Abstract
Lenalidomide is a synthetic derivative of thalidomide currently approved by the US Food and Drug Administration for use in patients affected by multiple myeloma (in combination with dexamethasone) and low or intermediate-1 risk myelodysplastic syndromes that harbor 5q cytogenetic abnormalities. For illustrative purposes, the mechanism of action of lenalidomide can be subdivided into a cancer cell-intrinsic, a stromal, and an immunological component. Indeed, lenalidomide not only exerts direct cell cycle-arresting and pro-apoptotic effects on malignant cells, but also interferes with their physical and functional interaction with the tumor microenvironment and mediates a robust, pleiotropic immunostimulatory activity. In particular, lenalidomide has been shown to stimulate the cytotoxic functions of T lymphocytes and natural killer cells, to limit the immunosuppressive impact of regulatory T cells, and to modulate the secretion of a wide range of cytokines, including tumor necrosis factor α, interferon γ as well as interleukin (IL)-6, IL-10, and IL-12. Throughout the last decade, the antineoplastic and immunostimulatory potential of lenalidomide has been investigated in patients affected by a wide variety of hematological and solid malignancies. Here, we discuss the results of these studies and review the status of clinical trials currently assessing the safety and efficacy of this potent immunomodulatory drug in oncological indications.
Keywords: CC-5013, IMiDs, TNFα, chronic lymphocytic leukemia, pomalidomide, regulatory T cells
Introduction
Together with pomalidomide (Pomalyst®, initially known as CC-4047), lenalidomide (Revlimid®, initially known as CC-5013) is a synthetic derivative of thalidomide (Thalomid®) originally developed in the 1990s to achieve improved potency in the absence of significant side effects.1 As a matter of fact, in 1957, the release of thalidomide as an over-the-counter sedative, tranquilizer, and antiemetic for morning sickness in Germany was followed by a peak of infants born with malformation of the limbs (phocomelia), resulting in the rapid withdrawal of the drug from the market.2 Similar measures were rapidly undertaken worldwide, with Canada being the last country to discontinue the use of the drug (in 1962).3 Current estimates indicate that 10,000–20,000 cases of phocomelia recorded in 46 countries in the late 1950s and early 1960s can be attributed to thalidomide.2 Irrespective of its high teratogenic potential, the interest around thalidomide increased again in the 1990s, following the demonstration that this agent significantly inhibits the production of tumor necrosis factor α (TNFα), a pro-inflammatory cytokine involved in the etiology of erythema nodosum leprosum (ENL, a complication of leprosy).4 In 1998, the US Food and Drug Administration (FDA) authorized Celgene Corp. to market thalidomide for the therapy of ENL patients, provided that the drug would be distributed under a strict control. Approximately in the same period, the combination of thalidomide with dexamethasone (a glucocorticoid) turned out to mediate robust antineoplastic effects in subjects affected by some hematological malignancies,5 eventually leading to the accelerated approval by the US FDA of this regimen for use in newly diagnosed multiple myeloma (MM) patients (in 2006). Alongside, the development and (pre)clinical characterization of lenalidomide demonstrated that this agent resembles thalidomide in its capacity to robustly inhibit TNFα production, but is associated with significantly reduced neurotoxic effects, although it mediates some degree of teratogenicity.6-8 Conversely, pomalidomide appears to retain the pharmacological properties of thalidomide and lenalidomide while exerting limited, if any, teratogenic activity.9 As it stands, lenalidomide is approved by the US FDA for the treatment of individuals affected by MM (in combination with dexamethasone)10,11 and low or intermediate-1 risk myelodysplastic syndromes that harbor 5q cytogenetic abnormalities (as a standalone intervention).12,13 Of note, no earlier than a few months ago (February 2013), the US FDA has also authorized the use of pomalidomide by patients with MM who have received at least 2 prior therapies, including lenalidomide and bortezomib, and have demonstrated disease progression on or within 60 d of completion of the last therapy.14-17 Also the European Medicine Agency (EMA) has approved the clinical use of thalidomide, lenalidomide, and pomalidomide, the latter no earlier than a few days ago (August 2013) (source http://www.ema.europa.eu/).
