Top Banner
Trial Watch: Immunogenic cell death inducers for anticancer chemotherapy Jonathan Pol 1,2,3,y , Erika Vacchelli 1,2,3,y , Fernando Aranda 4,y , Francesca Castoldi 1,2,3,5,6 , Alexander Eggermont 1 , Isabelle Cremer 2,7,8 , Catherine Saut es-Fridman 2,7,8 , Jitka Fucikova 6,9 ,J er^ ome Galon 2,8,10,11 , Radek Spisek 6,9 , Eric Tartour 11,12,13,14 , Laurence Zitvogel 1,15 , Guido Kroemer 2,3,11,16,17,z, * , and Lorenzo Galluzzi 1,2,3,11,z 1 Gustave Roussy Cancer Campus; Villejuif, France; 2 INSERM, U1138; Paris, France; 3 Equipe 11 labellis ee par la Ligue Nationale contre le Cancer, Center de Recherche des Cordeliers; Paris, France; 4 Group of Immune receptors of the Innate and Adaptive System, Institut dInvestigacions Biom ediques August Pi i Sunyer (IDIBAPS); 5 Facult e de Medicine; Universit e Paris Sud/Paris XI; Le Kremlin-Bic^ etre, France; 6 Sotio a.c.; Prague, Czech Republic; 7 Equipe 13, Center de Recherche des Cordeliers; Paris, France; 8 Universit e Pierre et Marie Curie/ Paris VI; Paris, France; 9 Department of Immunology, 2 nd Faculty of Medicine and University Hospital Motol, Charles University; Prague, Czech Republic; 10 Laboratory of Integrative Cancer Immunology, Center de Recherche des Cordeliers; Paris, France; 11 Universit e Paris Descartes/Paris V; Sorbonne Paris Cit e; Paris, France; 12 INSERM, U970; Paris, France; 13 Paris-Cardiovascular Research Center (PARCC); Paris, France; 14 Service dImmunologie Biologique, H^ opital Europ een Georges Pompidou (HEGP); AP-HP; Paris, France; 15 INSERM, U1015; CICBT507; Villejuif, France; 16 P^ ole de Biologie, H^ opital Europ een Georges Pompidou; AP-HP; Paris, France; 17 Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus; Villejuif, France y These authors contributed equally to this work. z These authors share senior co-authorship. Keywords: antigen-presenting cell, autophagy, damage-associated molecular pattern, dendritic cell, endoplasmic reticulum stress, type I 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 employed to indicate a functionally peculiar form of apoptosis that is sufcient for immunocompetent hosts to mount an adaptive immune response against dead cell-associated antigens. Several drugs have been ascribed with the ability to provoke ICD when employed as standalone therapeutic interventions. These include various chemotherapeutics routinely employed in the clinic (e.g., doxorubicin, epirubicin, idarubicin, mitoxantrone, bleomycin, bortezomib, cyclophosphamide and oxaliplatin) as well as some anticancer agents that are still under preclinical or clinical development (e.g., some microtubular inhibitors of the epothilone family). In addition, a few drugs are able to convert otherwise non-immunogenic instances of cell death into bona de ICD, and may therefore be employed as chemotherapeutic adjuvants within combinatorial regimens. This is the case of cardiac glycosides, like digoxin and digitoxin, and zoledronic acid. Here, we discuss recent developments on anticancer chemotherapy based 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 – can elicit an immune response against dead cell-associated antigens in the absence of any adjuvant. 1,2 Indeed, the subcutaneous inocula- tion of cancer cells succumbing to doxorubicin (an anthracycline approved by regulatory agencies for the treatment of several tumors, see below) in vitro was sufficient to protect syngeneic mice against a re-challenge with malignant cells of the same type, but not with cancer cells of distinct origin. 2 Subsequent studies by us and others identified various mechanisms that underlie not only the ability of a specific stimulus to trigger bona fide ICD as opposed to a non-immunogenic instance of apoptosis, but also the 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 of a 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 of the non-histone chromatin-binding protein high mobility group box 1 (HMGB1), 13-20 and immunostimulatory cytokines, such as 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], Lorenzo Galluzzi; Email: [email protected] Submitted: 01/13/2015; Accepted: 01/14/2015 http://dx.doi.org/10.1080/2162402X.2015.1008866 www.tandfonline.com e1008866-1 OncoImmunology OncoImmunology 4:4, e1008866; April 2015; © 2015 Taylor & Francis Group, LLC REVIEW Downloaded by [UNIVERSITAT DE BARCELONA] at 00:55 28 April 2015
13

Trial Watch: Immunogenic cell death inducers for anticancer chemotherapy

May 13, 2023

Download

Documents

Welcome message from author
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
Page 1: 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

Dow

nloa

ded

by [U

NIV

ERSI

TAT

DE

BARC

ELO

NA

] at 0

0:55

28

Apr

il 20

15

Page 2: Trial Watch: Immunogenic cell death inducers for anticancer chemotherapy

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

e1008866-2 Volume 4 Issue 4OncoImmunology

Dow

nloa

ded

by [U

NIV

ERSI

TAT

DE

BARC

ELO

NA

] at 0

0:55

28

Apr

il 20

15

Page 3: Trial Watch: Immunogenic cell death inducers for anticancer chemotherapy

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.

www.tandfonline.com e1008866-3OncoImmunology

Dow

nloa

ded

by [U

NIV

ERSI

TAT

DE

BARC

ELO

NA

] at 0

0:55

28

Apr

il 20

15

Page 4: Trial Watch: Immunogenic cell death inducers for anticancer chemotherapy

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).

e1008866-4 Volume 4 Issue 4OncoImmunology

Dow

nloa

ded

by [U

NIV

ERSI

TAT

DE

BARC

ELO

NA

] at 0

0:55

28

Apr

il 20

15

Page 5: Trial Watch: Immunogenic cell death inducers for anticancer chemotherapy

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.

www.tandfonline.com e1008866-5OncoImmunology

Dow

nloa

ded

by [U

NIV

ERSI

TAT

DE

BARC

ELO

NA

] at 0

0:55

28

Apr

il 20

15

Page 6: Trial Watch: Immunogenic cell death inducers for anticancer chemotherapy

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.

e1008866-6 Volume 4 Issue 4OncoImmunology

Dow

nloa

ded

by [U

NIV

ERSI

TAT

DE

BARC

ELO

NA

] at 0

0:55

28

Apr

il 20

15

Page 7: Trial Watch: Immunogenic cell death inducers for anticancer chemotherapy

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.

www.tandfonline.com e1008866-7OncoImmunology

Dow

nloa

ded

by [U

NIV

ERSI

TAT

DE

BARC

ELO

NA

] at 0

0:55

28

Apr

il 20

15

Page 8: Trial Watch: Immunogenic cell death inducers for anticancer chemotherapy

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

e1008866-8 Volume 4 Issue 4OncoImmunology

Dow

nloa

ded

by [U

NIV

ERSI

TAT

DE

BARC

ELO

NA

] at 0

0:55

28

Apr

il 20

15

Page 9: Trial Watch: Immunogenic cell death inducers for anticancer chemotherapy

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).

References1. Kroemer G, Galluzzi L, Kepp O, Zitvogel L. Immu-

nogenic cell death in cancer therapy. Annu RevImmunol 2013; 31:51-72; PMID:23157435; http://dx.doi.org/10.1146/annurev-immunol-032712-100008

2. Casares N, Pequignot MO, Tesniere A, GhiringhelliF, Roux S, Chaput N, Schmitt E, Hamai A, Hervas-Stubbs S, Obeid M, et al. Caspase-dependent immu-nogenicity of doxorubicin-induced tumor cell death. JExp Med 2005; 202:1691-701; PMID:16365148;http://dx.doi.org/10.1084/jem.20050915

3. Kepp O, Senovilla L, Vitale I, Vacchelli E, AdjemianS, Agostinis P, et al. Consensus guidelines for thedetection of immunogenic cell death. Oncoimmunol-ogy 2014; 3:e955691; http://dx.doi.org/10.4161/21624011.2014.955691.

