Trial Watch: Immunomodulatory monoclonal antibodies for oncological indications

Abstract

Immunomodulatory monoclonal antibodies (mAbs) differ from their tumor-targeting counterparts because they exert therapeutic effects by directly interacting with soluble or (most often) cellular components of the immune system. Besides holding promise for the treatment of autoimmune and inflammatory disorders, immunomodulatory mAbs have recently been shown to constitute a potent therapeutic weapon against neoplastic conditions. One class of immunomodulatory mAbs operates by inhibiting safeguard systems that are frequently harnessed by cancer cells to establish immunological tolerance, the so-called “immune checkpoints.” No less than 3 checkpoint-blocking mAbs have been approved worldwide for use in oncological indications, 2 of which during the past 12 months. These molecules not only mediate single-agent clinical activity in patients affected by specific neoplasms, but also significantly boost the efficacy of several anticancer chemo-, radio- or immunotherapies. Here, we summarize recent advances in the development of checkpoint-blocking mAbs, as well as of immunomodulatory mAbs with distinct mechanisms of action.

Introduction

Initially conceived as a means to treat autoimmune diseases and inflammatory conditions,^1,2 immunomodulatory monoclonal antibodies (mAbs), i.e., mAbs that bind to (hence altering the function of) soluble or cellular component of the immune system,^3,4 have been increasingly recognized as a promising tool for cancer therapy.^5-7 Indeed, virtually all solid tumors and at least some hematological malignancies fail to respond to chemo-, radio-, and immunotherapy owing to the establishment of potent immunosuppressive networks that operate locally (i.e., within the tumor mass) and systemically (i.e., in the circulation and bone marrow).^8-12 Importantly, some (but not all) of these immunosuppressive mechanisms are the same that operate to terminate immune responses and/or prevent autoimmune reactions in physiological scenarios.^13,14 Thus, in the course of tumor progression malignant cells acquire the ability to harness immunosuppressive mechanisms to their own benefit, hence avoiding recognition and elimination by the host immune system.^15,16

These considerations have driven the development of several immunomodulatory mAbs aimed at activating novel, or reinstating existing, tumor-targeting immune responses. At least hypothetically, these objectives can be achieved by at least 3 distinct strategies corresponding to 3 classes of immunomodulatory mAbs potentially useful for anticancer therapy. First, tumor-targeting immune responses can be elicited by means of mAbs that inhibit immunosuppressive receptors expressed on the surface of activated T lymphocytes or natural killer (NK) cells, such as cytotoxic T lymphocyte-associated protein 4 (CTLA4), programmed cell death 1 (PDCD1, best known as PD-1), and various members of the killer cell immunoglobulin-like receptor (KIR) family; or their ligands, like the PD-1-binding partner CD274 (best known as PD-L1 or B7-H1).^17-29 CTLA4 and PD-1 are critically involved in so-called “immune checkpoints,”, safeguard systems that control the physiological extinction of immune responses and the maintenance of peripheral tolerance (hence avoiding autoimmune reactions).^30,31 Moreover, potential tumor-reactive lymphocytes are often kept in check by CTLA- and/or PD-1-transduced signals, reflecting the ability of many cancers to express increased levels of their ligands.^27,32-35 Some KIRs deliver inhibitory signals to NK cells upon binding to MHC Class I molecules, hence preventing unwarranted innate immune responses against healthy cells (which generally express high levels of MHC Class I molecules).^24,25 Cancer cells generally preserve the expression of MHC Class I molecules, hence evading NK cell-dependent anticancer immunosurveillance.

Second, anticancer immune responses can be (re-)established with mAbs that activate co-stimulatory receptors expressed on the surface of T lymphocytes and/or NK cells, such as tumor necrosis factor receptor superfamily, member 4 (TNFRSF4, best known as OX40),^36-40, TNFRSF9 (best known as CD137 or 4-1BB).^41-43, and TNFRSF18 (best known as GITR).^44-46. Most immune cells require several signals for acquiring full-blown effector functions, constituting yet another safeguard mechanism against autoimmunity or disproportioned immune reactions.^3,4 Such signals are generally not provided within the tumor microenvironment, often as a consequence of functional alterations of the myeloid cell compartment.^8-12

Third, tumor-specific immune responses can be initiated or restored by mAbs that neutralize immunosuppressive factors released in the tumor microenvironment, such as transforming growth factor β1 (TGFβ1) and interleukin-10 (IL-10).^47,48 Tumor-infiltrating myeloid cells, including “alternatively-activated” M2 macrophages, secrete immunosuppressive factors in considerable amounts.¹⁰ These molecules promote the functional impairment of potentially tumor-reactive immune effector cells, both directly and via indirect circuitries involving other immunosuppressive cell populations like CD4⁺CD25⁺FOXP3⁺ regulatory T cells (Tregs).^49-51

