Trial Watch: Immunogenic cell death inducers for anticancer chemotherapy

Trial Watch: Immunogenic cell death inducersfor anticancer chemotherapy

Jonathan Pol1,2,3,y, Erika Vacchelli1,2,3,y, Fernando Aranda4,y, Francesca Castoldi1,2,3,5,6, Alexander Eggermont1,Isabelle Cremer2,7,8, Catherine Saut!es-Fridman2,7,8, Jitka Fucikova6,9, J"erome Galon2,8,10,11, Radek Spisek6,9,

Eric Tartour11,12,13,14, Laurence Zitvogel1,15, Guido Kroemer2,3,11,16,17,z,*, and Lorenzo Galluzzi1,2,3,11,z

1Gustave Roussy Cancer Campus; Villejuif, France; 2INSERM, U1138; Paris, France; 3Equipe 11 labellis"ee par la Ligue Nationale contre le Cancer, Center de Recherche des Cordeliers;Paris, France; 4Group of Immune receptors of the Innate and Adaptive System, Institut d’Investigacions Biom"ediques August Pi i Sunyer (IDIBAPS); 5Facult"e de Medicine; Universit"eParis Sud/Paris XI; Le Kremlin-Bicetre, France; 6Sotio a.c.; Prague, Czech Republic; 7Equipe 13, Center de Recherche des Cordeliers; Paris, France; 8Universit"e Pierre et Marie Curie/Paris VI; Paris, France; 9Department of Immunology, 2nd Faculty of Medicine and University Hospital Motol, Charles University; Prague, Czech Republic; 10Laboratory of Integrative

Cancer Immunology, Center de Recherche des Cordeliers; Paris, France; 11Universit"e Paris Descartes/Paris V; Sorbonne Paris Cit"e; Paris, France; 12INSERM, U970; Paris, France;13Paris-Cardiovascular Research Center (PARCC); Paris, France; 14Service d’Immunologie Biologique, Hopital Europ"een Georges Pompidou (HEGP); AP-HP; Paris, France;15INSERM, U1015; CICBT507; Villejuif, France; 16Pole de Biologie, Hopital Europ"een Georges Pompidou; AP-HP; Paris, France; 17Metabolomics and Cell Biology Platforms,

Gustave Roussy Cancer Campus; Villejuif, France

yThese authors contributed equally to this work.zThese authors share senior co-authorship.

Keywords: antigen-presenting cell, autophagy, damage-associated molecular pattern, dendritic cell, endoplasmic reticulum stress, typeI interferon

Abbreviations: AML, acute myeloid leukemia; ALL, acute lymphoblastic leukemia; CML, chronic myeloid leukemia; DAMP,damage-associated molecular pattern; EGFR, epidermal growth factor receptor; EOX, epirubicin plus oxaliplatin plus capecitabine;ER, endoplasmic reticulum; FDA, Food and Drug Administration; FOLFIRINOX, folinic acid plus 5-fluorouracil plus irinotecan

plus oxaliplatin; FOLFOX, folinic acid plus 5-fluorouracil plus oxaliplatin; GEMOX, gemcitabine plus oxaliplatin; GM-CSF,granulocyte-macrophage colony-stimulating factor; HCC, hepatocellular carcinoma; ICD, immunogenic cell death; mAb, monoclo-nal antibody; MM, multiple myeloma; NHL, non-Hodgkin’s lymphoma; NSCLC, non-small cell lung carcinoma; TACE, transcath-

eter arterial chemoembolization; XELOX, capecitabine plus oxaliplatin.

The term “immunogenic cell death” (ICD) is now employedto indicate a functionally peculiar form of apoptosis that issufficient for immunocompetent hosts to mount an adaptiveimmune response against dead cell-associated antigens.Several drugs have been ascribed with the ability to provokeICD when employed as standalone therapeutic interventions.These include various chemotherapeutics routinely employedin the clinic (e.g., doxorubicin, epirubicin, idarubicin,mitoxantrone, bleomycin, bortezomib, cyclophosphamideand oxaliplatin) as well as some anticancer agents that arestill under preclinical or clinical development (e.g., somemicrotubular inhibitors of the epothilone family). In addition,a few drugs are able to convert otherwise non-immunogenicinstances of cell death into bona fide ICD, and may thereforebe employed as chemotherapeutic adjuvants withincombinatorial regimens. This is the case of cardiac glycosides,like digoxin and digitoxin, and zoledronic acid. Here, wediscuss recent developments on anticancer chemotherapybased on ICD inducers.

Introduction

Ten years ago, we were the first to introduce the term“immunogenic cell death” (ICD) to indicate a functionally pecu-liar type of apoptosis that – in immunocompetent hosts – canelicit an immune response against dead cell-associated antigens inthe absence of any adjuvant.1,2 Indeed, the subcutaneous inocula-tion of cancer cells succumbing to doxorubicin (an anthracyclineapproved by regulatory agencies for the treatment of severaltumors, see below) in vitro was sufficient to protect syngeneicmice against a re-challenge with malignant cells of the same type,but not with cancer cells of distinct origin.2 Subsequent studiesby us and others identified various mechanisms that underlie notonly the ability of a specific stimulus to trigger bona fide ICD asopposed to a non-immunogenic instance of apoptosis, but alsothe capacity of the host to detect ICD and hence mount a thera-peutically relevant immune response against dying cells.1,3-6

Schematically, ICD itself relies on the coordinated emission ofa series of damage-associated molecular patterns (DAMPs),7-12

including the exposure of endoplasmic reticulum (ER) chaper-ones on the cell surface, the secretion of ATP and the release ofthe non-histone chromatin-binding protein high mobility groupbox 1 (HMGB1),13-20 and immunostimulatory cytokines, suchas type I interferons.21 When emitted in the correct spatiotempo-ral pattern,22-24 such DAMPs recruit antigen-presenting cells,including dendritic cells, to the site of ICD and activate them to