4. Krysko DV, Garg AD, Kaczmarek A, Krysko O,Agostinis P, Vandenabeele P. Immunogenic cell deathand DAMPs in cancer therapy. Nat Rev Cancer 2012;12:860-75; PMID:23151605; http://dx.doi.org/10.1038/nrc3380

5. Kepp O, Galluzzi L, Martins I, Schlemmer F, Adje-mian S, Michaud M, Sukkurwala AQ, Menger L, Zit-vogel L, Kroemer G. Molecular determinants ofimmunogenic cell death elicited by anticancer chemo-therapy. Cancer Metastasis Rev 2011; 30:61-9;PMID:21249425; http://dx.doi.org/10.1007/s10555-011-9273-4

6. Cirone M, Di Renzo L, Lotti LV, Conte V, Trivedi P,Santarelli R, Gonnella R, Frati L, Faggioni A. Activa-tion of dendritic cells by tumor cell death. Oncoim-munology 2012; 1:1218-9; PMID:23170286; http://dx.doi.org/10.4161/onci.20428

7. Brenner C, Galluzzi L, Kepp O, Kroemer G. Decod-ing cell death signals in liver inflammation. J Hepatol2013; 59:583-94; PMID:23567086; http://dx.doi.org/10.1016/j.jhep.2013.03.033

8. Galluzzi L, Kepp O, Kroemer G. Mitochondria: mas-ter regulators of danger signalling. Nat Rev Mol CellBiol 2012; 13:780-8; PMID:23175281; http://dx.doi.org/10.1038/nrm3479

9. Garg AD, Martin S, Golab J, Agostinis P. Dangersignalling during cancer cell death: origins, plastic-ity and regulation. Cell Death Differ 2014; 21:26-38; PMID:23686135; http://dx.doi.org/10.1038/cdd.2013.48

10. Garg AD, Dudek AM, Agostinis P. Cancer immu-nogenicity, danger signals, and DAMPs: what,when, and how? Biofactors 2013; 39:355-67;PMID:23900966; http://dx.doi.org/10.1002/biof.1125

11. Garg AD, Krysko DV, Vandenabeele P, Agostinis P.DAMPs and PDT-mediated photo-oxidative stress:exploring the unknown. Photochem Photobiol Sci2011; 10:670-80; PMID:21258717; http://dx.doi.org/10.1039/c0pp00294a

12. Garg AD, Nowis D, Golab J, Vandenabeele P, KryskoDV, Agostinis P. Immunogenic cell death, DAMPsand anticancer therapeutics: an emerging amalgam-ation. Biochim Biophys Acta 2010; 1805:53-71;PMID:19720113

13. Obeid M, Panaretakis T, Joza N, Tufi R, TesniereA, van Endert P, Zitvogel L, Kroemer G. Calreti-culin exposure is required for the immunogenicityof gamma-irradiation and UVC light-induced apo-ptosis. Cell Death Differ 2007; 14:1848-50;PMID:17657249; http://dx.doi.org/10.1038/sj.cdd.4402201

14. Ghiringhelli F, Apetoh L, Tesniere A, Aymeric L, MaY, Ortiz C, Vermaelen K, Panaretakis T, Mignot G,Ullrich E, et al. Activation of the NLRP3 inflamma-some in dendritic cells induces IL-1beta-dependentadaptive immunity against tumors. Nat Med 2009;15:1170-8; PMID:19767732; http://dx.doi.org/10.1038/nm.2028

15. Apetoh L, Ghiringhelli F, Tesniere A, Obeid M, OrtizC, Criollo A, Mignot G, Maiuri MC, Ullrich E, Saul-nier P, et al. Toll-like receptor 4-dependent contribu-tion of the immune system to anticancerchemotherapy and radiotherapy. Nat Med 2007;13:1050-9; PMID:17704786; http://dx.doi.org/10.1038/nm1622

16. Michaud M, Martins I, Sukkurwala AQ, AdjemianS, Ma Y, Pellegatti P, Shen S, Kepp O, ScoazecM, Mignot G, et al. Autophagy-dependent anti-cancer immune responses induced by chemothera-peutic agents in mice. Science 2011; 334:1573-7;PMID:22174255; http://dx.doi.org/10.1126/science.1208347

17. Spisek R, Charalambous A, Mazumder A, Vesole DH,Jagannath S, Dhodapkar MV. Bortezomib enhancesdendritic cell (DC)-mediated induction of immunityto human myeloma via exposure of cell surface heatshock protein 90 on dying tumor cells: therapeuticimplications. Blood 2007; 109:4839-45;PMID:17299090; http://dx.doi.org/10.1182/blood-2006-10-054221

18. Garg AD, Dudek AM, Ferreira GB, Verfaillie T, Van-denabeele P, Krysko DV, Mathieu C, Agostinis P.ROS-induced autophagy in cancer cells assists in eva-sion from determinants of immunogenic cell death.Autophagy 2013; 9:1292-307; PMID:23800749;http://dx.doi.org/10.4161/auto.25399

19. Fucikova J, Kralikova P, Fialova A, Brtnicky T, RobL, Bartunkova J, Sp"ısek R. Human tumor cells killedby anthracyclines induce a tumor-specific immuneresponse. Cancer Res 2011; 71:4821-33;PMID:21602432; http://dx.doi.org/10.1158/0008-5472.CAN-11-0950

20. Fucikova J, Moserova I, Truxova I, Hermanova I,Vancurova I, Partlova S, Fialova A, Sojka L, CartronPF, Houska M, et al. High hydrostatic pressure indu-ces immunogenic cell death in human tumor cells. IntJ Cancer 2014; 135:1165-77; PMID:24500981;http://dx.doi.org/10.1002/ijc.28766

21. Sistigu A, Yamazaki T, Vacchelli E, Chaba K,Enot DP, Adam J, Vitale I, Goubar A, BaraccoEE, Rem"edios C, et al. Cancer cell-autonomouscontribution of type I interferon signaling to theefficacy of chemotherapy. Nat Med 2014;20:1301-9; PMID:25344738; http://dx.doi.org/10.1038/nm.3708

22. Zitvogel L, Kepp O, Kroemer G. Decoding cell deathsignals in inflammation and immunity. Cell 2010;140:798-804; PMID:20303871; http://dx.doi.org/10.1016/j.cell.2010.02.015

23. Zitvogel L, Kepp O, Kroemer G. Immune param-eters affecting the efficacy of chemotherapeuticregimens. Nat Rev Clin Oncol 2011; 8:151-60;PMID:21364688; http://dx.doi.org/10.1038/nrclinonc.2010.223

24. Ladoire S, Hannani D, Vetizou M, Locher C,Aymeric L, Apetoh L, Kepp O, Kroemer G, Ghir-inghelli F, Zitvogel L. Cell-death-associated molec-ular patterns as determinants of cancerimmunogenicity. Antioxid Redox Signal 2014;20:1098-116; PMID:23394620; http://dx.doi.org/10.1089/ars.2012.5133

25. Ma Y, Adjemian S, Galluzzi L, Zitvogel L, KroemerG. Chemokines and chemokine receptors required foroptimal responses to anticancer chemotherapy.Oncoimmunology 2014; 3:e27663; PMID:24800170; http://dx.doi.org/10.4161/onci.27663

26. Ma Y, Adjemian S, Mattarollo SR, Yamazaki T,Aymeric L, Yang H, Portela Catani JP, Hannani D,Duret H, Steegh K, et al. Anticancer chemotherapy-induced intratumoral recruitment and differentiationof antigen-presenting cells. Immunity 2013; 38:729-41; PMID:23562161; http://dx.doi.org/10.1016/j.immuni.2013.03.003

27. Ma Y, Adjemian S, Yang H, Catani JP, Hannani D,Martins I, Michaud M, Kepp O, Sukkurwala AQ,Vacchelli E, et al. ATP-dependent recruitment, sur-vival and differentiation of dendritic cell precursors inthe tumor bed after anticancer chemotherapy.Oncoimmunology 2013; 2:e24568; PMID:23894718; http://dx.doi.org/10.4161/onci.24568

28. Ma Y, Aymeric L, Locher C, Mattarollo SR, Dela-haye NF, Pereira P, Boucontet L, Apetoh L, Ghir-inghelli F, Casares N, et al. Contribution of IL-17-producing gamma delta T cells to the efficacyof anticancer chemotherapy. J Exp Med 2011;208:491-503; PMID:21383056; http://dx.doi.org/10.1084/jem.20100269

29. Ma Y, Mattarollo SR, Adjemian S, Yang H, AymericL, Hannani D, Portela Catani JP, Duret H, TengMW, Kepp O, et al. CCL2/CCR2-dependent recruit-ment of functional antigen-presenting cells intotumors upon chemotherapy. Cancer Res 2013; 74(2):436-45