Immunomodulatory mAbs that target CTLA4-like receptors and their ligands are cumulatively referred to as “checkpoint blockers” or “checkpoint-blocking mAbs.”⁵² Several mAbs of this class are relatively well tolerated and mediate antineoplastic effects, either as standalone immunotherapeutic interventions or in combination with other anticancer agents, in patients affected by a wide panel of solid neoplasms.^52-54 In line with this notion, 3 checkpoint blockers have already been approved by the US Food and Drug Administration (FDA) and/or equivalent regulatory agencies worldwide for use in oncological indications (Table 1): (1) ipilimumab (Yervoy™), an anti-CTLA4 mAb originally approved by the US FDA for the treatment of unresectable or metastatic melanoma on 2011, March 25th;^55-59 pembrolizumab (Keytruda™), a PD-1-targeting mAb that received accelerated approval by the US FDA for use in subjects with advanced or unresectable melanoma who fail to respond to other therapies on 2014, September 4th;^52,60-64 and nivolumab (Opvido™), yet another PD-1-targeting mAb first licensed by the Japanese Ministry of Health and Welfare for use in humans on 2014, July 07^th (and obtaining accelerated approval by the US FDA on 2014, December 22nd).^65,66 Conversely, no co-stimulatory mAb has been approved by the US FDA or equivalent regulatory agency worldwide for use in cancer patients yet, despite the promising clinical results achieved by some molecules, including the CD137-targeting mAbs urelumab and PF-0582566.^3,67,68 Similarly, no TGFβ1-neutralizing mAb is licensed for use in humans today (source http://www.fda.gov).

Table 1.

Immunomodulatory mAbs currently approved for cancer therapy^*

mAb	Target	First approved	Type	Indication(s)
Ipilimumab	CTLA	2011	Human IgG1κ	Unresectable or metastatic melanoma
Nivolumab	PD-1	2014	Human IgG4	Unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAFV600 mutation positive, a BRAF inhibitor
Pembrolizumab	PD-1	2014	Humanized IgG4	Unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAFV600 mutation positive, a BRAF inhibitor

Abbreviations: BRAF, B-Raf proto-oncogene, serine/threonine kinase; CTLA4, cytotoxic T lymphocyte-associated protein 4; PD-1, programmed cell death 1.

^*By the US Food and Drug Administration or equivalent regulatory agency worldwide on the day of submission.

Along the lines of our monthly Trial Watch series,^69,70 here we discuss recent advances in the development of immunomodulatory mAbs for cancer therapy.

Update on the Development of Immunomodulatory Monoclonal Antibodies

Completed clinical trials

Since the submission of our latest Trial Watch dealing with this topic (November 2013),⁵³ the results of more than 120 studies assessing the safety and/or efficacy of immunomodulatory mAbs (or biomarkers associated with their clinical profile) have been published in the peer-reviewed scientific literature (source http://www.ncbi.nlm.nih.gov/pubmed) or presented at international meetings (sources http://meetinglibrary.asco.org/, http://aacrmeetingabstracts.org/ and http://www.hematology.org/Annual-Meeting/Abstracts/). The largest fraction of these studies involved ipilimumab,^71-125 pembrolizumab,^{63,83,126-140} or nivolumab,^{66,71,76,84,86,106,112,115,141-154} employed either as on-label or off-label immunotherapeutic interventions. Moreover, several publications/abstracts released during the last 13 months reported the results of clinical trials involving (1) additional checkpoint blockers, such as the CTLA4-targeting mAb tremelimumab,^155-161 the PD-1-targeting mAb pidilizumab,^162,163 and the PD-L1-targeting mAbs MEDI4736,^{156,159,164-168} MPDL3280A,^169 171 and MSB0010718C;¹⁷² (2) the KIR-inhibitory mAbs lirilumab and IPH2101;^151,173 (3) co-stimulatory mAbs, such as the CD137-targeting mAbs PF-05082566 and urelumab,^174,175 the CD27-targeting mAb CDX-1127,^176,177 the CD40-targeting mAbs ChiLob 7/4, dacetuzumab and lucatumumab,^178,179 and an OX40-targeting molecule;¹⁸⁰ and (4) the TGFβ1-neutralizing mAb fresolimumab.¹⁸¹ Taken together, these studies involved patients affected by a relatively large and heterogeneous panel of neoplasms, including (but not limited to): melanoma^{63,66,72,75,77,78,81-83,86,88-92,95-97,101-105,108-110,112,114,116-119, 121,122,124,125,129-131,135,152,153,162,166,181-185} non-small cell lung carcinoma (NSCLC),^{127,128,136,142 144,159,170,186,187} renal cell carcinoma (RCC);^{84,133,141,145,148,188,189} and breast carcinoma.^{79,98,99,140,171,190}

