholar
  48. A. Chanan-Khan, K. C. Miller, D. Lawrence et al., “Tumor flare reaction associated with lenalidomide treatment in patients with chronic lymphocytic leukemia predicts clinical response,” Cancer, vol. 117, no. 10, pp. 2127–2135, 2011. View at: Publisher Site | Google Scholar
  49. M. V. Dhodapkar, M. D. Geller, D. H. Chang et al., “A reversible defect in natural killer T cell function characterizes the progression of premalignant to malignant multiple myeloma,” Journal of Experimental Medicine, vol. 197, no. 12, pp. 1667–1676, 2003. View at: Publisher Site | Google Scholar
  50. R. T. Perri, M. M. Oken, and N. E. Kay, “Enhanced T cell suppression is directed toward sensitive circulating B cells in multiple myeloma,” Journal of Laboratory and Clinical Medicine, vol. 99, no. 4, pp. 512–519, 1982. View at: Google Scholar
  51. R. A. Kyle and S. V. Rajkumar, “Drug therapy: multiple myeloma,” The New England Journal of Medicine, vol. 351, no. 18, pp. 1860–1921, 2004. View at: Publisher Site | Google Scholar
  52. I. Breitkreutz, M. S. Raab, S. Vallet et al., “Lenalidomide inhibits osteoclastogenesis, survival factors and bone-remodeling markers in multiple myeloma,” Leukemia, vol. 22, no. 10, pp. 1925–1932, 2008. View at: Publisher Site | Google Scholar
  53. H. Geitz, S. Handt, and K. Zwingenberger, “Thalidomide selectively modulates the density of cell surface molecules involved in the adhesion cascade,” Immunopharmacology, vol. 31, no. 2-3, pp. 213–221, 1996. View at: Publisher Site | Google Scholar
  54. A. Lichtenstein, Y. Tu, C. Fady, R. Vescio, and J. Berenson, “Interleukin-6 inhibits apoptosis of malignant plasma cells,” Cellular Immunology, vol. 162, no. 2, pp. 248–255, 1995. View at: Publisher Site | Google Scholar
  55. R. D. Brown, B. Pope, A. Murray et al., “Dendritic cells from patients with myeloma are numerically normal but functionally defective as they fail to up-regulate CD80 (B7-1) expression after huCD40LT stimulation because of inhibition by transforming growth factor-β1 and interleukin-10,” Blood, vol. 98, no. 10, pp. 2992–2998, 2001. View at: Publisher Site | Google Scholar
  56. M. Ratta, F. Fagnoni, A. Curti et al., “Dendritic cells are functionally defective in multiple myeloma: the role of interleukin-6,” Blood, vol. 100, no. 1, pp. 230–237, 2002. View at: Publisher Site | Google Scholar
  57. O. Christensen, A. Lupu, S. Schmidt et al., “Melan-A/MART1 analog peptide triggers anti-myeloma T-cells through crossreactivity with HM1.24,” Journal of Immunotherapy, vol. 32, no. 6, pp. 613–621, 2009. View at: Publisher Site | Google Scholar
  58. T. Barlozzari, C. W. Reynolds, and R. B. Herberman, “In vivo role of natural killer cells: involvement of large granular lymphocytes in the clearance of tumor cells in anti-asialo GM1-treated rats,” The Journal of Immunology, vol. 131, no. 2, pp. 1024–1027, 1983. View at: Google Scholar
  59. V. C. Huber, J. M. Lynch, D. J. Bucher, J. Le, and D. W. Metzger, “Fc receptor-mediated phagocytosis makes a significant contribution to clearance of influenza virus infections,” The Journal of Immunology, vol. 166, no. 12, pp. 7381–7388, 2001. View at: Google Scholar
  60. L. E. Wai, J. A. Garcia, O. M. Martinez, and S. M. Krams, “Distinct roles for the NK cell-activating receptors in mediating interactions with dendritic cells and tumor cells,” The Journal of Immunology, vol. 186, no. 1, pp. 222–229, 2011. View at: Publisher Site | Google Scholar