30. Elliott MR, Chekeni FB, Trampont PC, Lazarow-ski ER, Kadl A, Walk SF, Park D, Woodson RI,Ostankovich M, Sharma P, et al. Nucleotidesreleased by apoptotic cells act as a find-me signalto promote phagocytic clearance. Nature 2009;461:282-6; PMID:19741708; http://dx.doi.org/10.1038/nature08296

31. Chekeni FB, Elliott MR, Sandilos JK, Walk SF,Kinchen JM, Lazarowski ER, Armstrong AJ,Penuela S, Laird DW, Salvesen GS, et al. Pan-nexin 1 channels mediate ’find-me’ signal releaseand membrane permeability during apoptosis.Nature 2010; 467:863-7; PMID:20944749; http://dx.doi.org/10.1038/nature09413

32. Panaretakis T, Kepp O, Brockmeier U, TesniereA, Bjorklund AC, Chapman DC, Durchschlag M,Joza N, Pierron G, van Endert P, et al. Mecha-nisms of pre-apoptotic calreticulin exposure inimmunogenic cell death. EMBO J 2009; 28:578-90; PMID:19165151; http://dx.doi.org/10.1038/emboj.2009.1

33. Michaud M, Sukkurwala AQ, Martins I, Shen S,Zitvogel L, Kroemer G. Subversion of the chemo-therapy-induced anticancer immune response bythe ecto-ATPase CD39. Oncoimmunology 2012;1:393-5; PMID:22737627; http://dx.doi.org/10.4161/onci.19070

34. Apetoh L, Ghiringhelli F, Tesniere A, Criollo A, OrtizC, Lidereau R, Mariette C, Chaput N, Mira JP, Dela-loge S, et al. The interaction between HMGB1 andTLR4 dictates the outcome of anticancer chemother-apy and radiotherapy. Immunol Rev 2007; 220:47-59; PMID:17979839; http://dx.doi.org/10.1111/j.1600-065X.2007.00573.x

35. Galluzzi L, Bravo-San Pedro JM, Vitale I, AaronsonSA, Abrams JM, Adam D, Alnemri ES, Altucci L,Andrews D, Annicchiarico-Petruzzelli M, et al. Essen-tial versus accessory aspects of cell death:

www.tandfonline.com e1008866-9OncoImmunology

Dow

nloa

ded

by [U

NIV

ERSI

TAT

DE

BARC

ELO

NA

] at 0

0:55

28

Apr

il 20

15

Page 10: Trial Watch: Immunogenic cell death inducers for anticancer chemotherapy

recommendations of the NCCD 2015. Cell DeathDiffer 2014; 22(1):58-73

36. Dudek AM, Garg AD, Krysko DV, De Ruysscher D,Agostinis P. Inducers of immunogenic cancer celldeath. Cytokine Growth Factor Rev 2013; 24:319-33; PMID:23391812; http://dx.doi.org/10.1016/j.cytogfr.2013.01.005

37. Cirone M, Garufi A, Di Renzo L, Granato M,Faggioni A, D’Orazi G. Zinc supplementation isrequired for the cytotoxic and immunogenic effectsof chemotherapy in chemoresistant p53-function-ally deficient cells. Oncoimmunology 2013; 2:e26198; PMID:24228232; http://dx.doi.org/10.4161/onci.26198

38. Bracci L, Schiavoni G, Sistigu A, Belardelli F.Immune-based mechanisms of cytotoxic chemother-apy: implications for the design of novel and ratio-nale-based combined treatments against cancer. CellDeath Differ 2014; 21:15-25; PMID:23787994;http://dx.doi.org/10.1038/cdd.2013.67

39. Galluzzi L, Morselli E, Vitale I, Kepp O, Senovilla L,Criollo A, Servant N, Paccard C, Hup"e P, Robert T,et al. miR-181a and miR-630 regulate cisplatin-induced cancer cell death. Cancer Res 2010; 70:1793-803; PMID:20145152; http://dx.doi.org/10.1158/0008-5472.CAN-09-3112

40. Galluzzi L, Senovilla L, Vitale I, Michels J, Martins I,Kepp O, Castedo M, Kroemer G. Molecular mecha-nisms of cisplatin resistance. Oncogene 2012;31:1869-83; PMID:21892204; http://dx.doi.org/10.1038/onc.2011.384

41. Galluzzi L, Vitale I, Michels J, Brenner C, Szabad-kai G, Harel-Bellan A, Castedo M, Kroemer G.Systems biology of cisplatin resistance: past, pres-ent and future. Cell Death Dis 2014; 5:e1257;PMID:24874729; http://dx.doi.org/10.1038/cddis.2013.428

42. Galluzzi L, Vitale I, Senovilla L, Olaussen KA, PinnaG, Eisenberg T, Goubar A, Martins I, Michels J, Kra-tassiouk G, et al. Prognostic impact of vitamin B6metabolism in lung cancer. Cell Rep 2012; 2:257-69;PMID:22854025; http://dx.doi.org/10.1016/j.celrep.2012.06.017

43. Kepp O, Menger L, Vacchelli E, Locher C, AdjemianS, Yamazaki T, Martins I, Sukkurwala AQ, MichaudM, Senovilla L, et al. Crosstalk between ER stress andimmunogenic cell death. Cytokine Growth FactorRev 2013; 24:311-8; PMID:23787159; http://dx.doi.org/10.1016/j.cytogfr.2013.05.001

44. Martins I, Kepp O, Schlemmer F, Adjemian S,Tailler M, Shen S, Michaud M, Menger L,Gdoura A, Tajeddine N, et al. Restoration of theimmunogenicity of cisplatin-induced cancer celldeath by endoplasmic reticulum stress. Oncogene2011; 30:1147-58; PMID:21151176; http://dx.doi.org/10.1038/onc.2010.500

45. Sukkurwala AQ, Adjemian S, Senovilla L,Michaud M, Spaggiari S, Vacchelli E, Baracco EE,Galluzzi L, Zitvogel L, Kepp O, et al. Screeningof novel immunogenic cell death inducers withinthe NCI Mechanistic Diversity Set. Oncoimmu-nology 2014; 3:e28473; PMID:25050214; http://dx.doi.org/10.4161/onci.28473

46. Zitvogel L, Galluzzi L, Smyth MJ, Kroemer G. Mech-anism of action of conventional and targeted antican-cer therapies: reinstating immunosurveillance.Immunity 2013; 39:74-88; PMID:23890065; http://dx.doi.org/10.1016/j.immuni.2013.06.014

47. Galluzzi L, Senovilla L, Zitvogel L, Kroemer G.The secret ally: immunostimulation by anticancerdrugs. Nat Rev Drug Discov 2012; 11:215-33;PMID:22301798; http://dx.doi.org/10.1038/nrd3626

48. Galluzzi L, Vacchelli E, Bravo-San Pedro J, Buque A,Senovilla L, Baracco EE, Bloy N, Castoldi F, Abas-tado JP, Agostinis P, et al. Classification of currentanticancer immunotherapies. Oncotarget 2014; 5(24):12472-508; PMID:25537519

49. Obeid M, Tesniere A, Ghiringhelli F, Fimia GM,Apetoh L, Perfettini JL, Castedo M, Mignot G, Pan-aretakis T, Casares N, et al. Calreticulin exposure dic-tates the immunogenicity of cancer cell death. NatMed 2007; 13:54-61; PMID:17187072; http://dx.doi.org/10.1038/nm1523

50. Bugaut H, Bruchard M, Berger H, Derangere V,Odoul L, Euvrard R, Ladoire S, Chalmin F, V"egranF, R"eb"e C, et al. Bleomycin exerts ambivalent antitu-mor immune effect by triggering both immunogeniccell death and proliferation of regulatory T cells. PLoSOne 2013; 8:e65181; PMID:23762310; http://dx.doi.org/10.1371/journal.pone.0065181

51. Demaria S, Santori FR, Ng B, Liebes L, Formenti SC,Vukmanovic S. Select forms of tumor cell apoptosisinduce dendritic cell maturation. J Leukoc Biol 2005;77:361-8; PMID:15569694; http://dx.doi.org/10.1189/jlb.0804478

52. Cirone M, Di Renzo L, Lotti LV, Conte V, Trivedi P,Santarelli R, Gonnella R, Frati L, Faggioni A. Primaryeffusion lymphoma cell death induced by bortezomiband AG 490 activates dendritic cells through CD91.PLoS One 2012; 7:e31732; PMID:22412839; http://dx.doi.org/10.1371/journal.pone.0031732