Taken together, the results of these studies demonstrate that first generation immunomodulatory mAbs used as monotherapeutic agents are well tolerated by cancer patients or cause side effects that are generally manageable with treatment discontinuation and/or corticoids. Moreover, when employed as standalone therapeutic interventions, these immunomodulatory mAbs induce objective clinical responses in 10-90% of patients, depending on the specific scenario (i.e., immunomodulatory paradigm, cancer type, disease stage, etc.). The clinical profile of immunomodulatory mAbs combined with conventional chemotherapeutics, targeted anticancer agents, irradiation (in one of its variants) or other immunotherapies is being intensively investigated. Some of these combinatorial regimens, including the administration of ipilimumab plus nivolumab or vemurafenib (a chemical inhibitor of mutant BRAF)¹⁹¹ to melanoma patients, as well as the administration of ipilimumab plus pazopanib or sunitinib (2 multi-targeted receptor tyrosine kinase inhibitors) to RCC patients, have already been associated with very high objective response rates.^141,192,193 However, all these combinations also provoke severe (Grade 3-4) adverse effects in a consistent (>50%) fraction of patients,^141,192,193 constituting a big obstacle against their further development.

From the abundant clinical literature published during the last 13 month on immunomodulatory mAbs, we would like to highlight the work of (1) Kwon and colleagues (Mayo Clinic Comprehensive Cancer Center; Rochester, MN, US), who reported that the administration of ipilimumab after radiotherapy fails to improve the overall survival of patients with metastatic castration-resistant prostate cancer progressing after docetaxel chemotherapy, although it may beneficial for a sub-group of patients showing no visceral involvement;¹²³ (2) Hodi and co-authors (Dana-Farber Cancer Institute; Boston, MA, US), who demonstrated that the addition of recombinant granulocyte macrophage colony-stimulating factor (GM-CSF, also known as sargramostim) to ipilimumab-based immunotherapy limits side effects while improving overall, but not progression-free, survival in patients with unresectable Stage III or IV melanoma;¹²⁵ (3) Lebbé and collaborators (Hôpital Saint-Louis; Paris, France), who reported not only that the responses of subjects with advanced melanoma to ipilimumab are durable (lasting up to 5-6 years in some cases), but also that in some patients the re-administration of ipilimumab can re-establish disease control upon progression on induction ipilimumab-based immunotherapy;¹²⁴ (4) Weber et al. (Moffitt Cancer Center; Tampa, FL, US), who demonstrated the favorable clinical profile of nivolumab administered in combination with a multipeptide-based vaccine to individuals with ipilimumab-refractory or -naive melanoma;¹⁵² (5) Topalian and colleagues (Smilow Cancer Center; New Haven, CT, US), who reported long-term safety and efficacy data from a clinical trial testing the therapeutic profile of nivolumab in advanced melanoma patients;¹⁵³ (6) Robert and collaborators (Gustave Roussy Cancer Campus; Villejuif, France), who demonstrated not only that nivolumab ameliorates disease outcome among previously untreated subjects with BRAF^WT melanoma, but also that pembrolizumab constitutes an effective therapeutic option for melanoma patients progressing on ipilimumab-based immunotherapy;^63,66 (7) Westin and co-authors (MD Anderson Cancer Center; Houston, TX, US), who proved that pidilizumab is well tolerated and improves the clinical activity of the CD20-targeting mAb rituximab in patients with relapsed follicular lymphoma;¹⁶³ as well as (8) Ansell et al. (Mayo Clinic Comprehensive Cancer Center; Rochester, MN, US) and Moskowitz et al. (Memorial Sloan Kettering Cancer Center; New York, NY, US), who reported that nivolumab or pembrolizumab employed as standalone therapeutic interventions induced a high rate of objective clinical responses among relapsed or refractory Hodgkin's lymphoma patients.^139,194