  61. F. E. Davies, N. Raje, T. Hideshima et al., “Thalidomide and immunomodulatory derivatives augment natural killer cell cytotoxicity in multiple myeloma,” Blood, vol. 98, no. 1, pp. 210–216, 2001. View at: Publisher Site | Google Scholar
  62. D. Zhu, L. G. Corral, Y. W. Fleming, and B. Stein, “Immunomodulatory drugs Revlimid® (lenalidomide) and CC-4047 induce apoptosis of both hematological and solid tumor cells through NK cell activation,” Cancer Immunology, Immunotherapy, vol. 57, no. 12, pp. 1849–1859, 2008. View at: Publisher Site | Google Scholar
  63. A. K. Hsu, H. Quach, T. Tai et al., “The immunostimulatory effect of lenalidomide on NK-cell function is profoundly inhibited by concurrent dexamethasone therapy,” Blood, vol. 117, no. 5, pp. 1605–1613, 2011. View at: Publisher Site | Google Scholar
  64. E. Carbone, P. Neri, M. Mesuraca et al., “HLA class I, NKG2D, and natural cytotoxicity receptors regulate multiple myeloma cell recognition by natural killer cells,” Blood, vol. 105, no. 1, pp. 251–258, 2005. View at: Publisher Site | Google Scholar
  65. L. Wu, A. Parton, L. Lu, M. Adams, P. Schafer, and J. B. Bartlett, “Lenalidomide enhances antibody-dependent cellular cytotoxicity of solid tumor cells in vitro: influence of host immune and tumor markers,” Cancer Immunology, Immunotherapy, vol. 60, no. 1, pp. 61–73, 2011. View at: Publisher Site | Google Scholar
  66. D. M. Benson Jr., C. E. Bakan, S. Zhang et al., “IPH2101, a novel anti-inhibitory KIR antibody, and lenalidomide combine to enhance the natural killer cell versus multiple myeloma effect,” Blood, vol. 118, no. 24, pp. 6387–6391, 2011. View at: Publisher Site | Google Scholar
  67. M. J. Butte, M. E. Keir, T. B. Phamduy, A. H. Sharpe, and G. J. Freeman, “Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses,” Immunity, vol. 27, no. 1, pp. 111–122, 2007. View at: Publisher Site | Google Scholar
  68. M. E. Keir, M. J. Butte, G. J. Freeman, and A. H. Sharpe, “PD-1 and its ligands in tolerance and immunity,” Annual Review of Immunology, vol. 26, pp. 677–704, 2008. View at: Publisher Site | Google Scholar
  69. D. M. Benson, C. E. Bakan, A. Mishra et al., “The PD-1/PD-L1 axis modulates the natural killer cell versus multiple myeloma effect: a therapeutic target for CT-011, a novel monoclonal anti-PD-1 antibody,” Blood, vol. 116, no. 13, pp. 2286–2294, 2010. View at: Publisher Site | Google Scholar
  70. L. Wu, M. Adams, T. Carter et al., “Lenalidomide enhances natural killer cell and monocyte-mediated antibody-dependent cellular cytotoxicity of rituximab-treated CD20+ tumor cells,” Clinical Cancer Research, vol. 14, no. 14, pp. 4650–4657, 2008. View at: Publisher Site | Google Scholar
  71. E. Vivier, E. Tomasello, M. Baratin, T. Walzer, and S. Ugolini, “Functions of natural killer cells,” Nature Immunology, vol. 9, no. 5, pp. 503–510, 2008. View at: Publisher Site | Google Scholar
  72. H. Kaufmann, M. Raderer, S. Wöhrer et al., “Antitumor activity of rituximab plus thalidomide in patients with relapsed/refractory mantle cell lymphoma,” Blood, vol. 104, no. 8, pp. 2269–2271, 2004. View at: Publisher Site | Google Scholar
  73. L. Zhang, Z. Qian, Z. Cai et al., “Synergistic antitumor effects of lenalidomide and rituximab on mantle cell lymphoma in vitro and in vivo,” American Journal of Hematology, vol. 84, no. 9, pp. 553–559, 2009. View at: Publisher Site | Google Scholar
  74. N. H. Fowler MP, L. Kwak, F. Hagemeister et al., “Lenalidomide and rituximab for untreated indolent non-Hodgkin's lymphoma,” Journal of Clinical Oncology, vol. 27, 15s, 2009, Abstract no. 8548. View at: Google Scholar
