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Review

Trial watch: Peptide-based vaccines in anticancer therapy

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Article: e1511506 | Received 10 Aug 2018, Published online: 06 Sep 2018

ABSTRACT

Peptide-based anticancer vaccination aims at stimulating an immune response against one or multiple tumor-associated antigens (TAAs) following immunization with purified, recombinant or synthetically engineered epitopes. Despite high expectations, the peptide-based vaccines that have been explored in the clinic so far had limited therapeutic activity, largely due to cancer cell-intrinsic alterations that minimize antigenicity and/or changes in the tumor microenvironment that foster immunosuppression. Several strategies have been developed to overcome such limitations, including the use of immunostimulatory adjuvants, the co-treatment with cytotoxic anticancer therapies that enable the coordinated release of damage-associated molecular patterns, and the concomitant blockade of immune checkpoints. Personalized peptide-based vaccines are also being explored for therapeutic activity in the clinic. Here, we review recent preclinical and clinical progress in the use of peptide-based vaccines as anticancer therapeutics.Abbreviations: CMP: carbohydrate-mimetic peptide; CMV: cytomegalovirus; DC: dendritic cell; FDA: Food and Drug Administration; HPV: human papillomavirus; MDS: myelodysplastic syndrome; MHP: melanoma helper vaccine; NSCLC: non-small cell lung carcinoma; ODD: orphan drug designation; PPV: personalized peptide vaccination; SLP: synthetic long peptide; TAA: tumor-associated antigen; TNA: tumor neoantigen

Introduction

Immunotherapy constitutes an efficient way to treat cancer based on the (re)activation of the natural capacity of the host immune system to recognize malignant cells as “non-self” and hence eliminate them.Citation1-Citation7 Over the past years, a panoply of different approaches has been developed or repurposed to (re)initiate anticancer immunity,Citation8-Citation12 including immune checkpoint blockers targeting cytotoxic T lymphocyte-associated protein 4 (CTLA4), programmed cell death 1 (PDCD1, best known as PD-1) and its main ligand CD274 (best known as PD-L1);Citation13-Citation19 chemotherapy with immunogenic cell death (ICD) inducers,Citation20-Citation25 recombinant cytokines,Citation26,Citation27 monoclonal antibodies (mAbs) that activate co-activatory receptors,Citation28,Citation29 adoptively transferred T cells engineered to express a tumor-specific chimeric antigen receptor (CAR),Citation30-Citation36 as well as multiple small molecules targeting distinct immunosuppressive pathways operating within the tumor microenvironment.Citation37-Citation40 Although some of these strategies have demonstrated unprecedented activity in patients with advanced tumors refractory to several lines of conventional treatment,Citation41 the fraction of individuals responding to single-agent immunotherapy is generally low,Citation42-Citation45 arguably with the sole exception of CAR-expressing T cells, which have been associated with >70% overall response rate in pediatric patients with B-cell acute lymphocytic leukemia (ALL).Citation46-Citation48 Thus, immunotherapy is most often implemented as part of combinatorial regimens involving other treatment modalities such as surgery, chemotherapy and/or radiation therapy (RT).Citation49-Citation54

Importantly, all tumors express proteins that differ in quality or quantity from their germline-encoded counterparts, owing to genetic and/or epigenetic alterations that accumulate as the disease progress.Citation55-Citation57 Once processed by the proteasome, these proteins can give rise to antigens that are not covered by central or peripheral tolerance and hence can be productively presented by dendritic cells (DCs) to T lymphocytes to drive an adaptive immune response.Citation55,Citation58-Citation64 Such antigens are commonly known as “tumor-associated antigens” (TAAs).Citation55,Citation65 A large list of TAAs with sequences that bind human MHC Class I or II molecules and the TCR can be found at http://cvc.dfci.harvard.edu/tadb (the Tantigen database). One specific class of TAAs is constituted by so-called “tumor neoantigens” (TNAs).Citation66-Citation71 At odds with other variants of TAAs including oncofetal antigens and cancer-testis antigens, which can be expressed by healthy tissues (at least at some stage of development),Citation37,Citation72-Citation75 TNAs are produced as a consequence of genetic alterations that are highly specific for the tumor, or even portions thereof.Citation76-Citation78 Similarly, TNAs that are fully tumor-specific occur upon the rearrangement of immunoglobulin-coding genes in clonal B-cell malignancies.Citation79 Finally, tumor-specific TAAs can be generated as a consequence of viral transformation,Citation80 as in the case of human papillomavirus type 16 (HPV-16)-driven oral and cervical tumors.Citation81,Citation82