Preclinical and translational advances

Reflecting the ever-increasing interest of clinicians and pharmaceutical companies in this paradigm of active immunotherapy, a high number of preclinical/translational papers dealing with the use of immunomodulatory mAbs for cancer therapy have been published in peer-reviewed scientific journals during the last 13 months. From such an abundant literature, we found of particular interest the works of: (1) Gubin and colleagues (Washington University School of Medicine; St. Louis, MO, US), who used genomic and bioinformatic approaches to identify cancer-specific mutant proteins as a major class of T-cell rejection antigens in mice bearing progressively growing sarcomas treated with CTLA4- or PD-1-targeting mAbs;¹⁹⁵ (2) Snyder and co-authors (Weill Cornell Medical College; New York, NY, US), who defined a genetic basis for benefit from CTLA4 blockade in melanoma patients, providing a rationale for examining the exomes of individuals for whom CTLA4-targeting mAbs agents are being considered as a therapeutic option;¹⁹⁶ (3) Herbst and collaborators (Yale Comprehensive Cancer Center; New Haven, CT, US), who demonstrated that MPDL3280A is most effective in patients in which pre-existing immunity is suppressed by PD-L1;¹⁹⁷ (4) Tumeh et al. (University of California Los Angeles; Los Angeles, CA, US), who proved that tumor regression in response to PD-1-targeting mAbs relies on pre-existing tumor-targeting CD8⁺ T lymphocytes that are kept in check by PD-1/PD-L1-dependent immunosuppression;⁶⁰ (5) Noman and colleagues (Gustave Roussy Cancer Campus; Villejuif, France), who discovered that tumor-infiltrating myeloid cells express increased amounts of PD-L1, a phenotype reflecting the activation of hypoxia-inducible factor 1 (HIF-1) by the tumor microenvironment;¹⁹⁸ (6) Fan and co-authors (MD Anderson Cancer Center; Houston, TX, US), who reported that simultaneously blocking CTLA4 and promoting inducible co-stimulator (ICOS) signaling mediates superior antineoplastic effects in mice bearing established melanomas or prostate carcinoma;¹⁹⁹ (7) Madireddi and collaborators (La Jolla Institute for Allergy and Immunology; La Jolla, CA, US), who found that lectin, galactoside-binding, soluble, 9 (LGALS9, best known as galectin-9) physically interacts with CD137, hence regulating its co-stimulatory activity;²⁰⁰ (8) Kong et al. (La Jolla Institute for Allergy and Immunology; La Jolla, CA, US), who demonstrated that protein kinase C, eta (PRKCH) operates downstream of CTLA4 to control the immunosuppressive activity of Tregs;²⁰¹ (9) Hermann and colleagues (Beckman Research Institute at City of Hope, Comprehensive Cancer Center; Duarte, CA, US), who designed CTLA4-targeting aptamers that are capable of delivering signal transducer and activator of transcription 3 (STAT3)-specific siRNAs to tumor-infiltrating CD8⁺ T lymphocytes, hence unleashing their effector functions;²⁰² (10) Deng and collaborators (The Ludwig Center for Metastasis Research; Chicago, IL, US), who demonstrated that combining PD-L1-targeting mAbs with radiation therapy exerts superior antineoplastic effects in tumor-bearing mice as it robustly alters (qualitatively and quantitatively) the tumor-infiltrating myeloid cell compartment;²⁰³ (11) Hannani and co-authors (Gustave Roussy Cancer Campus; Villejuif, France), who showed an opposite role for IL-2 and soluble IL-2 receptor α (sIL2RA, best known as sCD25) in antitumor responses elicited by ipilimumab in mice and melanoma patients, identifying the circulating levels of sCD25 and lactate dehydrogenase as biomarkers of ipilimumab resistance;²⁰⁴ and (12) Voron et al. (Hôpital Européen Georges Pompidou; Paris, France) who showed that vascular endothelial growth factor A (VEGFA) promotes the expression of PD-1 and other molecules involved in immunological checkpoints, delineating a therapeutically relevant, immunosuppressive response to hypoxia that can be reverted by anti-angiogenic agents targeting VEGFA or its receptors.²⁰⁵

Recently initiated clinical trials

Since the submission of our latest Trial Watch dealing with this topic (November 2013),⁵³ no less than 117 clinical studies have been initiated to investigate the safety and/or efficacy of immunomodulatory mAbs in cancer patients (source http://clinicaltrials.gov/). Although a significant proportion of these studies are intended to test molecules approved by the US FDA or similar regulatory agencies (ipilimumab, 43 studies; pembrolizumab, 28 studies; nivolumab, 22 studies), these mAbs are employed as on-label immunostimulatory interventions in a relatively limited number of trials (ipilimumab, 27 studies; pembrolizumab, 7 studies; nivolumab, 2 studies). Thus, most clinical trials that have been initiated during the last 13 months that involve ipilimumab, pembrolizumab and nivolumab enroll patients with neoplasms other than melanoma (ipilimumab, 19 studies; pembrolizumab, 24 studies; nivolumab, 20 studies). In addition, multiple trials have recently been launched to test the clinical profile of hitherto experimental immunomodulatory mAbs, including (1) the CD40-targeting co-stimulatory mAb CP-870,893 (2 studies);²⁰⁶ (2) the OX40-targeting co-stimulatory mAb MEDI6469 (2 studies);^39,207,208 (3) the CD137-targeting co-stimulatory mAbs PF-05082566 (1 study) and urelumab (3 studies);^46,209 211 (4) the CTLA4-targeting checkpoint-blocking mAb tremelimumab (8 studies);^212 214 (5) the PD-1-targeting checkpoint-blocking mAbs MEDI0680 (1 study) and pidilizumab (1 study);²¹⁵ (6) the PD-L1-targeting checkpoint-blocking mAbs MEDI4736 (16 studies), MPDL3280A (8 studies), and MSB0010718C (1 study);²¹⁵ and the KIR-inhibitory mAb lirilumab (1 study).²¹⁶ Ninety-eight of these trials are early Phase I/II studies, while 17 of them are advanced Phase III-IV studies. The latter obviously encompass multiple trials evaluating the clinical profile of ipilimumab (6 studies), pembrolizumab (4 studies) and nivolumab (7 studies) (Table 2).