53. Schiavoni G, Sistigu A, Valentini M, Mattei F,Sestili P, Spadaro F, Sanchez M, Lorenzi S,D’Urso MT, Belardelli F, et al. Cyclophosphamidesynergizes with type I interferons through systemicdendritic cell reactivation and induction of immu-nogenic tumor apoptosis. Cancer Res 2011;71:768-78; PMID:21156650; http://dx.doi.org/10.1158/0008-5472.CAN-10-2788

54. Tesniere A, Schlemmer F, Boige V, Kepp O, MartinsI, Ghiringhelli F, Aymeric L, Michaud M, Apetoh L,Barault L, et al. Immunogenic death of colon cancercells treated with oxaliplatin. Oncogene 2010;29:482-91; PMID:19881547; http://dx.doi.org/10.1038/onc.2009.356

55. Hoffmann J, Vitale I, Buchmann B, Galluzzi L,Schwede W, Senovilla L, Skuballa W, Vivet S, Licht-ner RB, Vicencio JM, et al. Improved cellular phar-macokinetics and pharmacodynamics underlie thewide anticancer activity of sagopilone. Cancer Res2008; 68:5301-8; PMID:18593931; http://dx.doi.org/10.1158/0008-5472.CAN-08-0237

56. Senovilla L, Vitale I, Martins I, Tailler M, Pail-leret C, Michaud M, Galluzzi L, Adjemian S,Kepp O, Niso-Santano M, et al. An immunosur-veillance mechanism controls cancer cell ploidy.Science 2012; 337:1678-84; PMID:23019653;http://dx.doi.org/10.1126/science.1224922

57. Pellicciotta I, Yang CP, Goldberg GL, Shahabi S.Epothilone B enhances Class I HLA and HLA-A2 sur-face molecule expression in ovarian cancer cells. Gyne-col Oncol 2011; 122:625-31; PMID:21621254;http://dx.doi.org/10.1016/j.ygyno.2011.05.007

58. Garrido G, Rabasa A, Sanchez B, Lopez MV, BlancoR, Lopez A, Hern"andez DR, P"erez R, Fern"andez LE.Induction of immunogenic apoptosis by blockade ofepidermal growth factor receptor activation with aspecific antibody. J Immunol 2011; 187:4954-66;PMID:21984704; http://dx.doi.org/10.4049/jimmunol.1003477

59. de La Motte Rouge T, Galluzzi L, Olaussen KA,Zermati Y, Tasdemir E, Robert T, Ripoche H,Lazar V, Dessen P, Harper F, et al. A novel epi-dermal growth factor receptor inhibitor promotesapoptosis in non-small cell lung cancer cells resis-tant to erlotinib. Cancer Res 2007; 67:6253-62;PMID:17616683; http://dx.doi.org/10.1158/0008-5472.CAN-07-0538

60. Thomas ES, Gomez HL, Li RK, Chung HC, Fein LE,Chan VF, Jassem J, Pivot XB, Klimovsky JV, de Men-doza FH, et al. Ixabepilone plus capecitabine for met-astatic breast cancer progressing after anthracyclineand taxane treatment. J Clin Oncol 2007; 25:5210-7;PMID:17968020; http://dx.doi.org/10.1200/JCO.2007.12.6557

61. Aranda F, Vacchelli E, Eggermont A, Galon J,Fridman WH, Zitvogel L, Kroemer G, Galluzzi L.Trial Watch: Immunostimulatory monoclonal anti-bodies in cancer therapy. Oncoimmunology 2014;3:e27297; PMID:24701370; http://dx.doi.org/10.4161/onci.27297

62. Vacchelli E, Eggermont A, Galon J, Sautes-FridmanC, Zitvogel L, Kroemer G, Galluzzi L. Trial watch:Monoclonal antibodies in cancer therapy. Oncoim-munology 2013; 2:e22789; PMID:23482847; http://dx.doi.org/10.4161/onci.22789

63. Vacchelli E, Aranda F, Eggermont A, Galon J,Sautes-Fridman C, Zitvogel L, Kroemer G, Gal-luzzi L. Trial Watch: Tumor-targeting monoclonalantibodies in cancer therapy. Oncoimmunology2014; 3:e27048; PMID:24605265; http://dx.doi.org/10.4161/onci.27048

64. Menger L, Vacchelli E, Kepp O, Eggermont A, Tar-tour E, Zitvogel L, Kroemer G, Galluzzi L. Trialwatch: Cardiac glycosides and cancer therapy.Oncoimmunology 2013; 2:e23082; PMID:23525565; http://dx.doi.org/10.4161/onci.23082

65. Ibrahim A, Scher N, Williams G, Sridhara R, Li N,Chen G, Leighton J, Booth B, Gobburu JV, RahmanA, et al. Approval summary for zoledronic acid fortreatment of multiple myeloma and cancer bonemetastases. Clin Cancer Res 2003; 9:2394-9;PMID:12855610

66. Menger L, Vacchelli E, Adjemian S, Martins I, MaY, Shen S, Yamazaki T, Sukkurwala AQ, MichaudM, Mignot G, et al. Cardiac glycosides exert anti-cancer effects by inducing immunogenic cell death.Sci Transl Med 2012; 4:143ra99; PMID:22814852; http://dx.doi.org/10.1126/scitranslmed.3003807

67. Kepp O, Menger L, Vacchelli E, Adjemian S, MartinsI, Ma Y, Sukkurwala AQ, Michaud M, Galluzzi L,Zitvogel L, et al. Anticancer activity of cardiac glyco-sides: At the frontier between cell-autonomous andimmunological effects. Oncoimmunology 2012;1:1640-2; PMID:23264921; http://dx.doi.org/10.4161/onci.21684

68. Riganti C, Castella B, Kopecka J, Campia I, CosciaM, Pescarmona G, Bosia A, Ghigo D, Massaia M.Zoledronic acid restores doxorubicin chemosensitivityand immunogenic cell death in multidrug-resistanthuman cancer cells. PLoS One 2013; 8:e60975;PMID:23593363; http://dx.doi.org/10.1371/journal.pone.0060975

69. Riganti C, Massaia M. Inhibition of the mevalo-nate pathway to override chemoresistance and pro-mote the immunogenic demise of cancer cells:Killing two birds with one stone. Oncoimmunol-ogy 2013; 2:e25770; PMID:24327936; http://dx.doi.org/10.4161/onci.25770

70. Galluzzi L, Vacchelli E, Eggermont A, Fridman WH,Galon J, Sautes-Fridman C, Tartour E, Zitvogel L,Kroemer G. Trial Watch: Experimental Toll-likereceptor agonists for cancer therapy. Oncoimmunol-ogy 2012; 1:699-716; PMID:22934262; http://dx.doi.org/10.4161/onci.20696

71. Vacchelli E, Aranda F, Eggermont A, Sautes-FridmanC, Tartour E, Kennedy EP, et al. Trial Watch: IDOinhibitors in cancer therapy. Oncoimmunology 2014;3:e957994; http://dx.doi.org/10.4161/21624011.2014.957994

72. Pol J, Bloy N, Obrist F, Eggermont A, Galon J,Cremer I, Erbs P, Limacher JM, Preville X, Zitvo-gel L, et al. Trial Watch: Oncolytic viruses forcancer therapy. Oncoimmunology 2014; 3:e28694;PMID:25097804; http://dx.doi.org/10.4161/onci.28694

73. Korbelik M, Sun J, Cecic I. Photodynamic therapy-induced cell surface expression and release of heatshock proteins: relevance for tumor response. CancerRes 2005; 65:1018-26; PMID:15705903

74. Panzarini E, Inguscio V, Dini L. Immunogenic celldeath: can it be exploited in PhotoDynamic Therapy

e1008866-10 Volume 4 Issue 4OncoImmunology

Dow

nloa

ded

by [U

NIV

ERSI

TAT

DE

BARC

ELO

NA

] at 0

0:55

28

Apr

il 20

15

Page 11: Trial Watch: Immunogenic cell death inducers for anticancer chemotherapy

for cancer? Biomed Res Int 2013; 2013:482160;PMID:23509727; http://dx.doi.org/10.1155/2013/482160

75. Vacchelli E, Vitale I, Tartour E, Eggermont A, Sautes-Fridman C, Galon J, Zitvogel L, Kroemer G, GalluzziL. Trial Watch: Anticancer radioimmunotherapy.Oncoimmunology 2013; 2:e25595; PMID:24319634; http://dx.doi.org/10.4161/onci.25595