Throughout the last decade, the molecular and cellular cascades underlying the robust antineoplastic activity of lenalidomide (see below) have been intensively investigated. Thus, lenalidomide has been shown to mediate anticancer effects via (at least) 3 general mechanisms: (1) it inhibits the proliferation of malignant cells and stimulate their apoptotic demise; (2) it interferes with the physical and trophic interaction between neoplastic cells and their stroma; and (3) it exerts a profound and pleiotropic immunomodulatory activity.18-22
The antiproliferative effects of lenalidomide mostly originate from its ability to upregulate several cyclin-dependent kinase inhibitors (CDKNs), including CDKN1A (best known as p21CIP1), CDKN1B (best known as p21KIP1), CDKN2A (best known as p16INK4A), and CDKN2B (best known as p15INK4B), hence promoting a robust cell cycle arrest.23-25 In addition, lenalidomide has been shown to trigger both the extrinsic (caspase-8-dependent) and intrinsic (mitochondrial) pathways of apoptosis.26-31 At least in part, this activity reflects the capacity of lenalidomide to antagonize pro-survival signals transduced by NFκB, resulting in the downregulation of anti-apoptotic factors such as CASP8 and FADD-like apoptosis regulator (CFLAR) and baculoviral IAP repeat containing 3 (BIRC3).32 The TNFα-suppressing functions of lenalidomide and thalidomide (underpinning the clinical use of the latter against ENL) mainly (though perhaps not entirely) also rely on their ability to inhibit NFκB.33,34
Besides directly impacting on the proliferative potential and viability of neoplastic cells, lenalidomide inhibits their physical and functional interactions with the tumor stroma. Thus, owing to its capacity to abrogating the self-amplificatory signaling cascade linking the NFκB-mediated secretion of TNFα to further NFκB activation,35,36 lenalidomide abrogates the release of interleukin (IL)-6,37,38 a crucial trophic and cytoprotective factor for MM cells as well as for other cancer cells of both hematological and epithelial origin.39-43 Upon exposure to lenalidomide, both cancer cells and bone marrow stromal cells have been shown to express reduced levels of multiple adhesion molecules, including (though presumably not limited to) intercellular adhesion molecule 1 (ICAM1), ICAM2, vascular cell adhesion molecule 1 (VCAM1), integrin α8 (ITGA8), as well as integrins β1 and β2 (ITGB1 and ITGB2, also known as VFA-4 and LFA-1, respectively).44-46 This significantly limits the physical interaction between stromal and malignant cells, hence limiting the delivery of contact-dependent survival signals to the latter as well as the secretion of trophic cytokines (including IL-6, IL-8, and insulin-like growth factor 1, IGF1) from the former.47,48 Among other effects on the tumor microenvironment, lenalidomide inhibits the production of vascular endothelial growth factor (VEGF) and fibroblast growth factor 2 (FGF2),37,38 thus mediating robust antiangiogenic effects.30,31 The capacity of lenalidomide to limit TNFα release contributes to this effect.49,50 Finally, lenalidomide appears also to interfere with osteoclastogenesis in vivo, hence inhibiting the generation of a metastatic niche for malignant cells.51
A major component of the antineoplastic activity of lenalidomide reflects its capacity to modulate humoral as well as cellular aspects of innate and adaptive immune responses. For instance, lenalidomide has been shown to significantly alter the immunological profile of the tumor microenvironment by inhibiting the release of TNFα, IL-1β, and IL-6, while favoring that of IL-2, IL-10, IL-12, and interferon γ (IFNγ) at least under some circumstances.37,38,52-54 Indeed, lenalidomide appears to promote the secretion of IL-12 by peripheral blood mononuclear cells (PBMCs) exposed to CD3-crosslinking antibodies (mimicking the activation of the T-cell receptor, TCR), but not by PBMCs stimulated with relatively unspecific immunostimulatory agents such as the Toll-like receptor (TLR) agonist lipopolysaccharide (LPS).54 Along similar lines, lenalidomide might promote (rather than inhibit) the release of TNFα by T cells upon TCR stimulation.55,56 Thus, although lenalidomide does not directly stimulate the proliferation of T cells per se,57 it significantly amplify the ability of several stimuli, including CD3 ligation