*Correspondence to: Guido Kroemer; Email: [email protected], LorenzoGalluzzi; Email: [email protected]: 01/13/2015; Accepted: 01/14/2015http://dx.doi.org/10.1080/2162402X.2015.1008866

www.tandfonline.com e1008866-1OncoImmunology

OncoImmunology 4:4, e1008866; April 2015; © 2015 Taylor & Francis Group, LLCREVIEW

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engulf dead cell-associated antigens, process and present them toCD4C and CD8C T lymphocytes in the context of co-stimula-tory signals, resulting in the priming of a robust, antigen-specificimmune response.25-31 In line with this notion, the ability of can-cer cells undergoing ICD to elicit a protective immune responseupon inoculation to syngeneic mice is abrogated: (1) when themolecular pathways underlying the emission of the abovemen-tioned DAMPs are pharmacologically or genetically inhibited inmalignant cells;13,32,33 as well as (2) in mice affected by relativelygeneralized forms or immunodeficiency or lacking specific com-ponents of the DAMP-sensing machinery, such as Toll-likereceptor 4 (Tlr4) or type I interferon (a and b) receptor 1(Ifnar1).15,21,34 A more detailed description of these signal trans-duction pathways and cellular circuitries goes beyond the scopeof this Trial Watch and can be found in several recentreviews.1,3,4

Importantly, some – but not all – cell death inducers are capa-ble of eliciting ICD,35 and this property cannot be anticipated bystructural or functional considerations.3,36-38 Indeed, while cis-platin and oxaliplatin both exert cytostatic/cytotoxic effects asthey induce inter- and intra-strand DNA adducts,39-42 only thelatter triggers bona fide ICD as it provokes a pre-mortem ERstress response.43,44 Thus, although assays for the detection ofsurrogate ICD markers are available,45 the gold standardapproach for determining whether a cytotoxic intervention pro-vokes bona fide ICD still relies on vaccination experimentsinvolving murine cancer cells and syngeneic, immunocompetentmice.3 In addition, the ability of a specific stimulus to induceICD can be inferred by testing its antineoplastic effects ontumors established in immunocompetent versus immunodeficienthosts.3 However, this approach cannot replace vaccinationexperiments as several therapeutic agents mediate optimal anti-neoplastic effects in immunocompetent hosts only as they havean off-target immunostimulatory activity but do not induceICD.46-48

So far, only a few stimuli have been ascribed with the ability totrigger ICD, encompassing both chemical and physicalagents.3,36 Interestingly, such bona fide ICD inducers include var-ious anticancer chemotherapeutics that have been successfullyemployed in the clinic for several years (Table 1), like (1) doxo-rubicin, an anthracycline approved by the US Food and DrugAdministration (FDA) for the treatment of acute lymphoblasticleukemia (ALL), acute myeloid leukemia (AML), breast carci-noma, gastric cancer, lymphoma, multiple myeloma (MM), neu-roblastoma, ovarian carcinoma, small cell lung carcinoma, softtissue and bone sarcomas, thyroid carcinoma, transitional cellbladder carcinoma and Wilms’ tumor;2,49 (2) epirubicin, ananthracycline licensed for use in breast carcinoma patients;2,49

(3) idarubicin, an anthracycline currently employed for the treat-ment of AML;19,49 (4) mitoxantrone, an anthracenedionelicensed for use in individuals with AML, breast carcinoma, non-Hodgkin’s lymphoma (NHL) and prostate carcinoma;2,49

(5) bleomycin, a glycopeptide antibiotic commonly employed asa palliative treatment for Hodgkin’s lymphoma, NHL, penilecancer, testicular cancer, and squamous carcinomas of the headand neck, cervix and vulva;50 (6) bortezomib, a proteasomal

inhibitor approved for use in subjects with MM and mantle celllymphoma;17,51,52 (7) cyclophosphamide, an alkylating agentnowadays employed for the treatment of ALL, AML, chroniclymphocytic leukemia, breast carcinoma, chronic myeloid leuke-mia (CML), lymphoma, MM, mycosis fungoides, neuroblas-toma, ovarian carcinoma and retinoblastoma;53 and(8) oxaliplatin, a platinum derivative approved for use in combi-nation with 5-fluorouracil and folinic acid for the therapy ofadvanced colorectal carcinoma.40,44,54 Moreover, at least in somecell types, ICD can be provoked by patupilone, an experimentalmicrotubular inhibitor of the epothilone family,55-57 and by7A7, a monoclonal antibody (mAb) targeting the murine epider-mal growth factor receptor (EGFR).58,59 However, for the rea-sons mentioned above, FDA-approved epothilones (i.e.,ixabepilone, which is licensed for the treatment of breast carci-noma)60 and EGFR-targeting mAbs (i.e., cetuximab and panitu-mumab, which are currently employed for the treatment of headand neck cancer and colorectal carcinoma)61-63 may not sharethis ability with patupilone and 7A7, respectively. Finally, itshould be noted that some FDA-approved agents such as digoxinand digitoxin (which are licensed for the treatment of various car-diac disorders),64 as well as zoledronic acid (which is commonlyemployed for the treatment of MM or hypercalcemia and bonelesions of oncological origin),65 are very efficient at boosting theimmunogenicity of otherwise non-immunogenic instances of celldeath, although they are unable to elicit ICD per se.66-69 Theseagents may be particularly relevant for the development of com-binatorial chemotherapeutic regimens that actively engage thehost immune system against malignant cells.