76. Bloy N, Pol J, Manic G, Vitale I, Eggermont A, GalonJ, et al. Trial Watch: Radioimmunotherapy for onco-logical indications. Oncoimmunology 2014; 3:e954929; http://dx.doi.org/10.4161/21624011.2014.954929

77. Garg AD, Dudek AM, Agostinis P. Autophagy-dependent suppression of cancer immunogenicity andeffector mechanisms of innate and adaptive immunity.Oncoimmunology 2013; 2:e26260; PMID:24353910; http://dx.doi.org/10.4161/onci.26260

78. Garg AD, Krysko DV, Vandenabeele P, Agostinis P.The emergence of phox-ER stress induced immuno-genic apoptosis. Oncoimmunology 2012; 1:786-8;PMID:22934283; http://dx.doi.org/10.4161/onci.19750

79. Garg AD, Krysko DV, Verfaillie T, Kaczmarek A,Ferreira GB, Marysael T, Rubio N, Firczuk M,Mathieu C, Roebroek AJ, et al. A novel pathway com-bining calreticulin exposure and ATP secretion inimmunogenic cancer cell death. EMBO J 2012;31:1062-79; PMID:22252128; http://dx.doi.org/10.1038/emboj.2011.497

80. Galluzzi L, Kepp O, Kroemer G. Immunogenic celldeath in radiation therapy. Oncoimmunology 2013;2:e26536; PMID:24404424; http://dx.doi.org/10.4161/onci.26536

81. Ko A, Kanehisa A, Martins I, Senovilla L, Chargari C,Dugue D, Mari~no G, Kepp O, Michaud M, PerfettiniJL, et al. Autophagy inhibition radiosensitizes in vitro,yet reduces radioresponses in vivo due to deficientimmunogenic signalling. Cell Death Differ 2014;21:92-9; PMID:24037090; http://dx.doi.org/10.1038/cdd.2013.124

82. Formenti SC, Demaria S. Radiation therapy to con-vert the tumor into an in situ vaccine. Int J RadiatOncol Biol Phys 2012; 84:879-80; PMID:23078897;http://dx.doi.org/10.1016/j.ijrobp.2012.06.020

83. Vacchelli E, Aranda F, Eggermont A, Galon J, Sautes-Fridman C, Cremer I, Zitvogel L, Kroemer G, Gal-luzzi L. Trial Watch: Chemotherapy with immuno-genic cell death inducers. Oncoimmunology 2014; 3:e27878; PMID:24800173; http://dx.doi.org/10.4161/onci.27878

84. Butts C, Socinski MA, Mitchell PL, Thatcher N,Havel L, Krzakowski M, Nawrocki S, Ciuleanu TE,Bosqu"ee L, Trigo JM, et al. Tecemotide (L-BLP25)versus placebo after chemoradiotherapy for stage IIInon-small-cell lung cancer (START): a randomised,double-blind, phase 3 trial. Lancet Oncol 2014;15:59-68; PMID:24331154; http://dx.doi.org/10.1016/S1470-2045(13)70510-2

85. Roulstone V, Khan K, Pandha HS, Rudman S, CoffeyM, Gill GM, Melcher AA, Vile RG, Harrington KJ,de Bono JS, et al. Phase I trial of cyclophosphamideas an immune modulator for optimizing oncolyticreovirus delivery to solid tumors. Clin Cancer Res2015; PMID:25424857.

86. Kharaziha P, De Raeve H, Fristedt C, Li Q,Gruber A, Johnsson P, Kokaraki G, Panzar M,Laane E, Osterborg A, et al. Sorafenib has potentantitumor activity against multiple myeloma invitro, ex vivo, and in vivo in the 5T33MM mousemodel. Cancer Res 2012; 72:5348-62;PMID:22952216; http://dx.doi.org/10.1158/0008-5472.CAN-12-0658

87. Kharaziha P, Rodriguez P, Li Q, Rundqvist H, Bjor-klund AC, Augsten M, Ull"en A, Egevad L, WiklundP, Nilsson S, et al. Targeting of distinct signaling cas-cades and cancer-associated fibroblasts define the effi-cacy of Sorafenib against prostate cancer cells. Cell

Death Dis 2012; 3:e262; PMID:22278289; http://dx.doi.org/10.1038/cddis.2012.1

88. Bazzola L, Foroni C, Andreis D, Zanoni V, M RC,Allevi G, Aguggini S, Strina C, Milani M, VenturiniS, et al. Combination of letrozole, metronomic cyclo-phosphamide and sorafenib is well-tolerated andshows activity in patients with primary breast cancer.Br J Cancer 2014; 112(1):52-60; PMID:25461806

89. Lutz ER, Wu AA, Bigelow E, Sharma R, Mo G,Soares K, Solt S, Dorman A, Wamwea A, Yager A,et al. Immunotherapy converts nonimmunogenicpancreatic tumors into immunogenic foci of immuneregulation. Cancer Immunol Res 2014; 2:616-31;PMID:24942756; http://dx.doi.org/10.1158/2326-6066.CIR-14-0027

90. Springett GM. Novel pancreatic cancer vaccines couldunleash the army within. Cancer Control 2014;21:242-6; PMID:24955709

91. Marks E, Saif MW, Jia Y. Updates on first-line ther-apy for metastatic pancreatic adenocarcinoma. JOP2014; 15:99-102; PMID:24618427

92. Antonarakis ES, Carducci MA. Combining low-dosecyclophosphamide with GM-CSF-secreting prostatecancer immunotherapy enhances antitumor immuneeffects. Expert Opin Investig Drugs 2010; 19:311-4;PMID:20047504; http://dx.doi.org/10.1517/13543780903530678

93. Zheng L, Edil BH, Soares KC, El-Shami K, Uram JN,Judkins C, Zhang Z, Onners B, Laheru D, Pardoll D,et al. A safety and feasibility study of an allogeneiccolon cancer cell vaccine administered with a granulo-cyte-macrophage colony stimulating factor-producingbystander cell line in patients with metastatic colorec-tal cancer. Ann Surg Oncol 2014; 21:3931-7;PMID:24943235; http://dx.doi.org/10.1245/s10434-014-3844-x

94. Hong YS, Nam BH, Kim KP, Kim JE, Park SJ, ParkYS, Park JO, Kim SY, Kim TY, Kim JH, et al. Oxali-platin, fluorouracil, and leucovorin versus fluorouraciland leucovorin as adjuvant chemotherapy for locallyadvanced rectal cancer after preoperative chemoradio-therapy (ADORE): an open-label, multicentre, phase2, randomised controlled trial. Lancet Oncol 2014;15:1245-53; PMID:25201358; http://dx.doi.org/10.1016/S1470-2045(14)70377-8

95. Noh SH, Park SR, Yang HK, Chung HC, Chung IJ,Kim SW, Kim HH, Choi JH, Kim HK, Yu W, et al.Adjuvant capecitabine plus oxaliplatin for gastric can-cer after D2 gastrectomy (CLASSIC): 5-year follow-up of an open-label, randomised phase 3 trial. LancetOncol 2014; 15:1389-96; PMID:25439693; http://dx.doi.org/10.1016/S1470-2045(14)70473-5

96. Yamada Y, Higuchi K, Nishikawa K, Gotoh M, FuseN, Sugimoto N, Nishina T, Amagai K, Chin K, NiwaY, et al. Phase III study comparing oxaliplatin plus S-1 with cisplatin plus S-1 in chemotherapy-naivepatients with advanced gastric cancer. Ann Oncol2015; 26:141-8; PMID:25316259; http://dx.doi.org/10.1093/annonc/mdu472

97. Oettle H, Riess H, Stieler JM, Heil G, Schwaner I,Seraphin J, G€orner M, M€olle M, Greten TF, LaknerV, et al. Second-line oxaliplatin, folinic acid, and fluo-rouracil versus folinic acid and fluorouracil alone forgemcitabine-refractory pancreatic cancer: outcomesfrom the CONKO-003 trial. J Clin Oncol 2014;32:2423-9; PMID:24982456; http://dx.doi.org/10.1200/JCO.2013.53.6995

98. O’Reilly EM, Perelshteyn A, Jarnagin WR, SchattnerM, Gerdes H, Capanu M, Tang LH, LaValle J, Win-ston C, DeMatteo RP, et al. A single-arm, non-randomized phase II trial of neoadjuvant gemcitabineand oxaliplatin in patients with resectable pancreasadenocarcinoma. Ann Surg 2014; 260:142-8;PMID:24901360; http://dx.doi.org/10.1097/SLA.0000000000000251