as well as exposure to mature and immature dendritic cells (DCs), to do so.54,57-59 Several mechanisms may be involved in such an effect, including (1) an elevated local availability of IL-2, presumably reflecting an increase in the activity of the transcriptional factors AP-1 and/or T-box 21 (TBX21, best known as T-bet);55,56,60 (2) the downregulation of suppressor of cytokine signaling 1 (SOCS1), a prominent (cytokine-inducible) negative regulator of T-cell activity;61 (3); the upregulation and/or functional activation of the co-stimulatory receptor CD28 on T cells;57 (4) increased levels of co-stimulatory molecules (e.g., CD80, CD86) and MHC class I or II molecules on the surface of antigen-presenting cells (APCs).57,62,63 In addition, lenalidomide has been shown to exacerbate the antineoplastic functions of natural killer (NK) and NKT cells, in particular their ability to mediate antibody-dependent cell-mediated cytotoxicity (ADCC), in vitro and in vivo28,64-68 Such an effect has mainly been attributed to the ability of lenalidomide to upregulate the expression of FAS and granzyme B (2 major mediator of NK-cell cytotoxicity) in NK cells.28,65 However, both the expansion and antineoplastic potential NK cells may also benefit from an increased local availability of IL-2.69 Lenalidomide (as well as thalidomide and pomalidomide) has also been reported to inhibit the accumulation and immunosuppressive activity of myeloid-derived suppressor cells (MDSCs)70-72 and regulatory T cells (Tregs),73-76 in the latter case perhaps as it limits the expression of the transcription factor Forkhead box P3 (FOXP3). However, such an activity may not be a general prerequisite for the therapeutic efficacy of lenalidomide. Indeed, this immunomodulatory drug (IMiD) exhibited robust antineoplastic effects in a cohort of relapsed MM patients previously subjected to allogeneic stem cell transplantation while stimulating a transient increase in CD4+FOXP3+ Tregs.77 Interestingly, lenalidomide also reorganizes cytoskeletal fibers, hence restoring the ability of some malignant cells to engage with T lymphocytes in productive immunological synapses.78,79 Although such effect is de facto cancer cell-intrinsic, it has a major impact on the interaction between neoplastic cells and the immune system.
Taken together, these observations suggest that the antineoplastic potential of lenalidomide originate from both cancer cell-intrinsic and -extrinsic mechanisms. The ability of lenalidomide to influence several aspects of innate and adaptive immune responses is actually shared by pomalidomide, and these agents are cumulatively referred to as second-generation IMiDs.80 Of note, the molecular target of thalidomide and IMiDs has been identified relatively recently.81 In particular, the E3 ubiquitin ligase cereblon (CRBN) has been shown to underlie both the therapeutic and the teratogenic activity of these agents.81-83 The CRBN-elicited signaling cascades that may account for the immunomodulatory effects of lenalidomide have just begun to emerge.82,84,85 In this setting, a prominent role may be played by interferon-regulatory factor 4 (IRF4), a CRBN-regulated transcription factor implicated in several facets of innate and adaptive immunity.82,84,85 In addition, CRBN has been shown to influence the activity of the proteasome86 and AMP-activated protein kinase (AMPK).87,88 Of note, high expression levels of CRBN89,90 and IRF491 have been associated with improved disease outcome among MM patients receiving lenalidomide or thalidomide, but not with the sensitivity human myeloma cell lines to these agents in vitro.92 Taken together, these observations suggest that the cell-extrinsic component of the antineoplastic activity of lenalidomide generally prevails over its cell-intrinsic counterpart. In line with this notion, the therapeutic efficacy of lenalidomide is decreased upon the depletion of CD4+ T cells as well as in the presence of immunosuppressive agents (including dexamethasone), raising the possibility that the combination of lenalidomide with glucocorticoids might yield suboptimal therapeutic effects.93
Along the lines of our monthly Trial Watch series,58,59,94-100 here we discuss recently completed and currently ongoing clinical trials aimed at investigating the safety and therapeutic potential of lenalidomide in cancer patients.