TAAs in all their forms have been harnessed for the development of tumor-specific vaccines for therapeutic applications,Citation83-Citation86 including formulations based on recombinant or purified polypeptides generally administered together with an immunological adjuvant in suitable vehicles.Citation87-Citation103 However, TAAs often display limited antigenicity (reflecting the fact that they generally resemble self-antigens that are covered by tolerance).Citation104-Citation106 Moreover, tumors emerge and evolve as they become able to escape natural immunosurveillance,Citation107-Citation110 either because the lose expression of potentially antigenic proteins, and/or because they establish an immunosuppressive milieu that enforces local tolerance.Citation111-Citation116 Thus, besides a few exceptions and despite promising preclinical findings,Citation117 multiple studies demonstrate that peptide-based vaccines employed as standalone adjuvanted interventions have limited clinical activity (although they generally cause some signs of tumor-targeting immunity).Citation118-Citation121 In line with this notion, no peptide-based vaccines are currently approved by the US Food and Drug Administration (FDA) or equivalent agencies worldwide for use in cancer patients are therapeutic measures (source http://www.fda.gov). However, on 2017, July 10th, the FDA has granted Orphan Drug Designation (ODD), which is designed to encourage the preparation of new molecules for indications affecting fewer than 200,000 people in the US, to DSP-7888, a new peptide-based vaccine targeting Wilms tumor 1 (WT1).Citation122 Of note, Gardasil®, Gardasil 9® and Cervarix® are licensed for use in healthy women as prophylactic vaccines against multiple variants of HPV which are associated with the development of cervical carcinomas and anal cancers.Citation123-Citation128 That said, these agents technically represent antiviral vaccines and have limited activity against established HPV-driven tumors.Citation99,Citation129-Citation131

Recent attempts to improve the efficacy of peptide-based vaccines converged on the development of combinatorial immunotherapeutic regimens that simultaneously drive TAA-specific immunity as they inhibit local immunosuppression.Citation132 Considerable attention in this sense has been attracted by immune checkpoint blockers,Citation86,Citation133-Citation136 despite initial setbacks linked to the lack of added therapeutic value when ipilimumab (an FDA-approved mAb targeting CTLA) was combined with a peptide vaccine targeting premelanosome protein (PMEL, also known as gp100) in melanoma patients.Citation137 Along the lines of previous Trial Watches from our series,Citation138,Citation139 here we summarize recent clinical advances in the development of peptide-based therapeutic vaccines for cancer therapy.

Literature update

Clinical literature

Since the publication of the last Trial Watch dealing with this topic (April 2015),Citation118 the results of no less than 20 clinical trials testing peptide-based vaccination as a therapeutic approach in cancer patients have reported in the peer-reviewed literature (source https://www.ncbi.nlm.nih.gov/pubmed and http://meetinglibrary.asco.org/abstracts). Most of these trials were Phase I or II studies designed for testing the safety and immunogenicity (as opposed to the therapeutic efficacy) of TAA-derived peptides. Peptide-based vaccination was employed as a standalone adjuvanted intervention,Citation140-Citation146 or combined with chemotherapyCitation147-Citation149 radiation therapyCitation147,Citation150 or other forms of treatment including other immunotherapies.Citation148,Citation149,Citation151-Citation158 These studies enrolled patients with hematological malignancies,Citation151,Citation159 brain tumors,Citation152,Citation153 non-small cell lung carcinoma (NSCLC),Citation140,Citation147,Citation160 breast cancer,Citation141,Citation148,Citation161, prostate carcinoma, Citation142,Citation154 melanoma,Citation144-Citation146,Citation155-Citation158,Citation162. ovarian cancer.Citation149, cervical cancer,Citation163 hepatocellular carcinomaCitation164 and biliary tract cancer Citation165. The TAAs harnessed for the construction of peptide-based vaccines in these studies included the cancer/testis antigen 1B (CTAG1B; best known as NY-ESO-1),Citation144 MAGE family member A3 (MAGEA3),Citation140,Citation146,Citation147 TTK protein kinase (TTK),Citation158 WT1,Citation151,Citation166 baculoviral IAP repeat containing 5 (BIRC5; best known as survivin),Citation149 mutant epidermal growth factor receptor (EGFRvIII),Citation153 erb-b2 receptor tyrosine kinase 2 (ERBB2; best known as HER2),Citation148 indoleamine 2,3 dioxygenase 1 (IDO1),Citation157 TCR gamma alternative reading frame protein (TARP),Citation154 and multiple glioma-associated antigens.Citation152 Most often, peptide-based vaccines were well tolerated and no severe side effects were reported. Mild side effects were sporadic and included flu-like symptoms, fatigue and minor reactions at the injection site. Immunes responses driven by vaccination were documented in a variety of studies based on (1) interferon gamma (IFNG) production by T cells with enzyme-linked immunospot (ELISPOT) assays,Citation142,Citation151,Citation152,Citation154,Citation155 (2) tumor infiltration by CD4+ and CD8+ lymphocyte infiltration,Citation144,Citation145,Citation147,Citation157,Citation158 or (3) presence of peptide-specific antibodies in the serum.Citation158 Sporadic clinical responses were also documented (see below).