99. Schadt CR. Topical and oral bexarotene. DermatolTher 2013; 26:400-3; PMID:24099070

100. Delfino C, Grandi V, Pileri A, Rupoli S, Quaglino P,Alterini R, Goteri G, Canafoglia L, Pimpinelli N.Combination treatment in CTCL: the current role ofbexarotene. G Ital Dermatol Venereol 2012; 147:573-80; PMID:23149703

101. Knol AC, Quereux G, Brocard A, Ballanger F, Kham-mari A, Nguyen JM, Dr"eno B. Absence of modulationof CD4CCD25 regulatory T cells in CTCL patientstreated with bexarotene. Exp Dermatol 2010; 19:e95-102; PMID:19845755; http://dx.doi.org/10.1111/j.1600-0625.2009.00993.x

102. Knol AC, Quereux G, Brocard A, Ballanger F, Kham-mari A, Nguyen JM, Dr"eno B. About the cutaneoustargets of bexarotene in CTCL patients. Exp Derma-tol 2010; 19:e299-301; PMID:19845753; http://dx.doi.org/10.1111/j.1600-0625.2009.00995.x

103. Straus DJ, Duvic M, Horwitz SM, Hymes K, Goy A,Hernandez-Ilizaliturri FJ, Feldman T, Wegner B,Myskowski PL. Final results of phase II trial of doxo-rubicin HCl liposome injection followed by bexaro-tene in advanced cutaneous T-cell lymphoma. AnnOncol 2014; 25:206-10; PMID:24285015; http://dx.doi.org/10.1093/annonc/mdt480

104. Pallasch CP, Leskov I, Braun CJ, Vorholt D, Drake A,Soto-Feliciano YM, Bent EH, Schwamb J, IliopoulouB, Kutsch N, et al. Sensitizing protective tumormicroenvironments to antibody-mediated therapy.Cell 2014; 156:590-602; PMID:24485462; http://dx.doi.org/10.1016/j.cell.2013.12.041

105. Geissmann F, Manz MG, Jung S, Sieweke MH,Merad M, Ley K. Development of monocytes, macro-phages, and dendritic cells. Science 2010; 327:656-61; PMID:20133564; http://dx.doi.org/10.1126/science.1178331

106. Hashimoto D, Miller J, Merad M. Dendritic cell andmacrophage heterogeneity in vivo. Immunity 2011;35:323-35; PMID:21943488; http://dx.doi.org/10.1016/j.immuni.2011.09.007

107. Sulzmaier FJ, Jean C, Schlaepfer DD. FAK in cancer:mechanistic findings and clinical applications. NatRev Cancer 2014; 14:598-610; PMID:25098269;http://dx.doi.org/10.1038/nrc3792

108. Golubovskaya VM. Targeting FAK in human cancer:from finding to first clinical trials. Front Biosci (Land-mark Ed) 2014; 19:687-706; PMID:24389213;http://dx.doi.org/10.2741/4236

109. Lunardi S, Muschel RJ, Brunner TB. The stromalcompartments in pancreatic cancer: are there any ther-apeutic targets? Cancer Lett 2014; 343:147-55;PMID:24141189; http://dx.doi.org/10.1016/j.canlet.2013.09.039

110. Tavora B, Reynolds LE, Batista S, Demircioglu F,Fernandez I, Lechertier T, Lees DM, Wong PP, Alex-opoulou A, Elia G, et al. Endothelial-cell FAK target-ing sensitizes tumours to DNA-damaging therapy.Nature 2014; 514:112-6; PMID:25079333; http://dx.doi.org/10.1038/nature13541

111. STK4 inhibition promotes YAP1-mediated apoptosisin hematologic cancers. Cancer Discov 2014; 4:OF8;http://dx.doi.org/10.1158/2159-8290.CD-RW2014-112

112. Luk JM, Guan KL. An alternative DNA damage path-way to apoptosis in hematological cancers. Nat Med2014; 20:587-8; PMID:24901566; http://dx.doi.org/10.1038/nm.3593

113. Tomlinson V, Gudmundsdottir K, Luong P, LeungKY, Knebel A, Basu S. JNK phosphorylates Yes-asso-ciated protein (YAP) to regulate apoptosis. Cell DeathDis 2010; 1:e29; PMID:21364637; http://dx.doi.org/10.1038/cddis.2010.7

114. Lapi E, Di Agostino S, Donzelli S, Gal H, Domany E,Rechavi G, Pandolfi PP, Givol D, Strano S, Lu X,et al. PML, YAP, and p73 are components of a proa-poptotic autoregulatory feedback loop. Mol Cell2008; 32:803-14; PMID:19111660; http://dx.doi.org/10.1016/j.molcel.2008.11.019

115. Cottini F, Hideshima T, Xu C, Sattler M, DoriM, Agnelli L, ten Hacken E, Bertilaccio MT,

www.tandfonline.com e1008866-11OncoImmunology

Dow

nloa

ded

by [U

NIV

ERSI

TAT

DE

BARC

ELO

NA

] at 0

0:55

28

Apr

il 20

15

Page 12: Trial Watch: Immunogenic cell death inducers for anticancer chemotherapy

Antonini E, Neri A, et al. Rescue of Hippo coacti-vator YAP1 triggers DNA damage-induced apopto-sis in hematological cancers. Nat Med 2014;20:599-606; PMID:24813251; http://dx.doi.org/10.1038/nm.3562

116. Kroemer G, Galluzzi L, Brenner C. Mitochondrialmembrane permeabilization in cell death. Physiol Rev2007; 87:99-163; PMID:17237344; http://dx.doi.org/10.1152/physrev.00013.2006

117. Galluzzi L, Larochette N, Zamzami N, Kroemer G.Mitochondria as therapeutic targets for cancer chemo-therapy. Oncogene 2006; 25:4812-30; PMID:16892093; http://dx.doi.org/10.1038/sj.onc.1209598

118. Galluzzi L, Kepp O, Trojel-Hansen C, KroemerG. Mitochondrial control of cellular life, stress,and death. Circ Res 2012; 111:1198-207;PMID:23065343; http://dx.doi.org/10.1161/CIRCRESAHA.112.268946

119. Ichikawa Y, Ghanefar M, Bayeva M, Wu R, Khecha-duri A, Naga Prasad SV, Mutharasan RK, Naik TJ,Ardehali H. Cardiotoxicity of doxorubicin is mediatedthrough mitochondrial iron accumulation. J ClinInvest 2014; 124:617-30; PMID:24382354; http://dx.doi.org/10.1172/JCI72931

120. Liu Y, Asnani A, Zou L, Bentley VL, Yu M, Wang Y,Dellaire G, Sarkar KS, Dai M, Chen HH, et al. Vis-nagin protects against doxorubicin-induced cardiomy-opathy through modulation of mitochondrial malatedehydrogenase. Sci Transl Med 2014; 6:266ra170;PMID:25504881; http://dx.doi.org/10.1126/scitranslmed.3010189

121. Arthur JC, Perez-Chanona E, Muhlbauer M, Tomko-vich S, Uronis JM, Fan TJ, Campbell BJ, AbujamelT, Dogan B, Rogers AB, et al. Intestinal inflammationtargets cancer-inducing activity of the microbiota. Sci-ence 2012; 338:120-3; PMID:22903521; http://dx.doi.org/10.1126/science.1224820

122. Ashida H, Ogawa M, Kim M, Mimuro H, SasakawaC. Bacteria and host interactions in the gut epithelialbarrier. Nat Chem Biol 2012; 8:36-45; http://dx.doi.org/10.1038/nchembio.741

123. Brown EM, Sadarangani M, Finlay BB. The roleof the immune system in governing host-microbeinteractions in the intestine. Nat Immunol 2013;14:660-7; PMID:23778793; http://dx.doi.org/10.1038/ni.2611

124. Bultman SJ. Emerging roles of the microbiome incancer. Carcinogenesis 2014; 35:249-55;PMID:24302613; http://dx.doi.org/10.1093/carcin/bgt392

125. Viaud S, Daillere R, Yamazaki T, Lepage P, Boneca I,Goldszmid R, Trinchieri G, Zitvogel L. Why shouldwe need the gut microbiota to respond to cancer ther-apies? Oncoimmunology 2014; 3:e27574; PMID:24800167; http://dx.doi.org/10.4161/onci.27574

126. Viaud S, Saccheri F, Mignot G, Yamazaki T, DaillereR, Hannani D, Enot DP, Pfirschke C, Engblom C,Pittet MJ, et al. The intestinal microbiota modulatesthe anticancer immune effects of cyclophosphamide.Science 2013; 342:971-6; PMID:24264990; http://dx.doi.org/10.1126/science.1240537