Table 2.

Clinical trials recently started to evaluate the therapeutic profile of immunomodulatory mAbs in oncological indications

mAb	Indication(s)	Phase	Status	Notes	Ref.
CP-870,893	Solid tumors	0	Completed	As single agent	NCT02157831
I	Completed	As single agent	NCT02225002
Ipilimumab	HCC, lung carcinoma	I/II	Recruiting	Combined with radiation therapy	NCT02239900
HCC. melanoma	II	Recruiting	Combined with stereotactic radiosurgery	NCT02107755
Lung carcinoma	III	Not yet recruiting	Combined with carboplatin and paclitaxel	NCT02279732
Lymphoma, MCC	I/II	Recruiting	Combined with TLR9 agonist	NCT02254772
	II	Recruiting	As single agent	NCT02196961
	I	Completed	Combined with IDO1-targeting vaccine	NCT02077114
	Recruiting	Combined with a galectin inhibitor	NCT02117362
	Combined with panobinostat	NCT02032810
	Combined with radiation therapy	NCT01996202
	I/II	Recruiting	As single agent	NCT02115243
	Combined with GM-CSF	NCT02009397
	Combined with indoximod	NCT02073123
	Combined with RTA 408	NCT02259231
	Not yet recruiting	Combined with peptide-based vaccine and GM-CSF	NCT02275416
	Combined with dabrafenib	NCT02200562
	Terminated	Combined with vemurafenib and a PI3K inhibitor	NCT02095652
	II	Active, not recruiting	As single agent	NCT01990859
	Recruiting	As single agent	NCT02115139
	NCT02094391
	NCT02009384
	As single agent or combined HyperAcute®-Melanoma immunotherapy	NCT02054520
	As single agent or combined with bevacizumab and paclitaxel albumin-stabilized nanoparticles	NCT02158520
	Combined with oncolytic virotherapy	NCT02272855
	Combined with stereotactic radiosurgery	NCT02097732
	Not yet recruiting	Combined with aldesleukin	NCT02203604
		Combined with adoptively transferred CD8+ T cells	NCT02027935
	III	Recruiting	As single agent	NCT02278887
	IV	Active, not recruiting	As single agent	NCT02068196
Melanoma, sarcoma	I	Not yet recruiting	Combined with adoptively transferred CD4+ T cells	NCT02210104
NSCLC	II	Recruiting	Combined with radiation therapy	NCT02221739
Prostate carcinoma	II	Recruiting	Combined with degarelix and/or prostatectomy	NCT02020070
n.a.	Recruiting	As single agent	NCT02113657
Not yet recruiting	As single agent	NCT02279862
SCLC	II	Recruiting	As single agent	NCT02046733
Solid tumors	I	Recruiting	Combined with adoptively transferred T cells and peptide-loaded DCs	NCT02070406
Lirilumab	Multiple myeloma	I	Not yet recruiting	Combined with elotuzumab	NCT02252263
MEDI0680	Solid tumors	I	Recruiting	Combined with MEDI4736	NCT02118337
MEDI4736	CRC	II	Not yet recruiting	As single agent	NCT02227667
HNC	II	Not yet recruiting	As single agent	NCT02207530
MDS	I	Recruiting	As single agent	NCT02117219
Melanoma	I/II	Recruiting	Combined with trametinib and/or dabrafenib	NCT02027961
NSCLC	I	Recruiting	Combined with AZD9291 and selumetinib	NCT02143466
I	Recruiting	Combined with gefitinib	NCT02088112
II	Recruiting	As single agent	NCT02087423
II/III	Recruiting	As single agent	NCT02154490
III	Recruiting	As single agent	NCT02125461
MEDI6469	B-cell lymphoma, solid tumors	I/II	Recruiting	As single agent or combined with tremelimumab, MEDI4736 or rituximab	NCT02205333
	HNC	I	Recruiting	As single agent	NCT02274155
MPDL3280A	Bladder carcinoma	II	Recruiting	As single agent	NCT02108652
Lymphoma	I	Not yet recruiting	Combined with obinutuzumab	NCT02220842
NSCLC	I	Recruiting	Combined with erlotinib	NCT02013219
II	Recruiting	As single agent	NCT02031458
III	Recruiting	As single agent	NCT02008227
RCC	II	Recruiting	Combined with bevacizumab and/or sunitinib	NCT01984242
Solid tumors	I	Recruiting	Combined with cobimetinib	NCT01988896
Combined with ipilimumab or IFNα-2b	NCT02174172
MSB0010718C Nivolumab	MCC	II	Recruiting	As single agent	NCT02155647
AML	II	Not yet recruiting	As single agent	NCT02275533
Cervical carcinoma	II	Not yet recruiting	As single agent	NCT02257528
CML	I	Recruiting	Combined with dasatinib	NCT02011945
CRC	I/II	Recruiting	Combined with ipilimumab	NCT02060188