Clinical Profile of Lenalidomide
During the last decade, the safety profile and efficacy of lenalidomide have been investigated in clinical trials involving patients affected by a wide variety of neoplasms (Table 1). As of 2013, July 27th, we retrieved no less than 112 scientific publications reporting the results of such an intensive effort (source http://www.ncbi.nlm.nih.gov/pubmed). The vast majority of these clinical trials (88 studies) were conducted on patients bearing hematological malignancies, most often MM (42 studies),10,11,16,38,77,101-137 various forms of lymphoma (17 studies),66,138-153 chronic lymphocytic leukemia (CLL) (14 studies),62,149,154-165 myelodysplastic syndrome (MDS) (10 studies),12,13,166-173 and acute myeloid leukemia (AML) (8 studies).167,168,174-179 In addition, 24 clinical trials were performed to assess the therapeutic profile of lenalidomide in subjects affected by solid tumors, including melanoma (4 studies),180-183 prostate carcinoma (4 studies),184-187 and renal cell carcinoma (3 studies).188-190 In this setting, lenalidomide was most often employed at doses ranging from 10 to 25 mg/day, either as a standalone therapeutic intervention in combination with standard regimens, such as dexamethasone, prednisone, melphalan, or bortezomib (a proteasomal inhibitor)191 in MM patients, rituximab (a CD20-targeting monoclonal antibody) in CLL patients,192 and azacytidine (a demethylating agent)193,194 in subjects affected by AML. Taken together, these trials (14 of which were Phase III) report a low incidence of adverse events related to the use of lenalidomide, common toxicities including (1) myelosuppression, mainly manifesting with neutropenia, thrombocytopenia, leukopenia, or anemia, as well as with an increased susceptibility to infections; (2) thromboembolic events; (3) tumor flare, and (4) relatively mild effects including fatigue, nausea, diarrhea, headache, and skin rashes.8,195,196 Myelosuppression is currently considered as most common dose-limiting (grade III or higher) toxicity of lenalidomide.197 Of note, the teratogenicity of this agent is being actively prevented in the context of a Risk Evaluation and Mitigation Strategy (REMS) approach, formerly known as RevAssist,198 a tightly controlled distribution program established by Celgene upon an explicit request formulated by US FDA along with the approval of lenalidomide for use in humans (source http://www.revlimidrems.com/). Similar programs are also in place for what concerns thalidomide (source http://www.thalomidrems.com/) and pomalidomide (source http://www.pomalystrems.com/).6 Similar to thalidomide, lenalidomide has been suggested to increase the risk of patients to develop a second primary cancer,102,120,124,199 yet the underlying molecular mechanisms have not yet been elucidated.
Table 1. Completed clinical studies assessing the safety and therapeutic profile of lenalidomide in cancer patients*.
Cancer type | N° of studies | Phase** | Dose** | Notes | Ref. |
---|---|---|---|---|---|
Acute myeloid leukemia | 8 | I-II | 5–75 mg/day | As a standalone therapeutic intervention or combined with azacytidine |
167,168, 174–179 |
Chronic lymphocytic leukemia | 14 | I-III | 5–25 mg/day | As a standalone therapeutic intervention or combined with rituximab-based chemotherapy |
62,149, 154–165 |
Lymphoma | 17 | I-II | 10–25 mg/day | As a standalone therapeutic intervention or combined with rituximab | 66,138–153 |
Melanoma | 4 | I-III | 5–50 mg/day | As a standalone therapeutic intervention or combined with dacarbazine | 180–183 |
Myelodysplastic syndrome | 10 | I-III | 10–70 mg/day | As a standalone therapeutic intervention or combined with azacytidine |
12,13, 166–173 |
Multiple myeloma | 42 | I-III | 5–50 mg/day | Near to invariably combined with dexamethasone and a bortezomib- based chemotherapeutic regimen |
10,11,16,38, 77,101–137 |
Prostate carcinoma | 4 | I-II | 5–25 mg/day | As a standalone therapeutic intervention or combined with GM-CSF or paclitaxel | 184–187 |
Renal cell carcinoma | 3 | II | 25 mg/day | As a standalone therapeutic intervention | 188–190 |
Others | 15 | I-II | 5–70 mg/day | Most often employed as a standalone therapeutic intervention |
8,166,180, 247–258 |
Abbreviations: GM-CSF, granulocyte macrophage colony-stimulating factor. *Published in peer-reviewed scientific journals as of August, 1st 2013 (source http://www.ncbi.nlm.nih.gov/pubmed). **Range.
The intense wave of clinical investigation that developed around lenalidomide in the late 2000s resulted in the approval of this immunomodulatory drug by the USA FDA as well as by several other international regulatory agencies (e.g., EMA) for use in MM patients and in subjects affected by MDSs that harbor 5q cytogenetic abnormalities.10-13 In addition, various lenalidomide-based chemotherapeutic regimens were shown to exert promising therapeutic effects not only in patients affected by various other hematological neoplasms, including AML,167,168,174-179 CLL,62,149,154-165 and various forms of lymphoma,66,138-153 but also individuals bearing advanced, metastatic or recurrent solid tumors, such as melanoma,180-183 prostate cancer,184-187 and renal cell carcinoma.188-190 Although in the vast majority of these studies patients were not routinely monitored for immunological parameters, some evidence indicates that the clinical effects of lenalidomide may correlate with early signs of ongoing immunomodulation, such as the upregulation of CD80 on leukemic cells or that of MHC class II molecules on circulating CD4+ and CD8+ T lymphocytes;62,113 the downregulation of CD56 on the surface of peripheral NK cells;113 an increase in circulating macrophages, T lymphocytes, Tregs, and NK cells;77,113,141,152,200 a surge in the serum levels of TNFα, IL-8, IL-12, and granulocyte macrophage colony-stimulating factor (GM-CSF);180,201,202 or a reduction in the amounts of circulating chemokine (C-C motif) ligand 3 (CCL3), and CCL4.155 Of note, several signs of immunomodulation were documented in transplanted MM patients receiving lenalidomide as a maintenance regimen, a setting in which this IMiD turned out to provoke a high rate of severe graft-vs.-host reactions.113 Thus, the immunomodulatory activity of lenalidomide does not necessarily translate into a clinical benefit, in particular among transplanted patients. Irrespective of this caveat, an intense wave of clinical investigation has demonstrated that lenalidomide is generally well tolerated and exert promising antineoplastic activity, in particular in patients affects by hematological neoplasms.