Ott and colleagues (from the Dana-Farber Cancer Institute, Boston, MA, USA) tested a personalized peptide vaccination (PPV)Citation167 consisting of 20 patient-specific TNAs predicted from whole-exon DNA sequencing of malignant versus healthy cells, in 6 melanoma patients. This vaccine, which was named NeoVax, induced polyfunctional CD4+ and CD8+ T cells targeting 58 (60%) and 15 (16%) of the 97 unique TNAs used across patients, respectively. Four of 6 vaccinated patients had no recurrence at reporting (25 months follow-up). Two patients with recurrent disease received immune checkpoint inhibitors targeting PD-1 and experienced complete tumor regression.Citation168

Pujol and collaborators (from the Arnaud de Villeneuve Hospital, Montpellier, France) investigated the safety and immunogenicity of a MAGEA3-targeting peptide-based vaccine in 67 patients with stage IB-III MAGEA3+ NSCLC who were or were not undergoing standard cisplatin/vinorelbine chemotherapy. In this setting, 16 out of 19 (84%) patients who underwent vaccination concurrent with adjuvant chemotherapy experienced chemotherapy-related Grade 3/4 adverse effects, which was not the case of patients who underwent vaccination after adjuvant chemotherapy.Citation147 Vansteenkiste and co-authors (from the University Hospital KU Leuven, Leuven, Belgium) tested a MAGEA3-targeting vaccine in 2312 patients with completely resected stage IB, II, and IIIA MAGEA3+ NSCLC who did or did not receive adjuvant chemotherapy. In the context of this large, randomized, double-blind, placebo-controlled, vaccination failed to increase the disease-free survival of surgically resected NSCLC patients (as compared to placebo).Citation140 On the contrary, in the prospective Phase II study reported by Saiag et al. (from the Ambroise-Paré Hospital, Boulogne, France), vaccination with a MAGEA3-specific vaccine resulted in a 1-year overall survival (OS) rate of 83.5% amongst unresectable stage IIIB-C melanoma.Citation146 Thus, vaccination strategies targeting MAGEA3 appear to be best suited for the treatment of advanced unresectable (rather than resectable) or chemotherapy-ineligible NSCLCs.

Weller et al. (from University Hospital of Zurich, Zurich, Switzerland) designed a randomized double-blind Phase III clinical trial to investigate the efficacy of rindopepimut, a peptide-based vaccine targeting EGFRvIII, in patients with newly diagnosed glioblastoma receiving or not conventional temozolomide-based chemotherapy. No difference in OS was documented between group, calling for a re-evaluation of the therapeutic approach.Citation153

Taken together, these clinical findings corroborate the notion that TAA-targeting peptide-based vaccines are well tolerated by cancer patients and initiate tumor-targeting immune responses (at least to some degree), but mediate limited therapeutic effects when employed as standalone adjuvanted interventions. The promising results obtained in melanoma patients by Ott and collaborators with a TNA-targeting approachCitation168 will have to be validated in larger controlled, randomized Phase II studies. Moreover, the efficacy of TNA-based PPV (employed alone or combined with immune checkpoint blockers) against tumors with a relatively low mutational burdenCitation77,Citation169,Citation170 remains to be established.