In the context of our monthly series,70-72 this Trial Watch dis-cusses recent developments on anticancer chemotherapy withICD inducers. In line with this notion, irradiation and photody-namic therapy, 2 additional interventions that trigger bona fideICD and are commonly employed for the treatment of severalneoplasms,73-82 will not be considered further here.

Update on the Development of ICD-InducingChemotherapeutics

Completed clinical trials. On 2015, Jan 6th queryingPubMed with the string “cancer AND (patients OR trial) AND(doxorubicin OR epirubicin OR idarubicin OR mitoxantroneOR bortezomib OR bleomycin OR cyclophosphamide ORoxaliplatin)” returned 48,701 entries, some 2,000 of which werepublished since the submission of our latest Trial Watch dealingwith ICD-inducing chemotherapeutics (January 2014).83 Thisfigure obviously covers a number of preclinical research papers,review articles and editorials that is difficult to quantify with pre-cision. Moreover, in a significant fraction of the clinical articlesincluded in this figure, doxorubicin, epirubicin, idarubicin,mitoxantrone, bortezomib, bleomycin, cyclophosphamide andoxaliplatin are employed as part of standard chemotherapeuticregimens, in on-label indications (source (http://www.ncbi.nlm.nih.gov/pubmed). Among the clinical studies testing the safetyand efficacy of ICD-inducing chemotherapeutics employed as

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off-label indications, we would like to highlight the works of: (1)Butts and collaborators (Cross Cancer Institute; Edmonton,Canada), who reported that the therapeutic activity of a tumor-targeting vaccine administered to non-small cell lung carcinoma(NSCLC) patients previously receiving cyclophosphamide-basedchemotherapy may be influenced by the administration schedule(i.e., sequential vs. concurrent) of the latter;84 (2) Roulstone andcolleagues (The Institute of Cancer Research; London, UK), whodemonstrated that the pre-administration of high-dose cyclo-phosphamide to individuals with solid tumors is unable to pre-vent the development of humoral, neutralizing immunity againstoncolytic reoviruses;85 (3) Bazzola and co-authors (Azienda Isti-tuti Ospitalieri di Cremona; Cremona, Italy), who tested met-ronic cyclophosphamide combined with letrezole (a non-steroidal aromatase inhibitor) and sorafenib (a multi-targetedkinase inhibitor)86,87 in primary breast cancer patients, withpromising results;88 (4) Lutz et al. (The Sidney Kimmel CancerCenter; Baltimore, MD, US), who demonstrated that low-dosecyclophosphamide converts the tolerogenic microenvironment ofpancreatic adenocarcinoma into an immunogenic one, boostingthe clinical activity of an irradiated, granulocyte-macrophage col-ony-stimulating factor (GM-CSF)-secreting, allogeneic vac-cine;89-92 (5) Zheng and collaborators (Johns HopkinsUniversity School of Medicine; Baltimore, MD, US), who –along similar lines – proved the capacity of low-dose cyclophos-phamide to support the therapeutic activity of a vaccine com-posed of irradiated, allogeneic human colorectal cancer cells andGM-CSF-producing bystander cells;93 (6) Hong and colleagues(University of Ulsan College of Medicine; Seoul, South Korea),who reported that, as compared to adjuvant folinic acid and 5-fluorouracil, adjuvant FOLFOX (folinic acid plus 5-fluorouracilplus oxaliplatin) is associated with an improved disease-free

survival among patients with locally advanced rectal cancer afterpreoperative chemoradiotherapy and total mesorectal excision;94

(7) Noh and co-workers (Yonsei University College of Medicine;Seoul, South Korea) and Yamada et al. (National Cancer CenterHospital; Tokyo, Japan), who demonstrated the clinical efficacyof oxaliplatin in combination with capecitabine or S-1, respec-tively, in patients with gastric carcinoma;95,96 (8) Oettle and col-laborators (Charit#e Universit€atsmedizin; Berlin, Germany) andO’Reilly and colleagues (Memorial Sloan-Kettering Cancer Cen-ter, New York, NY, US), who provided evidence in support ofthe therapeutic activity of oxaliplatin as part of neoadjuvant che-motherapeutic regimens for patients with refractory or chemo-therapy-na€ıve pancreatic carcinoma;97,98 (9) Straus and co-authors (Memorial Sloan-Kettering Cancer Center, New York,NY, US), who reported that the administration of liposomaldoxorubicin to subjects with cutaneous T-cell lymphoma is asso-ciated with an objective responses rate that is among the highestever reported for similar patient cohorts, while the subsequentapplication of bexarotene (a retinoid)99-102 has negligible effectson response rate and duration.103

Preclinical and translational advances. Within the abundantpreclinical literature that has been published during the last 13months on ICD-inducing chemotherapeutics, we found of par-ticular interest the works of: (1) Pallasch and colleagues (Massa-chusetts Institute of Technology; Cambridge, MA, US), whodemonstrated that cyclophosphamide induces an acute secretoryphenotype in malignant cells, stimulating the release of variousimmunostimulatory cytokines that promotes a macrophage-driven, tumor-targeting innate immune response;104-106

(2) Tavora and collaborators (Barts Cancer Institute; London,UK), who showed that the inhibition of protein tyrosine kinase 2(PTK2, also known as FAK)107-109 in the endothelial tumor

Table 1. Immunogenic cell death inducers currently approved for cancer chemotherapy*

Drug First approved Indication(s) Ref.