Gastric carcinoma	III	Not yet recruiting	As single agent	NCT02267343
Glioblastoma	III	Recruiting	As single agent or combined with ipilimumab and bevacizumab	NCT02017717
HNC	III	Recruiting	As single agent	NCT02105636
Hodgkin's lymphoma	II	Recruiting	As single agent	NCT02181738
Lymphoma	II	Recruiting	As single agent	NCT02038946
Melanoma	II	Recruiting	As single agent	NCT02156804
III	Not yet recruiting	Combined with ipilimumab, dabrafenib and trametinib	NCT02224781
NHL	II	Recruiting	As single agent	NCT02038933
NSCLC	II	Recruiting	As single agent	NCT02175017
				NCT02259621
	III	Recruiting	As single agent	NCT02066636
			As single agent or combined with multimodal chemotherapy	NCT02041533
Pancreatic carcinoma	II	Not yet recruiting	Combined with multimodal immunochemotherapy	NCT02243371
RCC	II	Not yet recruiting	As single agent or combined with bevacizumab or ipilimumab	NCT02210117
III	Recruiting	Combined with ipilimumab	NCT02231749
Solid tumors	I	Not yet recruiting	As single agent	NCT02261285
NCT02261298
Pembrolizumab	Breast carcinoma	I/II	Not yet recruiting	As single agent	NCT02129556
CRC	II	Not yet recruiting	Combined with azacytidine	NCT02260440
Gastrointestinal tumors	I/II	Not yet recruiting	As single agent	NCT02268825
HNC	II	Recruiting	As single agent	NCT02255097
Not yet recruiting	Combined with radiation therapy	NCT02289209
III	Not yet recruiting	As single agent	NCT02252042
Melanoma	I	Recruiting	As single agent	NCT02180061
Combined with pegIFNα-2b	NCT02112032
I/II	Recruiting	Combined with oncolytic virotherapy	NCT02263508
Combined with trametinib and dabrafenib	NCT02130466
Melanoma, NSCLC	II	Recruiting	As single agent	NCT02085070
Melanoma, RCC	I	Recruiting	Combined with pazopanib	NCT02014636
I/II	Recruiting	Combined with pegIFNα-2b or ipilimumab	NCT02089685
Multiple myeloma	I	Recruiting	Combined with lenalidomide and dexamethasone	NCT02036502
I/II	Not yet recruiting	Combined with pomalidomide and dexamethasone	NCT02289222
Mycosis fungoides Sezary syndrome	II	Recruiting	As single agent	NCT02243579
Neuroendocrine skin carcinoma	II	Not yet recruiting	As single agent	NCT02267603
NSCLC	I	Active, not recruiting	As single agent	NCT02007070
I/II	Recruiting	Combined with multimodal chemotherapy	NCT02039674
III	Recruiting	As single agent	NCT02220894
As single agent or combined with carboplatin or cisplatin	NCT02142738
RCC	I	Not yet recruiting	As single agent	NCT02212730
Recruiting	Combined with axitinib	NCT02133742
Solid tumors	I	Recruiting	As single agent	NCT02054806
I/II	Recruiting	Combined with INCB024360	NCT02178722
Urothelial carcinoma	III	Recruiting	As single agent	NCT02256436
PF-05082566	Solid tumors	I	Recruiting	Combined with pembrolizumab	NCT02179918
Pidilizumab	Multiple myeloma	I/II	Recruiting	Combined with lenalidomide	NCT02077959
Tremelimumab	HNC	I	Recruiting	As single agent or combined with MEDI4736	NCT02262741
Lung carcinoma	I	Recruiting	Combined with MEDI4736	NCT02000947
Melanoma	I	Recruiting	Combined with MEDI3617	NCT02141542
NSCLC	I	Recruiting	Combined with gefitinib	NCT02040064
II	Recruiting	Combined with multimodal immunochemotherapy	NCT02179671
Solid tumors	I	Recruiting	Combined with MEDI4736	NCT02261220
NCT02141347
Urelumab	B-cell NHL, Solid tumors	I/II	Recruiting	Combined with nivolumab	NCT02253992
CRC, HNC	I	Recruiting	Combined with cetuximab	NCT02110082
Multiple myeloma	I	Not yet recruiting	Combined with elotuzumab	NCT02252263

Abbreviations: AML, acute myeloid leukemia, CML, chronic myeloid leukemia; CRC, colorectal carcinoma; GM-CSF, granulocyte macrophage colony-stimulating factor; HCC, hepatocellular carcinoma; HNC, head and neck cancer; IDO1, indoleamine 2,3-dioxygenase 1; IFNα-2b, interferon α2b; MCC, Merkel cell carcinoma; MDS, myelodysplastic syndrome; NHL, non-Hodgkin's lymphoma; NSCLC, non-small cell lung carcinoma; PI3K, phosphoinositide-3-kinase; RCC, renal cell carcinoma; SCLC, small cell lung carcinoma; TLR9, Toll-like receptor 9. *Initiated after November 1^st 2013.