Preclinical literature

Among recent preclinical studies dealing with peptide-based anticancer vaccines, we found of particular interest the works of: (1) Zhu and colleagues (from the National Institutes of Health, Bethesda, MD, USA), who developed self-assembling albumin-vaccine nanocomplexes that reportedly enable superior delivery and mediated robust therapeutic effect against transplantable tumors growing in immunocompetent mice, especially when combined with immune checkpoint blockers and chemotherapy;Citation94 (2) Gall et al. (from the MD Anderson Cancer Center, Houston, TX, USA), who unveiled a Fc receptor-mediated mechanism whereby the FDA-approved HER2-targeting mAB trastuzumab favors the uptake of a HER2-targeting vaccine by DCs, resulting in efficient cross-presentation of its immunodominant epitope in vivo and robust therapeutic effects against breast carcinoma;Citation171 (3) Tsuruta et al. (from Kumamoto University, Kumamoto, Japan), who developed DEP domain containing 1 (DEPDC1)- and M-phase phosphoprotein 1 (MPHOSPH1)-derived synthetic long peptides (SLPs) that efficiently induce both helper T (TH) cells and CTLs in vitro and in vivo;Citation172 (4) Petrizzu and collaborators (from the Istituto Nazionale per lo Studio e la Cura dei Tumori, Naples, Italy), who showed that metronomic chemotherapy plus a PD-1-targeting immune checkpoint blocker are highly efficient in potentiating the antitumor effects of a multi-peptide vaccine in a mouse model of melanoma;Citation173 and (5) Tanaka and co-workers (from the Yamaguchi University, Ube, Japan), who demonstrated that miR-125b-1 and miR-378a expression levels may be harnessed to predict the efficacy of peptide-based vaccination against colorectal carcinoma.Citation174

Alongside these promising findings, Hailemichael et al. and Huang et al. (both from the MD Anderson Cancer Center, Houston, TX, USA) highlighted pitfalls related to formulationCitation99 that potentially compromise therapeutic efficacy when peptide-based vaccines and immune checkpoint blockersCitation134 or chemotherapyCitation175 are combined. These data suggest that additional work is required to fully decode the pharmacological and immunological interactions between peptide-based anticancer vaccines and other treatment modalities.

Ongoing clinical trials

Since the last Trial Watch dealing with peptide-based vaccines for oncological indications has been published (April 2015),Citation118 no less than 66 clinical trials have been initiated to test this immunotherapeutic modality in cancer patients (source www.clinicaltrials.gov) (). A large majority of these studies involve either short TAA-derived peptides that can directly bind to MHC Class I or II molecules expressed by antigen-presenting cells Citation176 (42 studies), or SLPs that are processed intracellularly and then loaded on MHC Class I or II moleculesCitation172,Citation177,Citation178 (22 studies), most often in combination with immunological adjuvants Citation179-Citation182 like montanide ISA-51 (water-in-oil emulsion)Citation181,Citation183 Hiltonol® (poly-L-lysine in carboxymethylcellulose, a TLR3 ligand)Citation184 and GM-CSF.Citation183,Citation185-Citation187 In several instances, vaccination is further combined with standard treatment regimens including conventional chemotherapy,Citation117,Citation188-Citation191 radiation therapy,Citation52,Citation192-Citation195 and targeted anticancer agents,Citation196-Citation199 or with various immunotherapeutic interventions.Citation200-Citation205 The latter include (1) immune checkpoint blockers such as the anti-PD-1 mAbs pembrolizumab and nivolumab,Citation206-Citation208 the anti-PD-L1 mAbs durvalumab and atezolizumab,Citation209-Citation211 and the anti-CTLA4 mAb ipilimumab; Citation137,Citation186,Citation212-Citation215 (2) immunostimulatory antibodies such as utomilumab, which stimulates TNF receptor superfamily member 9 (TNFRSF9; best known as 4-1BB or CD137) signaling,Citation28,Citation216-Citation218 or the CD27 agonist varlilumab;Citation28,Citation216,Citation219,Citation220 and immunomodulatory agents such as lenalidomide.Citation221-Citation224 In line with preclinical and clinical data demonstrating that multi-epitope vaccines are generally more powerful than their single-epitope counterparts,Citation117,Citation225 the most common vaccination strategy employed by these studies consists in targeting simultaneously multiple TAAs (20 studies). Alongside, 15 studies are investigating the safety and efficacy of PPV, often consisting of MHC-matched peptides chosen from the immune repertoire of the patient before treatment.Citation226 Finally, several studies aim at testing the safety and therapeutic potential of peptide-based vaccines targeting one single TAA including not only viral antigens like HPV p16, E6 and E7,Citation227-Citation229 but also shared TAAs like HER2, NY-ESO-1, survivin and telomerase reverse transcriptase (TERT),Citation161,Citation230-Citation252 as well as TAAs involved in the establishment of immunosuppression, such as PD-L1 and indoleamine 2,3-dioxygenase 1 (IDO1).Citation253-Citation256