Bleomycin <1995 HNSCCLymphomaPenile cancer

SCC of the cervixSCC of the vulvaTesticular cancer

50

Bortezomib 2003 Mantle cell lymphoma Multiple myeloma 17,51,52Cyclophosphamide <1995 Breast carcinoma

LeukemiaLymphomaMultiple myeloma

Mycosis fungoidesNeuroblastomaOvarian carcinomaRetinoblastoma

53

Doxorubicin <1995 ALLAMLBladder carcinomaBone sarcomaBreast carcinomaGastric carcinomaLymphoma

Multiple myelomaNeuroblastomaOvarian carcinomaSCLCSoft tissue sarcomaThyroid carcinomaWilms’ tumor

2,49

Epirubicin 1999 Breast carcinoma 2,49Idarubicin <1995 AML 19,49Mitoxantrone <1995 AML

Breast carcinomaNHL

Prostate carcinoma2,49

Oxaliplatin 1996 Colorectal carcinoma 44,54

Abbreviations: ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; HNSCC, head and neck squamous cell carcinoma; NHL, non-Hodgkin’s lym-phoma; SCC, squamous cell carcinoma; SCLC, small cell lung carcinoma; *by the US Food and Drug Administration or equivalent agency worldwide.


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compartment sensitizes cancer cells to doxorubicin-based chemo-therapy;110 (3) Cottini and co-authors (Harvard Medical School;Boston, MA, US), who mechanistically involved the Hippo co-activator Yes-associated protein 1 (YAP1)111-114 in the responseof hematological tumors to DNA-damaging agents, includingdoxorubicin;112,115 (4) Ichikawa et al. (Northwestern UniversitySchool of Medicine; Chicago, Illinois, US) and Liu and col-leagues (Harvard Medical School; Boston, MA, US), who dem-onstrated that the accumulation of iron withinmitochondria8,116-118 and consequent alterations in the activityof enzymes of the Krebs’ cycle contribute to the cardiotoxicity ofdoxorubicin;119,120 (5) Viaud and co-authors (Gustave RoussyCancer Campus; Villejuif, France) and Iida and collaborators(National Cancer Institute; Frederick, MD, US), who provedthat specific changes in the gut microbiota121-124 induced bycyclophosphamide and oxaliplatin are responsible for their full-blown therapeutic activity as they favor the elicitation of antican-cer immune responses;125-127 (6) Morton et al. (MassachusettsInstitute of Technology; Cambridge, MA, US), who developed ananoparticle-based chemotherapy delivery system128 that allowsfor the finely controlled release of up to 2 drugs, a vehicle thatmay be particular relevant for promoting ICD;129 (7) Sistigu andco-authors (Gustave Roussy Cancer Campus; Villejuif, France),who demonstrated that the release of type I interferons fromdying cancer cells is required for the host immune system to per-ceive such event as immunogenic and mount an adaptiveimmune response against dead cell-associated antigens;21 andTriulzi and collaborators (Fondazione IRCCS Istituto Nazionaledei Tumori; Milan, Italy), who identified a role for serpin pepti-dase inhibitor, clade B (ovalbumin), member 5 (SERPINB5, bestknown as maspin)130-133 in the establishment of a collagen-enriched tumor microenvironment contributing to the resistanceof (at least a subset of) breast carcinomas to doxorubicin.134

Recently initiated clinical trials. Since the submission ofour latest Trial Watch dealing with this topic (January2014),83 no less than 374 clinical studies involving ICD-inducing chemotherapeutics have been initiated (doxorubicinD 75 studies; epirubicin D 23 studies; idarubicin D 18 stud-ies; mitoxantrone D 14 studies; bleomycin D 8 studies; bor-tezomib D 25 studies; cyclophosphamide D 128 studies;oxaliplatin D 83 studies). In the vast majority of these trials(250 studies), however, ICD inducers are employed as on-label therapeutic interventions, most often as (part of) thegold standard chemotherapeutic regimen given to the controlarm of the study. These studies will not be discussed furtherhere. In addition, no less than 125 clinical trials have recentlybeen initiated to test the therapeutic profile of doxorubicin(14 studies), epirubicin (8 studies), idarubicin (3 studies),mitoxantrone (4 studies), bleomycin (2 studies), bortezomib(7 studies), cyclophosphamide (34 studies), and oxaliplatin(53 studies) employed as off-label chemotherapeutic interven-tions (source http://clinicaltrials.gov/).

In particular, doxorubicin is being tested in subjects with (1)breast carcinoma, who receive the drug in pegylated liposomalformulation combined with carboplatin, a cisplatin derivativeapproved for the treatment of NSCLC and ovarian

carcinoma,135,136 and paclitaxel, a microtubular inhibitor oftenemployed in women with breast carcinoma137,138

(NCT02315196); (2) hepatocellular carcinoma (HCC), mostoften in the context of transcatheter arterial chemoembolization(TACE)139 (NCT02038296; NCT02070419; NCT02112656;NCT02125396; NCT02141906; NCT02147301;NCT02149771; NCT02182687; NCT02240771); (3) hepaticmetastases from other solid tumors, again in liposomal formula-tion (NCT02181075); (4) melanoma, who receive doxorubicinas a standalone therapeutic intervention (NCT02094872);(5) MM, in the context of a multimodal chemoimmunothera-peutic regimen involving the immunomodulatory drug thalido-mide140,141 (NCT02128230); and (6) peritoneal carcinomatosis,who are treated with doxorubicin plus cisplatin as pressurizedintraperitoneal aerosol chemotherapy (NCT02320448). Thetherapeutic profile of epirubicin is being evaluated in patientswith (1) bladder carcinoma, who receive epirubicin as a stand-alone intravesical chemotherapeutic (NCT02214602); (2) gastricor gastroesophageal carcinoma, invariably as part of the so-calledEOX regimen (epirubicin plus oxaliplatin plus capecitabine)142