127. Iida N, Dzutsev A, Stewart CA, Smith L, BouladouxN, Weingarten RA, Molina DA, Salcedo R, Back T,Cramer S, et al. Commensal bacteria control cancerresponse to therapy by modulating the tumor micro-environment. Science 2013; 342:967-70; PMID:24264989; http://dx.doi.org/10.1126/science.1240527

128. Schroeder A, Heller DA, Winslow MM, Dahlman JE,Pratt GW, Langer R, Jacks T, Anderson DG. Treatingmetastatic cancer with nanotechnology. Nat Rev Can-cer 2012; 12:39-50; http://dx.doi.org/10.1038/nrc3180

129. Morton SW, Lee MJ, Deng ZJ, Dreaden EC, SiouveE, Shopsowitz KE, Shah NJ, Yaffe MB, HammondPT. A nanoparticle-based combination chemotherapydelivery system for enhanced tumor killing bydynamic rewiring of signaling pathways. Sci Signal

2014; 7:ra44; PMID:24825919; http://dx.doi.org/10.1126/scisignal.2005261

130. Croucher DR, Saunders DN, Lobov S, Ranson M.Revisiting the biological roles of PAI2 (SERPINB2)in cancer. Nat Rev Cancer 2008; 8:535-45;PMID:18548086; http://dx.doi.org/10.1038/nrc2400

131. Affara NI, Coussens LM. IKKalpha at the crossroadsof inflammation and metastasis. Cell 2007; 129:25-6;PMID:17418780; http://dx.doi.org/10.1016/j.cell.2007.03.029

132. Hopkins PC, Whisstock J. Function of maspin. Sci-ence 1994; 265:1893-4; PMID:8091216; http://dx.doi.org/10.1126/science.8091216

133. Zou Z, Anisowicz A, Hendrix MJ, Thor A, Neveu M,Sheng S, Rafidi K, Seftor E, Sager R. Maspin, a serpinwith tumor-suppressing activity in human mammaryepithelial cells. Science 1994; 263:526-9; PMID:8290962; http://dx.doi.org/10.1126/science.8290962

134. Triulzi T, Ratti M, Tortoreto M, Ghirelli C, Aiello P,Regondi V, Di Modica M, Cominetti D, CarcangiuML, Moliterni A, et al. Maspin influences response todoxorubicin by changing the tumor microenviron-ment organization. Int J Cancer 2014; 134:2789-97;PMID:24242003; http://dx.doi.org/10.1002/ijc.28608

135. Pfisterer J, Plante M, Vergote I, du Bois A, Hirte H,Lacave AJ, Wagner U, St€ahle A, Stuart G, Kimmig R,et al. Gemcitabine plus carboplatin compared withcarboplatin in patients with platinum-sensitive recur-rent ovarian cancer: an intergroup trial of the AGO-OVAR, the NCIC CTG, and the EORTC GCG. JClin Oncol 2006; 24:4699-707; PMID:16966687;http://dx.doi.org/10.1200/JCO.2006.06.0913

136. Kelland L. The resurgence of platinum-based cancerchemotherapy. Nat Rev Cancer 2007; 7:573-84;PMID:17625587; http://dx.doi.org/10.1038/nrc2167

137. Miller K, Wang M, Gralow J, Dickler M, CobleighM, Perez EA, Shenkier T, Cella D, Davidson NE.Paclitaxel plus bevacizumab versus paclitaxel alone formetastatic breast cancer. N Engl J Med 2007;357:2666-76; PMID:18160686; http://dx.doi.org/10.1056/NEJMoa072113

138. Creelan BC, Antonia S, Bepler G, Garrett TJ, SimonGR, Soliman HH. Indoleamine 2,3-dioxygenaseactivity and clinical outcome following induction che-motherapy and concurrent chemoradiation in StageIII non-small cell lung cancer. Oncoimmunology2013; 2:e23428; PMID:23802083; http://dx.doi.org/10.4161/onci.23428

139. Boulin M, Guiu S, Chauffert B, Aho S, Cercueil JP,Ghiringhelli F, Krause D, Fagnoni P, Hillon P,Bedenne L, et al. Screening of anticancer drugs forchemoembolization of hepatocellular carcinoma.Anticancer Drugs 2011; 22:741-8; PMID:21487286;http://dx.doi.org/10.1097/CAD.0b013e328346a0c5

140. Semeraro M, Galluzzi L. Novel insights into themechanism of action of lenalidomide. Oncoimmunol-ogy 2014; 3:e28386; PMID:25340011; http://dx.doi.org/10.4161/onci.28386

141. Semeraro M, Vacchelli E, Eggermont A, Galon J, Zitvo-gel L, Kroemer G, Galluzzi L. Trial Watch: Lenalido-mide-based immunochemotherapy. Oncoimmunology2013; 2:e26494; PMID:24482747; http://dx.doi.org/10.4161/onci.26494

142. Okines AF, Ashley SE, Cunningham D, Oates J,Turner A, Webb J, Saffery C, Chua YJ, Chau I. Epiru-bicin, oxaliplatin, and capecitabine with or withoutpanitumumab for advanced esophagogastric cancer:dose-finding study for the prospective multicenter,randomized, phase II/III REAL-3 trial. J Clin Oncol2010; 28:3945-50; PMID:20679619; http://dx.doi.org/10.1200/JCO.2010.29.2847

143. Senovilla L, Aranda F, Galluzzi L, Kroemer G. Impactof myeloid cells on the efficacy of anticancer

chemotherapy. Curr Opin Immunol 2014; 30C:24-31; http://dx.doi.org/10.1016/j.coi.2014.05.009

144. Senovilla L, Vacchelli E, Galon J, Adjemian S, Egger-mont A, Fridman WH, Saut!es-Fridman C, Ma Y,Tartour E, Zitvogel L, et al. Trial watch: Prognosticand predictive value of the immune infiltrate in can-cer. Oncoimmunology 2012; 1:1323-43; PMID:23243596; http://dx.doi.org/10.4161/onci.22009

145. Galluzzi L, Kepp O, Vander Heiden MG, KroemerG. Metabolic targets for cancer therapy. Nat RevDrug Discov 2013; 12:829-46; PMID:24113830;http://dx.doi.org/10.1038/nrd4145

146. Aranda F, Vacchelli E, Obrist F, Eggermont A, GalonJ, Herve Fridman W, Cremer I, Tartour E, ZitvogelL, Kroemer G, et al. Trial Watch: Adoptive cell trans-fer for anticancer immunotherapy. Oncoimmunology2014; 3:e28344; PMID:25050207; http://dx.doi.org/10.4161/onci.28344

147. Vacchelli E, Eggermont A, Fridman WH, Galon J,Tartour E, Zitvogel L, Kroemer G, Galluzzi L.Trial Watch: Adoptive cell transfer for anticancerimmunotherapy. Oncoimmunology 2013; 2:e24238; PMID:23762803; http://dx.doi.org/10.4161/onci.24238

148. Rounbehler RJ, Li W, Hall MA, Yang C, FallahiM, Cleveland JL. Targeting ornithine decarboxyl-ase impairs development of MYCN-amplified neu-roblastoma. Cancer Res 2009; 69:547-53;PMID:19147568; http://dx.doi.org/10.1158/0008-5472.CAN-08-2968

149. Koomoa DL, Yco LP, Borsics T, Wallick CJ, Bach-mann AS. Ornithine decarboxylase inhibition bya-difluoromethylornithine activates opposing signal-ing pathways via phosphorylation of both Akt/proteinkinase B and p27Kip1 in neuroblastoma. Cancer Res2008; 68:9825-31; PMID:19047162; http://dx.doi.org/10.1158/0008-5472.CAN-08-1865

150. Tol J, Koopman M, Cats A, Rodenburg CJ,Creemers GJ, Schrama JG, Erdkamp FL, Vos AH,van Groeningen CJ, Sinnige HA, et al. Chemo-therapy, bevacizumab, and cetuximab in metastaticcolorectal cancer. N Engl J Med 2009; 360:563-72; PMID:19196673; http://dx.doi.org/10.1056/NEJMoa0808268