Table 1. Ongoing clinical trials testing TAAs or peptides as therapeutic interventions in patients affected by cancer.

Taken together, these clinical trials enroll patients with a wide panel of neoplasms, including (but not limited to) glioblastoma, glioma and other brain tumors (NCT02722512; NCT02924038; NCT03068832; NCT03299309; NCT02750891; NCT03149003; NCT02287428; NCT02455557; NCT02754362; NCT02864368; NCT03223103; NCT03422094; NCT02358187; NCT02454634; NCT02960230), breast carcinoma (NCT02276300; NCT02593227; NCT02636582; NCT03012100; NCT02826434; NCT03362060), hematological malignancies (NCT02240537; NCT02802943; NCT03219450; NCT02396134; NCT02750995; NCT03121677; NCT03361852; NCT03381768; NCT02436252), melanoma (NCT02320305; NCT02334735; NCT02382549; NCT02385669; NCT02425306; NCT02515227; NCT02696356; NCT03047928), ovarian carcinoma (NCT02764333; NCT02978222; NCT02737787; NCT02933073) and prostate cancer (NCT03412786; NCT02293707; NCT02452307; NCT03199872).

Although final statistical assessments are still awaited, preliminary results from 8 clinical trials that have been completed or terminated since the publication of our last Trial Watch dealing with peptide-based anticancer vaccines (April 2015)Citation118 have become available (source www.clinicaltrials.gov). NCT01423760, an open-label, common safety follow-up trial testing a MUC1-targeting vaccine (tecemotide) in patients with myeloma and NSCLC has been terminated prematurely as per decision of the sponsor. Out of 27 patients enrolled in the study, 20 were evaluable for toxicity, which was more severe in the NSCLC arm. NCT00409188, a Phase III study testing tecemotide in combination with single low-dose cyclophosphamide in subjects with NSCLC has been completed. Primary endpoint was not met, but notable survival benefits were achieved in patients treated with concurrent chemoradiotherapy,Citation257 NCT01507103, a Phase II study testing the therapeutic profile of tecemotide combined with cyclophosphamide or cyclophosphamide plus chemoradiation in subjects with rectal cancer, has been completed. No difference in incidence and severity of adverse events were noted. NCT01380145, an open-label, single-arm, pilot study of recombinant MAGEA3 adjuvanted with AS15Citation258 as consolidation for multiple myeloma patients undergoing autologous stem cell transplantation, has been completed. Treatment was immunologically active, but grade 3–4 adverse events were experienced by 12 of the 13 participants in the study. One year after treatment there were 4 patients in stringent complete response (CR), 1 in CR, 4 in very good partial response (PR) and 4 with progressive disease. NCT00849875, a Phase II study testing MUC1-targeting vaccination plus dacarbazine in melanoma patients, has been terminated due to lack of scientific justification to continue collect data. Of 48 participants analyzed, 10 had serious adverse events. Seroconversion occurred in all patients, but clinical activity was limited to 1 CRs and 3 PRs. NCT00706992, a Phase 2 trial testing a peptide-based vaccine specific for melan-A (MLANA; also known as MART-1) together with MART-1-targeting lymphocytes in high-risk melanoma patients, has been terminated owing to low accrual. No robust immunological responses were documented among 40 evaluable patients. Adverse events were common, but never serious. NCT01322815, a Phase II study assessing the therapeutic profile of a peptide-based vaccine targeting mutant KRAS combined with standard chemotherapy or a mAb specific for vascular endothelial growth factor A (VEGFA)Citation259 in patients with colorectal carcinoma, has been terminated owing to poor accrual rate. Four months after the initiation of treatment, 50% of patients were alive and free of progression, but 2 patients receiving GI-4000 plus chemotherapy suffered from serious adverse effects. NCT00643097, a Phase I-II trial investigating the safety and preliminary therapeutic profile of an EGFRvIII-directed vaccine adjuvanted with GM-CSF in patients with glioblastoma, has been completed. Of 30 participants evaluable for the immunogenicity of the vaccine, 10 presented robust immune responses, median progression-free survival was between 11.6 and 14.2 months. NCT01307618, a Phase II study testing a multi-epitope peptide-based vaccine in combination with a CD25-specific antibody (daclizumab) ± recombinant metastatic interleukin 12 (IL12) in patients with metastatic melanoma, was terminated due to lack of efficacy.