(NCT02128243; NCT02177552; NCT02158988); (3) HCC,in the context of TACE (NCT02220088); (4) MM, as part ofinduction or tumor-reduction chemotherapy followed by stemcell mobilization and consolidation chemotherapy(NCT02288741); and (5) soft tissue sarcoma, who receive epiru-bicin in combination with conventional chemotherapeuticsof trabectedin, a macrophage-repolarizing agent143,144

(NCT02050919; NCT02066675). The clinical activity of idaru-bicin is being assessed in individuals with (1) CML, who receiveidarubicin plus cladribine and cytarabine (2 inhibitors of nucleo-tide metabolism currently approved for the treatment of variousforms of leukemia)145 (NCT02115295); (2) myelodysplasticsyndrome, in the context of cytarabine-based chemotherapy anddonor lymphocyte infusion146,147 (NCT02046122); and(3) HCC, who receive idarubicin in the form of drug-loadedmicrobeads (NCT02185768). Mitoxantrone is being tested inpatients with: (1) ALL, in the context of combinatorial chemo-therapeutic regimen (NCT02101853; NCT02303821); (2) lym-phoma, who are treated with mitoxantrone as a single agent(NCT02131688); and (3) various solid tumors, who also receivemitoxantrone as standalone therapeutic intervention(NCT02043756). The clinical activity of bleomycin is beinginvestigated in subjects with: (1) HCC, in the context of electro-chemotherapy (NCT02291133); and (2) non-seminomatousmalignant germ cell tumors, who receive bleomycin in combina-tion with cisplatin-based chemotherapy (NCT02104986). Theefficacy of bortezomib is being assessed in individuals with(1) various hematological malignancies, who often receive borte-zomib as part of multimodal chemo- or immunotherapeutic regi-mens (NCT02037256; NCT02112916; NCT02208037;NCT02312102); (2) neuroblastoma, who are treated with borte-zomib plus difluoromethylornithine (a hitherto experimentalinhibitor of polyamine biosynthesis),148,149 (NCT02139397);and (3) various solid tumors, who receive bortezomib as stand-alone therapeutic agent or combined with standard chemother-apy (NCT02211755; NCT02220049) (Table 2).


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The efficacy of cyclophosphamide as an off-label therapeuticintervention is being evaluated in subjects with: (1) colorectal car-cinoma, often in the context of capecitabine-based chemother-apy150,151 (NCT02271464; NCT02280694; NCT02298946);(2) medulloblastoma, who often are treated with cyclophospha-mide plus a chemotherapeutic regimen based on cisplatin(NCT02066220; NCT02212574); (3) melanoma, to whomcyclophosphamide is administered as part of a lymphodepletingtreatment followed by adoptive cell transfer152-154

(NCT02062359; NCT02111863; NCT02278887); NSCLC, aspart of various chemo- or immunotherapeutic regimens

(NCT02049151; NCT02117024; NCT02133196;NCT02187367); (4) soft tissue sarcoma, as part of multimodalchemoimmunotherapy (NCT02059850; NCT02234050;NCT02306161); as well as breast carcinoma (NCT02276300),gastric carcinoma (NCT02276300; NCT02317471), ependy-doma (NCT02265770), osteosarcoma (NCT02273583), pan-creatic carcinoma (NCT02243371), prostate carcinoma(NCT02234921), testicular cancer (NCT02161692), germ celltumors (NCT02161692), rhabdoid malignancies(NCT02114229), and various other solid tumors(NCT02054104; NCT02070406; NCT02096614;

Table 2. Clinical trials recently started to evaluate the therapeutic profile of doxorubicin, epirubicin, idarubicin, mitoxantrone, bleomycin or bortezomib asoff-label chemotherapeutic interventions*

Drug Indication(s) Phase Status Notes Ref.

Doxorubicin Breast carcinoma II Not yet recruiting As PLD, combined with carboplatin and paclitaxel NCT02315196HCC n.a. Recruiting In the context of TACE NCT02141906

II Active, not recruiting In the context of TACE NCT02182687Not yet recruiting In the context of TACE NCT02147301Withdrawn In the context of TACE NCT02070419

II/III Recruiting In the context of TACE NCT02240771III Completed In the context of TACE NCT02038296

Not yet recruiting In the context of TACE NCT02125396Recruiting As thermosensitive liposomal doxorubicin NCT02112656

In the context of TACE NCT02149771Hepatic metastases I Recruiting As thermosensitive liposomal doxorubicin NCT02181075Melanoma II Recruiting As single agent NCT02094872Multiple myeloma II Active, not recruiting Combined with multimodal

chemoimmunotherapyNCT02128230

Peritoneal carcinomatosis II Not yet recruiting Combined with cisplatin as PIPAC NCT02320448Epirubicin Bladder carcinoma IV Recruiting As intravesical standalone chemotherapeutic NCT02214602

Gastric or gastroesophagealcarcinoma

II Recruiting EOX regimen NCT02177552EOX plus cisplatin and S-1 NCT02128243

III Recruiting EOX regimen §mitomycin C and cisplatin NCT02158988HCC II/III Recruiting In the context of TACE NCT02220088Multiple myeloma III Completed As a part of induction or tumor reduction

chemotherapy followedby stem cell mobilization

NCT02288741

Soft tissue sarcoma II Recruiting Combined with ifosfamide, sorafenib and RT NCT02050919Combined with trabectedin NCT02066675

Idarubicin AMLCML II Recruiting Combined with cladribine and cytarabine NCT02115295AMLMDS I Recruiting Combined with cytarabine and DLI NCT02046122HCC II Active, not recruiting As idarubicin-loaded microbeads NCT02185768