Ongoing Clinical Trials
When this Trial Watch was being redacted (August 2013), official sources listed 60 clinical trials initiated after 2012, January 1st to investigate the safety and therapeutic potential of lenalidomide in cancer patients (Table 2) (source http://www.clinicaltrials.gov). The vastest majority of these trials (55 studies) involve patients affected by hematological malignancies, including (but not limited to) various forms of MDS or leukemia (23 studies), lymphoma (26 studies), and MM (13 studies). Thus, lenalidomide is being tested: (1) as a standalone conditioning intervention in leukemia patients destined to a not-better specified form of bone marrow transplantation (NCT01615042); (2) in combination with melphalan as a conditioning regimen in patients CLL patients allocated to receive allogeneic cord blood-derived NK cells (NCT01619761); (3) as a standalone maintenance/consolidation regimen following standard induction chemotherapy in AML patients with more than 60 y of age (NCT01578954) as well as in CLL patients (NCT01556776; NCT01600053); (4) as a single therapeutic agent in patients with high-risk, early-stage B-cell CLL (NCT01649791), MDS patients who failed to respond to hypomethylating agents (NCT01673308), or adult patients with relapsed or recurrent T-cell leukemia or lymphoma (NCT01724177); (5) alone or combined with recombinant erythropoietin or eltrombopag (a synthetic agonist of the thrombopoietin receptor) in low and intermediate-1 risk MDS patients harboring no chromosome 5q abnormalities (NCT01718379; NCT01772420); (6) in combination with azacytidine for the treatment of high-risk MDS or AML patients exhibiting chromosome 5q defects (NCT01556477), relapsed or refractory AML patients (NCT01743859), or subjects affected by high-rick MDS or chronic myelomonocytic leukemia (NCT01522976); (7) together with rituximab-containing chemotherapeutic regimens in previously untreated CLL or small lymphocytic lymphoma (SLL) patients (NCT01703364; NCT01723839; NCT01754857; NCT01754870); (8) in combination with a potentially immunogenic chemotherapeutic cocktail203-206 in AML patients (NCT01681537); (9) combined with clofarabine (a nucleoside analog) for the treatment of high-risk MDS and AML patients (NCT01629082); (10) together with an autologous cell-based anticancer vaccine in B-cell CLL patients (NCT01604031); (11) combined with inhibitors of the enzymatic activity of BTK207 in subjects with CLL or SLL (NCT01732861; NCT01886859); and (12) combined with dexamethasone in previously untreated patients affected by primary plasma cell leukemia (NCT01553357).
Table 2. Clinical trials recently started to assess the safety and therapeutic profile of lenalidomide in cancer patients*.