151. Hoehler T, von Wichert G, Schimanski C, Kanzler S,Moehler MH, Hinke A, Seufferlein T, Siebler J,Hochhaus A, Arnold D, et al. Phase I/II trial of cape-citabine and oxaliplatin in combination with bevaci-zumab and imatinib in patients with metastaticcolorectal cancer: AIO KRK 0205. Br J Cancer 2013;109:1408-13; PMID:23963139; http://dx.doi.org/10.1038/bjc.2013.409

152. Lerret NM, Marzo AL. Adoptive T-cell transfer com-bined with a single low dose of total body irradiationeradicates breast tumors. Oncoimmunology 2013; 2:e22731; PMID:23525138; http://dx.doi.org/10.4161/onci.22731

153. Lee AF, Sieling PA, Lee DJ. Immune correlates ofmelanoma survival in adoptive cell therapy. Oncoim-munology 2013; 2:e22889; PMID:23525606; http://dx.doi.org/10.4161/onci.22889

154. Besser MJ. Is there a future for adoptive cell transfer inmelanoma patients? Oncoimmunology 2013; 2:e26098; PMID:24353909; http://dx.doi.org/10.4161/onci.26098

155. Lu JY, Xiao Y, Qiu HZ, Wu B, Lin GL, Xu L, ZhangGN, Hu K. Clinical outcome of neoadjuvant chemo-radiation therapy with oxaliplatin and capecitabine or5-fluorouracil for locally advanced rectal cancer. JSurg Oncol 2013; 108:213-9; PMID:23913795;http://dx.doi.org/10.1002/jso.23394

156. Njiaju UO, Tevaarwerk AJ, Kim K, Chang JE,Hansen RM, Champeny TL, Traynor AM, Mead-ows S, Van Ummersen L, Powers K, et al. Capeci-tabine and oxaliplatin in combination as first- orsecond-line therapy for metastatic breast cancer: aWisconsin Oncology Network trial. Cancer Che-mother Pharmacol 2013; 71:613-8; PMID:

e1008866-12 Volume 4 Issue 4OncoImmunology

Dow

nloa

ded

by [U

NIV

ERSI

TAT

DE

BARC

ELO

NA

] at 0

0:55

28

Apr

il 20

15

Page 13: Trial Watch: Immunogenic cell death inducers for anticancer chemotherapy

23228989; http://dx.doi.org/10.1007/s00280-012-2044-2

157. Giantonio BJ, Catalano PJ, Meropol NJ, O’DwyerPJ, Mitchell EP, Alberts SR, Schwartz MA, Ben-son AB 3rd; Eastern Cooperative Oncology GroupStudy E3200. Bevacizumab in combination withoxaliplatin, fluorouracil, and leucovorin (FOL-FOX4) for previously treated metastatic colorectalcancer: results from the Eastern CooperativeOncology Group Study E3200. J Clin Oncol2007; 25:1539-44; PMID:17442997; http://dx.doi.org/10.1200/JCO.2006.09.6305

158. Conroy T, Galais MP, Raoul JL, Bouche O, Gour-gou-Bourgade S, Douillard JY, Etienne PL, Boige V,Martel-Lafay I, Michel P, et al. Definitive chemora-diotherapy with FOLFOX versus fluorouracil and cis-platin in patients with oesophageal cancer(PRODIGE5/ACCORD17): final results of a rando-mised, phase 2/3 trial. Lancet Oncol 2014; 15:305-14; PMID:24556041; http://dx.doi.org/10.1016/S1470-2045(14)70028-2

159. Gujar SA, Clements D, Lee PW. Two is better thanone: Complementing oncolytic virotherapy with gem-citabine to potentiate antitumor immune responses.Oncoimmunology 2014; 3:e27622; PMID:24804161; http://dx.doi.org/10.4161/onci.27622

160. Vici P, Sergi D, Pizzuti L, Mariani L, Arena MG,Barba M, Maugeri-Sacc!a M, Vincenzoni C, Vizza E,Corrado G, et al. Gemcitabine-oxaliplatin (GEMOX)as salvage treatment in pretreated epithelial ovariancancer patients. J Exp Clin Cancer Res 2013; 32:49;PMID:23927758; http://dx.doi.org/10.1186/1756-9966-32-49

161. Conroy T, Desseigne F, Ychou M, Bouche O,Guimbaud R, Becouarn Y, Adenis A, Raoul JL,Gourgou-Bourgade S, de la Fouchardi!ere C, et al.

FOLFIRINOX versus gemcitabine for metastaticpancreatic cancer. N Engl J Med 2011; 364:1817-25; PMID:21561347; http://dx.doi.org/10.1056/NEJMoa1011923

162. Gourgou-Bourgade S, Bascoul-Mollevi C, DesseigneF, Ychou M, Bouche O, Guimbaud R, B"ecouarn Y,Adenis A, Raoul JL, Boige V, et al. Impact of FOL-FIRINOX Compared With Gemcitabine on Qualityof Life in Patients With Metastatic Pancreatic Cancer:Results From the PRODIGE 4/ACCORD 11 Ran-domized Trial. J Clin Oncol 2013; 31:23-9;PMID:23213101; http://dx.doi.org/10.1200/JCO.2012.44.4869

163. Urner-Bloch U, Urner M, Stieger P, Galliker N, Win-terton N, Zubel A, Moutouh-de Parseval L, DummerR, Goldinger SM. Transient MEK inhibitor-associ-ated retinopathy in metastatic melanoma. Ann Oncol2014; 25:1437-41; PMID:24864047; http://dx.doi.org/10.1093/annonc/mdu169

164. Yang J, Shi Y, Li C, Gui L, Zhao X, Liu P, Han X,Song Y, Li N, Du P, et al. Phase I clinical trial ofpegylated liposomal mitoxantrone plm60-s: pharma-cokinetics, toxicity and preliminary efficacy. CancerChemother Pharmacol 2014; 74:637-46;PMID:25034977; http://dx.doi.org/10.1007/s00280-014-2523-8

165. Necchi A, Mariani L, Di Nicola M, Lo Vullo S, Nico-lai N, Giannatempo P, Raggi D, Far!e E, Magni M,Piva L, et al. High-dose sequential chemotherapy(HDS) versus PEB chemotherapy as first-line treat-ment of patients with poor prognosis germ-celltumors: mature results of an Italian randomized phaseII studydagger. Ann Oncol 2015; 26:167-72;PMID:25344361; http://dx.doi.org/10.1093/annonc/mdu485

166. Vacchelli E, Prada N, Kepp O, Galluzzi L. Currenttrends of anticancer immunochemotherapy. Oncoim-munology 2013; 2:e25396; PMID:23894726; http://dx.doi.org/10.4161/onci.25396

167. Golden EB, Frances D, Pellicciotta I, Demaria S,Helen Barcellos-Hoff M, Formenti SC. Radiation fos-ters dose-dependent and chemotherapy-inducedimmunogenic cell death. Oncoimmunology 2014; 3:e28518; PMID:25071979; http://dx.doi.org/10.4161/onci.28518

168. Galluzzi L, Kroemer G, Eggermont A. Novelimmune checkpoint blocker approved for thetreatment of advanced melanoma. Oncoimmunol-ogy 2014; 3:e967147; http://dx.doi.org/10.4161/21624011.2014.967147

169. Robert L, Harview C, Emerson R, Wang X, Mok S,Homet B, Comin-Anduix B, Koya RC, Robins H,Tumeh PC, et al. Distinct immunological mecha-nisms of CTLA-4 and PD-1 blockade revealed by ana-lyzing TCR usage in blood lymphocytes.Oncoimmunology 2014; 3:e29244; PMID:25083336; http://dx.doi.org/10.4161/onci.29244

170. Robert C, Long GV, Brady B, Dutriaux C, Maio M,Mortier L, Hassel JC, Rutkowski P, McNeil C,Kalinka-Warzocha E, et al. Nivolumab in previouslyuntreated melanoma without BRAF mutation. NEngl J Med 2014; 372(4):320-30

171. Robert C, Ribas A, Wolchok JD, Hodi FS, Hamid O,Kefford R, Weber JS, Joshua AM, Hwu WJ, Gangad-har TC, et al. Anti-programmed-death-receptor-1treatment with pembrolizumab in ipilimumab-refrac-tory advanced melanoma: a randomised dose-compar-ison cohort of a phase 1 trial. Lancet 2014; 384:1109-17; PMID:25034862; http://dx.doi.org/10.1016/S0140-6736(14)60958-2

www.tandfonline.com e1008866-13OncoImmunology

Dow

nloa

ded

by [U

NIV

ERSI

TAT

DE

BARC

ELO

NA

] at 0

0:55

28

Apr

il 20

15