Mitoxantrone ALL I/II Not yet recruiting As part of combinatorial chemotherapy NCT02303821III Recruiting As part of combinatorial chemotherapy NCT02101853

Lymphoma I Recruiting As single agent NCT02131688Solid tumors I Completed As single agent NCT02043756

Bleomycin Liver cancer I/II Recruiting Combined with electrochemotherapy NCT02291133NSMGCT II Not yet recruiting Combined with cisplatin-based chemotherapy NCT02104986

Bortezomib Hematological malignancies n.a. Active, not recruiting Combined with G-CSF in promotingstem cell mobilization

NCT02037256

I Not yet recruiting Combined with lenalidomide NCT02312102II Recruiting Combined with methotrexate and tacrolimus NCT02208037III Recruiting As part of combinatorial chemotherapy NCT02112916

Neuroblastoma I/II Recruiting Combined with difluoromethylornithine NCT02139397Solid tumors I Recruiting Combined with clofarabine NCT02211755

Completed As single agent NCT02220049

Abbreviations: ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; CML, chronic myeloid leukemia; DLI, donor lymphocyte infusion; EOX, epi-rubicin plus oxaliplatin plus capecitabine; G-CSF, granulocyte colony-stimulating factor; HCC, hepatocellular carcinoma; MDS, myelodysplastic syndrome; n.a., not available; NSMGCT, non-seminomatous malignant germ cell tumor; PIPAC, pressurized intraperitoneal aerosol chemotherapy; PLD, pegylated lipo-somal doxorubicin; RT, radiation therapy; TACE, transcatheter arterial chemoembolization. *initiated after 2014, January 1st.


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Table 3. Clinical trials recently started to evaluate the therapeutic profile of cyclophosphamide as an off-label chemotherapeutic intervention*

Indication(s) Phase Status Notes Ref.

Breast carcinomaGastric carcinoma

I Recruiting Combined with GM-CSF, a peptide-basedanticancer vaccine and imiquimod

NCT02276300

Colorectal carcinoma I Recruiting Combined with a checkpoint blocker and RT NCT02298946II Recruiting As metronomic regimen combined with

bevacizumab, capecitabine and FOLFOXIRINCT02271464

Not yet recruiting Combined with capecitabine, celecoxiband methotrexate

NCT02280694

Ependymoma II/III Not yet recruiting Combined with conventionalchemotherapy and RT

NCT02265770

Gastric carcinoma I/II Recruiting Combined with a HSP-based vaccine,oxaliplatin and S-1

NCT02317471

Germ cell tumorsTesticular cancer

II Completed Combined with cisplatin, etoposideand bleomycin § carboplatin

NCT02161692

Medulloblastoma II/III Recruiting Combined with conventional chemotherapyand RT

NCT02066220

n.a. Not yet recruiting Combined with conventional chemotherapy NCT02212574Melanoma II Recruiting As part of a conditioning regimen followed by

adoptive cell transfer-based immunotherapyNCT02062359NCT02111863

III Recruiting As part of a conditioning regimen followed byadoptive cell transfer-based immunotherapy

NCT02278887

NSCLC II Recruiting As metronomic regimen combined witha cancer cell-based vaccine

NCT02117024

As part of a conditioning regimen followed byadoptive cell transfer-based immunotherapy

NCT02133196

III Active, not recruiting Combined with tecemotide NCT02049151Not yet recruiting Combined with an EGF-targeting vaccine NCT02187367

Osteosarcoma II Recruiting Combined with methotrexate NCT02273583Pancreatic carcinoma II Recruiting Combined with multimodal immunotherapy NCT02243371Prostate cancer I Recruiting Combined with imiquimod and a

peptide-based anticancer vaccineNCT02234921

Rhabdoid tumors II Recruiting As a part of induction chemotherapyfollowedby alisertib and RT

NCT02114229

Soft tissue sarcoma I Recruiting As part of a conditioning regimen followed byadoptive cell transfer-based immunotherapy

NCT02059850

II Not yet recruiting Combined with multimodalimmunochemotherapy

NCT02234050

Recruiting Combined with multimodalimmunochemotherapy

NCT02306161

Solid tumors I Not yet recruiting As part of a conditioning regimen followed byadoptive cell transfer-based immunotherapy

NCT02210104

Recruiting As part of a conditioning regimen followed byadoptive cell transfer-based immunotherapy

NCT02070406NCT02096614

Combined with GD2-specificCAR-expressing T cells

NCT02107963

Combined with mesothelin-specificCAR-expressing T cells

NCT02159716

I/II Not yet recruiting Combined with GM-CSF and TAA-pulsed DCs NCT02223312NCT02224599

Recruiting As metronomic chemotherapy combinedwith celecoxib and followed bylysate-based vaccine

NCT02054104

As part of a conditioning regimen followed byadoptive cell transfer-based immunotherapy

NCT02111850NCT02153905NCT02280811

Abbreviations: CAR, chimeric antigen receptor; DC, dendritic cell; EGF, epidermal growth factor; FOLFOXIRI, folinic acid plus 5-fluorouracil plus oxaliplatinplus irinotecan; GM-CSF, granulocyte macrophage colony stimulating factor; HSP, heat shock protein; n.a., not available; NSCLC, non-small cell lung carci-noma; RT, radiation therapy; TAA, tumor-associated antigen. *initiated after 2014, January 1st.


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Table 4. Clinical trials recently started to evaluate the therapeutic profile of oxaliplatin as an off-label chemotherapeutic intervention*

Indication(s) Phase Status Notes Ref.