Indications | Phase | Status | Notes | Ref. |
---|---|---|---|---|
Advanced cancers | I | Recruiting | Combined with ipilimumab | NCT01750983 |
AITL | II | Recruiting | Combined with CHOP | NCT01553786 |
AML CMML MDS |
I | Recruiting | As single agent | NCT01615042 |
I | Recruiting | As single agent | NCT01578954 | |
I | Recruiting | Combined with clofarabine | NCT01629082 | |
I | Recruiting | Combined with conventional chemotherapy | NCT01681537 | |
II | Recruiting | Combined with azacytidine | NCT01522976 | |
II | Recruiting | Combined with azacytidine | NCT01556477 | |
II | Recruiting | Combined with azacytidine | NCT01743859 | |
Astrocytoma Glioma |
II | Recruiting | As single agent | NCT01553149 |
B-cell lymphoma | I | Recruiting | Combined with BTK inhibitors | NCT01766583 |
I/II | Recruiting | Combined with ublituximab | NCT01744912 | |
I/II | Recruiting | Combined with rituximab-based chemotherapy | NCT01788189 | |
II | Not yet recruiting | Combined with rituximab-based chemotherapy | NCT01856192 | |
CLL | n.a. | Active not recruiting | As single agent | NCT01649791 |
I | Recruiting | As a conditioning regimen before the infusion of allogeneic cord blood-derived NK cells | NCT01619761 | |
I/II | Recruiting | Combined with autologous tumor cells expressing IL-2 and CD40L |
NCT01604031 | |
I/II | Recruiting | Combined with rituximab-based chemotherapy | NCT01703364 | |
II | Recruiting | As single agent | NCT01600053 | |
II | Recruiting | Combined with rituximab-based chemotherapy | NCT01723839 | |
III | Recruiting | As single agent | NCT01556776 | |
CLL SLL |
I | Recruiting | Combined with BTK inhibitors | NCT01732861 |
I | Recruiting | Combined with ibrutinib | NCT01886859 | |
II | Not yet recruiting | Combined with rituximab-based chemotherapy | NCT01754857 | |
II | Not yet recruiting | Combined with rituximab-based chemotherapy | NCT01754870 | |
Follicular lymphoma | I | Recruiting | Combined with rituximab-based chemotherapy | NCT01644799 |
I | Recruiting | Combined with rituximab-based chemotherapy | NCT01829568 | |
III | Recruiting | Combined with rituximab-based chemotherapy | NCT01650701 | |
HCC | II | Recruiting | As single agent | NCT01545804 |
Lymphoma | I | Recruiting | Combined with rituximab-based chemotherapy | NCT01542918 |
I | Recruiting | As single agent | NCT01750762 | |
I/II | Recruiting | Combined with obinutuzumab | NCT01582776 | |
I/II | Recruiting | Combined with romidepsin | NCT01742793 | |
I/II | Recruiting | As single agent | NCT01575860 | |
II | Recruiting | As single agent | NCT01556035 | |
MALT lymphoma | II | Recruiting | Combined with rituximab-based chemotherapy | NCT01611259 |
MCL | I/II | Recruiting | Combined with rituximab-based chemotherapy | NCT01729104 |
I/II | Recruiting | Combined with rituximab-based chemotherapy | NCT01838434 | |
II | Recruiting | Combined with rituximab-based chemotherapy | NCT01737177 | |
III | Not yet recruiting | Combined with rituximab, as maintenance therapy | NCT01865110 | |
MDS | II | Recruiting | As single agent | NCT01673308 |
II | Recruiting | As single agent or combined with recombinant erythropoietin |
NCT01718379 | |
II | Recruiting | Combined with eltrombopag | NCT01772420 | |
MM | I | Recruiting | Combined with MLN9708 and dexamethasone | NCT01645930 |
I/II | Recruiting | Combined with daratumumab and dexamethasone | NCT01615029 | |
II | Recruiting | Combined with bortezomib and dexamethasone, as maintenance therapy |
NCT01548573 | |
II | Terminated | As maintenance therapy | NCT01617213 | |
II | Recruiting | Combined with bortezomib, as maintenance therapy | NCT01706666 | |
II | Recruiting | Combined with bortezomib, as maintenance therapy | NCT01729338 | |
II | Recruiting | As conditioning and maintenance therapy, in the latter case in combination with bortezomib |
NCT01790737 | |
II | Recruiting | Combined with minocycline | NCT01793051 | |
II | Recruiting | Combined with bortezomib, as maintenance therapy | NCT01849783 | |
II | Not yet recruiting | Combined with taladafil ± MILs, as maintenance therapy |
NCT01858558 | |
NB | I | Recruiting | Combined with Ch14.18 ± isotretinoin | NCT01711554 |
NHL | I/II | Recruiting | Combined with romidepsin | NCT01755975 |
II | Active not recruiting | Combined with rituximab-based chemotherapy | NCT01830478 | |
Pancreatic cancer | I/II | Recruiting | Combined with gemcitabine | NCT01547260 |
PPCL | II | Completed | Combined with dexamethasone | NCT01553357 |
T-cell leukemia T-cell lymphoma |
II | Recruiting | As single agent | NCT01724177 |
Waldenstrom macroglobulinemia | II | Recruiting | Combined with rituximab and thalidomide | NCT01779167 |
Abbreviations: AITL, angioimmunoblastic T-cell lymphoma; AML, acute myeloid leukemia; CD40L, CD40 ligand; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; CLL, chronic lymphocytic leukemia; CMML, chronic myelomonocytic leukemia; DLBCL, diffuse large B-cell lymphoma; HCC, hepatocellular carcinoma; IL-2, interleukin-2; MALT, mucosa-associated lymphoid tissue; MCL, mantle cell lymphoma; MDS, myelodysplastic syndrome; MIL, marrow infiltrating lymphocyte; n.a., not available; NB, neuroblastoma; NHL, non-Hodgkin's lymphoma; NK, natural killer; PPCL, primary plasma cell leukemia; SLL, small lymphocytic lymphoma. *Started after 2012 January, 1st and not withdrawn, terminated or suspended at the day of submission (source www.clinicaltrials.gov).