The cohorts of patients enrolled in the context of these clinical trials are relatively heterogeneous (source http://clinicaltrials.gov/). No less than 36 studies involve subjects with melanoma, near-to-invariably as an on-label indication for ipilimumab-, pembrolizumab-, or nivolumab-based immunotherapy. In addition, the safety and efficacy of immunomodulatory mAbs are being assessed in cohorts of patients with NSCLC (19 studies) or other pulmonary neoplasms (4 studies), various hematological malignancies (14 studies), head and neck cancer (8 studies), renal cancer (7 studies), colorectal carcinoma (CRC, 4 studies), prostate carcinoma (3 studies), Merkel cell carcinoma (2 studies), hepatocellular carcinoma (2 studies), gastric or gastrointestinal tumors (2 studies), and several other solid malignancies (23 studies). Along similar lines, it is difficult to identify a therapeutic paradigm that attracts considerably more attention than others, with the obvious exceptions of immunomodulatory mAbs employed as standalone immunotherapeutic interventions (58 studies). Thus, immunomodulatory mAbs are currently being tested in combination with a wide panel of chemo-, radio-, and immunotherapeutic regimens, including (but not limited to): (1) conventional and immunogenic chemotherapeutics (7 studies),^217-222 (2) targeted anticancer agents (19 studies),^223,224 (3) radiation therapy, in one of its variants (6 studies),^225,226 (4) hormone therapy (1 study),^227-229 (5) surgery (1 study),^230-232 (6) tumor-targeting mAbs (10 studies),^54,233-237 (7) immunostimulatory cytokines (5 studies),^69,238-240 (8) anticancer vaccines (3 studies),^241-248 (9) Toll-like receptor (TLR) agonists (1 study),^249,250 (10) adoptive cell transfer (3 studies),^{236,237,251-253} (11) oncolytic virotherapy (2 studies),^70,254-256 (12) indoleamine 2,3-dioxygenase 1 (IDO1)-targeting strategies (3 studies),²⁵⁷ (13) so-called immunomodulatory drugs, i.e., thalidomide, lenalidomide or pomalidomide (3 studies),²⁵⁸ and (14) immunomodulatory mAbs with a distinct mechanism of action (17 studies)²⁵⁹ (Table 2).

Of note, all these studies are active (NCT status: “Active, not recruiting,” “Not yet recruiting” or “Recruiting”), with 4 notable exceptions. NCT02157831 (a Phase 0 study) and NCT02225002 (a Phase I study), both of which assessed the therapeutic profile of a single infusion of CP-870,893 in patients with advanced solid tumors, are listed as “Completed.” To the best of our knowledge, however, the results of these studies have not yet been released. Similarly, NCT02077114, a Phase I clinical trial investigating the safety and efficacy of an IDO1-targeting vaccine combined with ipilimumab in Stage III/IV melanoma patients, appears as “Completed,” but the results are not yet available. Finally, NCT02095652, a Phase I/II study testing ipilimumab in combination with an inhibitor of phosphoinositide-3-kinase/v-akt murine thymoma viral oncogene homolog 1 (PI3K/AKT1) signaling (namely, DNE3),²⁶⁰ was prematurely terminated owing to safety concerns linked to the administration of DNE3 (source http://clinicaltrials.gov/).

As for the clinical studies listed in our previous Trial Watches dealing with immunomodulatory mAbs,^53,54,261 the following trials have changed status during the last 13 months: NCT01721746, NCT01721772, NCT01730157, NCT01783938, NCT01832870, NCT01844505, NCT01846416, NCT01848834, NCT01866319, NCT01903993, and NCT01927419, which are now listed as “Active, not recruiting”; NCT01789827, NCT01804465, NCT01879306, NCT01896869, NCT01896999, NCT01919619, NCT01928394, NCT01952769, NCT01953692, and NCT01975831, which are now recruiting participants; NCT01769222, which has been suspended; NCT01913691, which has been withdrawn; NCT01715077, whose status is unknown; as well as NCT01665391, and NCT01709162, which have been completed. NCT01769222, a Phase I/II clinical trial testing ipilimumab plus radiation therapy in patients with recurrent melanoma, non-Hodgkin's lymphoma and CRC, has been suspended based on the results of a Data and Safety Monitoring Committee audit. NCT01913691, a Phase II clinical trial investigating the safety and efficacy of ipilimumab in Merkel cell carcinoma patients, has been withdrawn prior to enrollment for undisclosed reasons. Finally, to the best of our knowledge, the results of NCT01665391, a Phase 2 study comparing fresolimumab to placebo in subjects with a pseudo-malignant renal disease, and NCT01709162, a Phase II study comparing ipilimumab re-administration to standard chemotherapy in subjects with advanced melanoma who progressed on induction ipilimumab-based immunotherapy following initial disease stabilization, have yet to be disclosed (source http://www.clinicaltrials.gov).