Biliary tract carcinomaGallbladder carcinoma

I Not yet recruiting GEMOX regimen plus MEK inhibitor NCT02105350

Breast carcinoma 0 Recruiting As single agent NCT02077998Gastric cancer I/II Completed FLOT regimen combined withgastrectomy § bevacizumab NCT02048540

Recruiting Combined with a HSP-based vaccine, cyclophosphamide and S-1 NCT02317471II Completed XELOX regimen NCT02071043

Not yet recruiting XELOX regimen plus paclitaxel NCT02038621SOX regimen NCT02191566

Recruiting FOLFOX regimen combined with autologoustumor lysate-pulsed DCs and CIK cells

NCT02215837

FOLFOX regimen NCT02226380XELOX regimen plus trastuzumab NCT02250209XELOX regimen NCT02269904FLOT regimen NCT02289378SOX regimen § radiotherapy NCT02301481

III Not yet recruiting Combined with TAS-118 NCT02322593Recruiting FOLFOX or XELOX regimen NCT02114359

EOX regimen § cisplatin and mitomycin C NCT02158988XELOX regimen plus D2 lymphadenectomy NCT02240524

Gastroesophageal cancer I/II Not yet recruiting FOLFOX or FLOT or FOLFIRI regimen combinedwith tumor-targeting antibodies

NCT02213289

Recruiting XELOX regimen plus paclitaxel NCT02273713II Not yet recruiting SOX or XELOX regimen NCT02216149

FOLFOX or PEMOX regimen NCT02296671Recruiting FOLFOX regimen combined with RT § carboplatin and paclitaxel NCT02037048

EOX or FOLFOX regimen pluscisplatin and S-1 NCT02128243EOX regimen NCT02177552Combined with 5-FU and RT NCT02241499Combined with capecitabine, carboplatin, epirubicin,

5-FU, paclitaxel and RTNCT02287129

II/III Recruiting SOX regimen § radiotherapy NCT02193594Gastrointestinal cancer I Not yet recruiting FOLFOX regimen plus alisertib NCT02319018

Recruiting FOLFOX regimen plus arginine deiminase NCT02102022I/II Not yet recruiting FOLFOX regimen plus pembrolizumab NCT02268825

Recruiting XELOX regimen plus gemcitabine NCT02233205Hepatocellular carcinoma I Recruiting FOLFOX regimen plus ramucirumab NCT02069041

II Not yet recruiting SOX regimen plus sorafenib NCT02129322Recruiting PACOX regimen NCT02089633

III Recruiting Combined with doxorubicin for TACE NCT02149771Lymphoma I Not yet recruiting GEMOX regimen plus dexamethasone and G-CSF NCT02181218

II Recruiting GEMOX regimen plus asparaginase plus RT NCT02080234III Recruiting GEMOX regimen plus asparaginase NCT02085655

Pancreatic carcinoma I Recruiting FIRINOX regimen NCT02148549XELOX regimen plus momelotinib NCT02244489

I/II Recruiting FOLFOX regimen plus paclitaxel NCT02109341II Not yet recruiting FOLFIRINOX regimen plus RT NCT02128100

FOLFIRINOX regimen NCT02143219FOLFOX regimen plus encapsulated asparaginase NCT02195180

Recruiting GEMOX regimen plus RT NCT02035072FOLFIRINOX regimen NCT02047474FOLFOX regimen plus abraxane NCT02080221FOLFIRINOX regimen plus gemcitabine and paclitaxel NCT02125136

NCT02241551FOLFIRINOX regimen NCT02178709FOLFOX regimen plus gemcitabine and RT NCT02243358

II/III Not yet recruiting FOLFIRINOX regimen plus natriumfolinate NCT02172976Recruiting FOLFIRINOX regimen plus capecitabine and RT NCT02311439

Abbreviations: 5-FU, 5-fluorouracil; CIK, cytokine-inducer killer; DC, dendritic cell; EOX, epirubicin plus oxaliplatin plus capecitabine; FIRINOX, 5-FU plus irino-tecan plus oxaliplatin; FLOT, 5-FU plus oxaliplatin plus docetaxel; FOLFIRI, folinic acid plus 5-FU plus irinotecan; FOLFIRINOX, folinic acid plus 5-FU plus irino-tecan plus oxaliplatin; FOLFOX, folinic acid plus 5-FU plus oxaliplatin; G-CSF, granulocyte colony-stimulating factor; GEMOX, gemcitabine plus oxaliplatin;HSP, heat shock protein; PACOX, pegylated human arginase plus XELOX; PEMOX, pemetrexed plus oxaliplatin; RT, radiation therapy; SOX, S-1 plus oxalipla-tin; TACE, transcatheter arterial chemoembolization; XELOX, capecitabine plus oxaliplatin. *initiated after 2014, January 1st.


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NCT02107963; NCT02111850; NCT02153905;NCT02159716; NCT02210104; NCT02223312;NCT02224599; NCT02280811), in the context of a heteroge-neous panel of chemo-, radio- or immunotherapeutic regimens(Table 3).