Lenalidomide is also being investigated: (1) as a standalone maintenance intervention in lymphoma patients who previously received (rituximab-based) chemotherapy (NCT01556035; NCT01575860) or allogeneic bone marrow/stem cell transplantation (NCT01750762); (2) together with a potentially immunogenic chemotherapeutic cocktail (including the alkylating agent cyclophosphamide and bortezomib)203-206 as a first line approach to angioimmunoblastic T-cell lymphoma (NCT01553786); (3) in combination with rituximab-containing chemotherapeutic regimens in individuals affected by recurrent or refractory lymphomas of the central nervous system or the eye (NCT01542918), mucosa-associated lymphoid tissue lymphoma (NCT01611259), recurrent or previously untreated follicular lymphoma (NCT01644799; NCT01650701; NCT01829568), relapsed or refractory mantle cell lymphoma (MCL) (NCT01729104; NCT01737177; NCT01838434); relapsed aggressive B-cell lymphomas (NCT01788189), indolent non-Hodgkin’s lymphoma (NCT01830478); or newly-diagnosed Stage II-IV diffuse large B-cell lymphoma (NCT01856192); (4) together with rituximab as a maintenance regiment for old (> 60 y-old) patients with MCL (NCT01865110); (5) combined with romidepsin (an experimental histone deacetylase inhibitor)208,209 in subjects with relapsed or refractory lymphoma or MM (NCT01742793; NCT01755975); (6) in combination with obinutuzumab (an experimental monoclonal antibody targeting CD20)210,211 for the treatment of relapsed or refractory follicular and aggressive B-cell lymphoma (NCT01582776); (7) combined with ublituximab (yet another CD20-targeting monoclonal antibody)212 in patient with B-cell lymphoid neoplasms who have relapsed upon (or are primarily refractory to) CD20-directed therapies (NCT01744912); and (8) together with CC-292 in adult patients with relapsed or refractory B-cell lymphoma (NCT01766583).
The majority of clinical trials recently (after January 1st, 2012) registered at http://www.clinicaltrials.gov that involve MM patients aim at investigating the safety and therapeutic profile of lenalidomide as a conditioning (NCT01790737) or maintenance (NCT01548573; NCT01617213; NCT01706666; NCT01790737; NCT01849783; NCT01858558) regimen in the context of bone marrow or hematopoietic stem cell transplantation. In this setting, lenalidomide is invariably combined with dexamethasone and optionally with melphalan (NCT01617213), bortezomib-based chemotherapy (NCT01548573; NCT01706666; NCT01790737; NCT01849783), or tadalafil (an inhibitor of phosphodiesterase 5A best known for its use in the treatment of erectile dysfunction)213 plus autologous marrow-infiltrating lymphocytes (NCT01858558). In addition, lenalidomide is being tested: (1) in combination with dexamethasone and daratumumab (a CD38-targeting monoclonal antibody)214 in patients with relapsed or relapsed and refractory MM (NCT01615029); (2) together with dexamethasone and MLN9708 (an experimental inhibitor of the proteasome)215,216 in adults bearing refractory MM (NCT01645930); (3) combined with minocycline, in the context of not-better specified maintenance therapy for MM patients (NCT01793051); (4) as a maintenance regimen in newly diagnosed MM patients receiving first-line bortezomib-based chemotherapy (NCT01729338); and (5) together with rituximab and thalidomide in patients affected by Waldenstrom macroglobulinemia,217 another neoplasm originating from the hyperproliferation of plasma cells (NCT01779167).