Concluding remarks

In the past few years, tremendous progress has been made towards understanding the molecular and cellular pathways whereby the immune system can recognize and eradicate pre-malignant and malignant cells naturally as well as in response to some treatment regimens.Citation9,Citation20,Citation21,Citation260 Such knowledge has been instrumental for the development of a wide panel of therapeutic interventions that specifically aim at (re)establishing anticancer immunosurveillance (rather than merely causing the death of malignant cells), including peptide-based vaccination.Citation8,Citation105,Citation176,Citation261-Citation264 Unfortunately, it has soon become clear that the majority of immunotherapies developed so far is poorly active when employed as standalone therapeutic intervention, largely reflecting (1) natural and treatment-driven immunoediting, resulting in the selection of poorly immunogenic cancer cell populations;Citation115,Citation265,Citation266 and (2) the robust immunosuppression established by malignant cells, both locally and systemically.Citation267-Citation269 In line with this notion, the vast majority of peptide-based vaccines tested in the clinic so far mediated limited, if any, therapeutic activity, despite being able to elicit tumor-targeting immune responses, at least to some degree.Citation118 The field is therefore moving along three non-mutually exclusive directions: (1) combining peptide-based vaccination with additional forms of (immuno)therapy, with the specific aim of reverting immunosuppression and enabling therapeutically relevant immune responses,Citation270-Citation272 (2) targeting private antigenic epitopes that originate from mutations affecting only malignant cells (or sub-populations thereof), with PPV,Citation167,Citation272-Citation275 and (3) identifying specific patient populations that may obtain clinical benefit from the use of peptide-based vaccination.Citation174,Citation254 Although the feasibility of PPV on a large scale remains unclear, we surmise combining some variants of peptide-based vaccination with potent immunostimulatory agents including immune checkpoint blockers and oncolytic viruses may be the key to unlock the true potential of this hitherto unrealized therapeutic modality.

Acknowledgments

LB is supported by Bristol-Myers Squibb Foundation for Research in Immuno-Oncology (BMS). GK is supported by the Ligue contre le Cancer (équipe labelisée); Agence National de la Recherche (ANR) – Projets blancs; ANR under the frame of E-Rare-2, the ERA-Net for Research on Rare Diseases; Association pour la recherche sur le cancer (ARC); Fondation pour la Recherche Médicale (FRM); Cancéropôle Ile-de-France; Institut National du Cancer (INCa); Institut Universitaire de France; the European Commission (ArtForce); the European Research Council (ERC); the LeDucq Foundation; the LabEx Immuno-Oncology; the RHU Torino Lumière, the SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE); the SIRIC Cancer Research and Personalized Medicine (CARPEM); and the Paris Alliance of Cancer Research Institutes (PACRI). LG is supported by a startup grant from the Department of Radiation Oncology at Weill Cornell Medicine (New York, US) and by donations from Phosplatin Therapeutics (New York, US), Sotio a.s. (Prague, Czech Republic) and the Luke Heller TECPR2 Foundation (Boston, US).

Disclosure statement

LG provides remunerated consulting to OmniSEQ (Buffalo, NY, USA).

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