The clinical profile of off-label oxaliplatin is being assessed inpatients with: (1) gastric, gastroesophageal or gastrointestinal car-cinomas, most often in the context of either the so-calledXELOX (capecitabine plus oxaliplatin)155,156 or FOLFOX(folinic acid plus 5-fluorouracil plus oxaliplatin)157,158 regimen(NCT02038621; NCT02048540; NCT02071043;NCT02114359; NCT02158988; NCT02191566;NCT02215837; NCT02226380; NCT02240524;NCT02250209; NCT02269904; NCT02289378;NCT02301481; NCT02317471; NCT02322593;NCT02037048; NCT02128243; NCT02177552;NCT02193594; NCT02213289; NCT02216149;NCT02241499; NCT02273713; NCT02287129;NCT02296671; NCT02102022; NCT02233205;NCT02268825; NCT02319018); (2) HCC, who often receiveoxaliplatin combined with other conventional chemotherapeuticsor with targeted anticancer agents (NCT02069041;NCT02089633; NCT02129322; NCT02149771); (3) lym-phoma, invariably in the context of the so-called GEMOX (gem-citabine plus oxaliplatin) regimen159,160 (NCT02080234;NCT02085655; NCT02181218); (4) pancreatic carcinoma,most frequently as part of the so-called FOLFIRINOX (folinicacid plus 5-fluorouracil plus irinotecan plus oxaliplatin) regi-men161,162 (NCT02035072; NCT02047474; NCT02080221;NCT02109341; NCT02125136; NCT02128100;NCT02143219; NCT02148549; NCT02172976;NCT02178709; NCT02195180; NCT02241551;NCT02243358; NCT02244489; NCT02311439); (5) breastcarcinoma, who receive oxaliplatin as a standalone therapeuticagent (NCT02077998); and (6) biliary tract or gallbladder carci-noma, who are treated with the GEMOX regimen plus a MEKinhibitor163 (NCT02105350) (Table 4).

Of note, the vast majority of these studies is ongoing, with afew notable exceptions. Thus, NCT02070419, a Phase II studyinvestigating the therapeutic profile of doxorubicin-based TACEalone or combined with radiation therapy in HCC patients, hasbeen withdrawn as the principal investigator left the institution.Moreover, NCT02038296, a Phase III trial testing different pro-tocols for doxorubicin-based TACE in HCC patients,NCT02043756, a Phase I study investigating the pharmacoki-netic, safety and preliminary efficacy of a peculiar pegylated vari-ant of mitoxantrone given as a standalone therapeuticintervention to subjects with solid tumors, NCT02048540, aPhase I/II study testing oxaliplatin in combination with gastrec-tomy plus 5-fluorouracil, docetaxel and optional bevacizumab insubjects with gastric carcinoma, NCT02071043, a Phase II trialinvestigating the therapeutic profile of oxaliplatin plus capecita-bine in individuals with gastric carcinoma, NCT02161692, aPhase II study testing cyclophosphamide combined with cis-platin, etoposide, bleomycin and optional carboplatin in patientswith germ cell tumors or testicular cancer, NCT02220049, a

Phase I trial investigating the safety and efficacy of bortezomib-based chemotherapy in subjects with solid tumors, andNCT02288741, a Phase III study testing epirubicin as part ofinduction or tumor reduction chemotherapy followed by stemcell mobilization in MM patients, have all been already com-pleted (source http://clinicaltrials.gov/). The results ofNCT02043756, which suggest that a pegylated variant of mitox-antrone is well tolerated by patients with solid tumors up to adose of 18 mg/m2 and may exert clinical efficacy,164 andNCT02161692, which failed to meet the primary end point,165

have already been published. Conversely, to the best of ourknowledge, the results of NCT02038296, NCT02048540,NCT02071043, NCT02220049, and NCT02288741 have notbeen released yet.

Concluding Remarks

As discussed above, a bunch of clinically employed chemo-therapeutics are able to trigger an immunogenic variant of apo-ptosis that – in immunocompetent hosts – triggers an adaptiveimmune response against dead cell-associated antigens.3,36 Sincethese ICD inducers are not only approved by international regu-latory agencies for use in subjects with various hematological andsolid neoplasms, but also are part of consolidated therapeuticprotocols, safety concerns are generally limited. Thus, these mol-ecules are frequently included in clinical trials as (part of) thetherapeutic regimen(s) administered to the control arm of thestudy. Moreover, FDA-approved ICD inducers are often investi-gated in off-label oncological indications, either as standalonetherapeutic interventions or combined with other chemo-, radio-or immunotherapies. Consequently, a huge number of clinicalstudies involving chemical ICD inducers are initiated yearly.

Now, great efforts are being devoted to the development ofcombinatorial regimens relying on the co-administration of con-ventional or targeted anticancer agents plus one form of immu-notherapy.48,166 In this setting, it is tempting to hypothesize thatthe clinical profile of anticancer chemotherapy based on ICDinducers may be considerably ameliorated by the concomitantadministration of various immunostimulatory interventions,167

in particular checkpoint blockers such as the cytotoxic T lympho-cyte-associated protein 4 (CTLA4)-targeting mAb ipilimumaband the programmed cell death 1 (PDCD1)-targeting mAbspembrolizumab and nivolumab.168-171 The results of several tri-als that have already been launched will clarify the actual clinicalvalue of such combinatorial immunochemotherapeuticparadigms.

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Funding

Authors are supported by the Ligue contre le Cancer ("equipelabelis"ee); Agence National de la Recherche (ANR); Association


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pour la recherche sur le cancer (ARC); Canc"eropole Ile-de-France; AXA Chair for Longevity Research; Institut National duCancer (INCa); Fondation Bettencourt-Schueller; Fondation deFrance; Fondation pour la Recherche M"edicale (FRM); the Euro-pean Commission (ArtForce); the European Research Council

(ERC); the LabEx Immuno-Oncology; the SIRIC StratifiedOncology Cell DNA Repair and Tumor Immune Elimination(SOCRATE); the SIRIC Cancer Research and PersonalizedMedicine (CARPEM); and the Paris Alliance of Cancer ResearchInstitutes (PACRI).

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Trial Watch: Immunogenic cell death inducers for anticancer chemotherapy

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