Finally, lenalidomide is being evaluated: (1) as a second-line standalone therapeutic intervention in advanced hepatocellular carcinoma patients (NCT01545804); in combination with gemcitabine (a potentially immunogenic nucleoside analog)218,219 in individuals with pancreatic carcinoma (NCT01547260); (3) as a single agent in children affected by recurrent, refractory or progressive pilocytic astrocytoma or optic pathway glioma (NCT01553149); (4) together with isotretinoin (a retinoid)220 and/or Ch14.18 (a monoclonal antibody directed against ganglioside GD2)221-223 in children with refractory or recurrent neuroblastoma (NCT01711554); and (5) combined with ipilimumab (an FDA-approved monoclonal antibody that inhibits the immunological checkpoint mediated by cytotoxic T lymphocyte-associated protein 4, CTLA4)224,225 in patients affected by advanced tumors (NCT01750983).
Taken together, these observations suggest that the interest of clinicians into lenalidomide remains high, though it focuses on the use of this IMiD for the treatment of hematological, rather than solid, malignancies.
Concluding Remarks
A significant amount of clinical experience has nowadays accumulated to indicate that lenalidomide not only is well tolerated by a majority of cancer patients, but also exerts robust antineoplastic effects, in particular among individuals affected by hematological tumors. Although the molecular and cellular cascades underlying such a consistent anticancer activity have just begun to emerge, it's clear already that lenalidomide does not only exert direct antiproliferative and cytotoxic effects, but also influences in several ways the interaction between malignant cells and their microenvironment, including stromal and immune components. In particular, lenalidomide exhibits a pronounced and multipronged immunomodulatory activity.18,19,226
Lenalidomide is currently approved by international regulatory agencies for use in patients bearing specific hematological neoplasms, including MM and MDSs with chromosome 5q abnormalities.10-13 Of note, in both these settings, lenalidomide is administered in combination with low-dose glucocorticoids (most often dexamethasone or prednisone), which are well known for their immunosuppressive potential.227,228 Indeed, glucocorticoids not only exert profound transcriptional effects on immune cells, de facto suppressing their ability to elicit an inflammatory reaction, but also actively trigger their demise.229-231 At least in part, this explains the clinical success of glucocorticoids in the treatment of hematological malignancies. At the same time, however, it should raise doubts on whether combining an immunostimulatory agent such as lenalidomide with glucocorticoids might yield optimal therapeutic effects. Recent preclinical data actually argue against such a possibility, suggesting that the clinical potential of lenalidomide may be restricted, rather than maximized, by dexamethasone.93,232 In this scenario, it would be interesting to test whether the antineoplastic activity of lenalidomide can be potentiated by the co-administration of immunomodulatory agents such as TLR agonists,233-235 immunological checkpoint inhibitors,224,225,236,237 immunostimulatory cytokines,201,202,238,239 or immunogenic chemotherapy.71,240,241 The possibility of using lenalidomide as an adjuvant in support of more specific immunotherapeutic interventions including anticancer vaccines242,243 and adoptively transferred cells244-246 also warrants further investigation.
Acknowledgments
Authors are supported by the European Commission (ArtForce); European Research Council (ERC); Agence National de la Recherche (ANR); Ligue Nationale contre le Cancer; Fondation pour la Recherche Médicale (FRM); Institut National du Cancer (INCa); Association pour la Recherche sur le Cancer (ARC), LabEx Immuno-Oncologie; Fondation de France; Fondation Bettencourt-Schueller; AXA Chair for Longevity Research; Cancéropôle Ile-de-France, Paris Alliance of Cancer Research Institutes (PACRI) and Cancer Research for Personalized Medicine (CARPEM).
Glossary
Abbreviations:
- AML
acute myeloid leukemia
- CCL
circulating chemokine (C-C motif) ligand
- CDKN
cyclin-dependent kinase inhibitor
- CLL
chronic lymphocytic leukemia
- CRBN
cereblon
- EMA
European Medicine Agency
- ENL
erythema nodosum leprosum
- FDA
Food and Drug Administration
- FOXP3
Forkhead box P3
- ICAM
intercellular adhesion molecule
- IL
interleukin
- IMiD
immunomodulatory drug
- ITG
integrin
- MCL
mantle cell lymphoma
- MDS
myelodysplastic syndrome
- MM
multiple myeloma
- NK
natural killer
- PBMC
peripheral blood mononuclear cell
- SLL
small lymphocytic lymphoma
- TCR
T-cell receptor
- TLR
Toll-like receptor
- Treg
regulatory T cell
- TNFα
tumor necrosis factor α
Citation: Semeraro M, Vacchelli E, Eggermont A, Galon J, Zitvogel L, Kroemer G, Galluzzi L. Trial Watch: Lenalidomide-based immunochemotherapy. OncoImmunology 2013; 2:e26494; 10.4161/onci.26494
Footnotes
Previously published online: www.landesbioscience.com/journals/oncoimmunology/article/26494
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