  75. M. Veliz SR, J. E. Lancet, R. S. Komrokji et al., “Phase II study of lenalidomide in combination with rituximab for patients with CD5+/CD20+ hematologic malignancies who relapse or progress after rituximab: interim analysis,” Blood, vol. 114, article 2376, 2009. View at: Google Scholar
  76. J. Du, H. Yang, Y. Guo, and J. Ding, “Structure of the Fab fragment of therapeutic antibody Ofatumumab provides insights into the recognition mechanism with CD20,” Molecular Immunology, vol. 46, no. 11-12, pp. 2419–2423, 2009. View at: Publisher Site | Google Scholar
  77. W. G. Wierda, S. Padmanabhan, G. W. Chan, I. V. Gupta, S. Lisby, and A. Österborg, “Ofatumumab is active in patients with fludarabine-refractory CLL irrespective of prior rituximab: results from the phase 2 international study,” Blood, vol. 118, no. 19, pp. 5126–5129, 2011. View at: Publisher Site | Google Scholar
  78. E. Mössner, P. Brünker, S. Moser et al., “Increasing the efficacy of CD20 antibody therapy through the engineering of a new type II anti-CD20 antibody with enhanced direct and immune effector cell–mediated B-cell cytotoxicity,” Blood, vol. 115, no. 22, pp. 4393–4402, 2010. View at: Publisher Site | Google Scholar
  79. T. Robak, “GA-101, a third-generation, humanized and glyco-engineered anti-CD20 mAb for the treatment of B-cell lymphoid malignancies,” Current Opinion in Investigational Drugs, vol. 10, no. 6, pp. 588–596, 2009. View at: Google Scholar
  80. L. Bologna, E. Gotti, M. Manganini et al., “Mechanism of action of type II, glycoengineered, anti-CD20 monoclonal antibody GA101 in B-chronic lymphocytic leukemia whole blood assays in comparison with rituximab and alemtuzumab,” The Journal of Immunology, vol. 186, no. 6, pp. 3762–3769, 2011. View at: Publisher Site | Google Scholar
  81. F. C. G. Morschhauser, T. Lamy, N. Milpied et al., “Phase I study of RO5072759 (GA101) in relapsed /refractory CLL,” in ASH Ann Meeting Abstract, vol. 114, 2009, Abstract no. 364. View at: Google Scholar
  82. L. H. Sehn AS, D. A. Steward, J. Mangel, P. Pisa, J. Kothari, and M. Crump, “A Phase I study of GA101 (RO5072759) monotherapy followed by maintenance in patients with multiple relapsed/refractory CD20+ malignant disease,” in ASH Ann Meeting Abstract, vol. 114, 2009, Abstract no. 385. View at: Google Scholar
  83. X. Badoux, O. 'Brien SM, W. G. Wierda et al., “Combination of ofatumumab and lenalidomide in patients with relapsed chronic lymphocytic leukemia: initial results of a phase II trial,” Blood (ASH Annual Meeting Abstracts), vol. 116, 2010, Abstract no. 2464. View at: Google Scholar
  84. S. Lonial, R. Vij, J. L. Harousseau et al., “Elotuzumab in combination with lenalidomide and low-dose dexamethasone in relapsed or refractory multiple myeloma,” Journal of Clinical Oncology, vol. 30, no. 16, pp. 1953–1959, 2012. View at: Google Scholar
  85. K. Staveley-O'Carroll, E. Sotomayor, J. Montgomery et al., “Induction of antigen-specific T cell anergy: an early event in the course of tumor progression,” Proceedings of the National Academy of Sciences of the United States of America, vol. 95, no. 3, pp. 1178–1183, 1998. View at: Publisher Site | Google Scholar
  86. P. Horna and E. M. Sotomayor, “Cellular and molecular mechanisms of tumor-induced T-cell tolerance,” Current Cancer Drug Targets, vol. 7, no. 1, pp. 41–53, 2007. View at: Publisher Site | Google Scholar

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