Concluding Remarks

One year ago, the Editors of Science Magazine designed anticancer immunotherapy “Breakthrough of the Year,” celebrating the extraordinary clinical success achieved by this therapeutic paradigm throughout the past decade.^262,263 Immunomodulatory mAbs, and in particular checkpoint blockers, enacted a major part in this play. Accumulating lines of evidence indicate that checkpoint-blocking mAbs indeed not only represent a promising means to induce robust and durable responses when employed as single agents,^{20,21,192,264-269} but also can be harnessed to boost the activity of several (immuno)therapeutic regimens.²⁷⁰ These include (but are not limited to) tumor-targeting mAbs,^{54,156,271,272} adoptive cell transfer,^{251,252,264,273-275} dendritic cell-, peptide- and DNA-based anticancer vaccines,^{115,241-245,276-278} oncolytic viruses,^{70,254,279,280} TLR agonists,^249,250,281 immunostimulatory cytokines,^{69,238,282,283} radiation therapy,^{225,226,284-288} and immunomodulatory drugs (e.g., lenalidomide),^138,258,289 as well as conventional and targeted chemotherapeutics (in particular when these also mediate immunostimulatory effects).^{133,141,142,149,150,183,217,218,221,222,269,290}

Combinatorial strategies that simultaneously inhibit distinct immunological checkpoints, such as the co-administration of PD-1- and CTLA-targeting mAbs, also appear to mediate superior clinical activity, especially in the treatment of neoplasms such as melanoma¹⁹² and RCC,⁸⁴ which are particularly sensitive to immunotherapy. Along similar lines, combining checkpoint blockers like ipilimumab or nivolumab with co-stimulatory mAbs such as MEDI6469 may be clinically advantageous as compared to monotherapeutic regimens.²⁹¹ Therapeutic paradigms of this type, involving the co-administration of immunomodulatory mAbs with distinct mechanisms of action, are being intensively investigated in both preclinical and clinical scenarios.²⁷⁰

Importantly, the use of some checkpoint blockers like ipilimumab has been associated with a limited, but non-negligible, rate of severe/fatal autoimmune reactions.^55,193,-294 One of the strategies currently under investigation to limit the toxicity of checkpoint-blocking mAbs has yielded promising results (at least in preclinical settings), relies on local, as opposed to systemic, administration.²⁹⁵ Interestingly, this approach appears to resemble radiation therapy in that it provokes an abscopal effect, i.e., it elicits a tumor-targeting immune response that attacks distant, non-treated lesions.^295,296 Additional approaches for uncoupling the efficacy of checkpoint blockers from their toxicity may involve the gut microbiota.²⁹⁷ Of note, the clinical profile of the intratumoral co-administration of ipilimumab and a TLR9 agonist (i.e., SD-101) combined with local radiation therapy is currently being evaluated in patients affected by low-grade, recurrent B-cell lymphoma (NCT02254772).

Similar to their tumor-targeting counterparts, immunomodulatory mAbs are expensive (the use of pembrolizumab is expected to cost 12,500 USD per month) (source http://www.nytimes.com/2014/09/05/business/merck-wins-approval-of-novel-immune-system-drug-for-cancer.html?_r=0). Thus, it now imperative to identify biomarkers that predict the efficacy of immunomodulatory mAbs and hence allow for the identification of patients who are likely to obtain actual benefits from this type of immunotherapy.^{9,129,298-304} We believe that adequately monitoring immune system-related parameters among patients enrolled in clinical trials (immunomonitoring) and bridging these data with the genomic/exomic profile of tumors will further increase the benefits brought about to the community by immunomodulatory mAbs.^305-309

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Funding

Authors are supported by the Ligue contre le Cancer (équipe labelisée); Agence National de la Recherche (ANR); Association pour la recherche sur le cancer (ARC); Cancéropôle Ile-de-France; AXA Chair for Longevity Research; Institut National du Cancer (INCa); Fondation Bettencourt-Schueller; Fondation de France; Fondation pour la Recherche Médicale (FRM); the European Commission (ArtForce); the European Research Council (ERC); the LabEx Immuno-Oncology; the SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE); the SIRIC Cancer Research and Personalized Medicine (CARPEM); and the Paris Alliance of Cancer Research Institutes (PACRI).