Therapy of Established Tumors with Rationally Designed Multiple Agents Targeting Diverse Immune-Tumor Interactions: Engage, Expand, Enable.

Abstract:

:Immunotherapy of immunologically cold solid tumors may require multiple agents to engage immune effector cells, expand effector populations and activities, and enable immune responses in the tumor microenvironment (TME). To target these distinct phenomena, we strategically chose five clinical-stage immuno-oncology agents, namely, (i) a tumor antigen-targeting adenovirus-based vaccine (Ad-CEA) and an IL15 superagonist (N-803) to activate tumor-specific T cells, (ii) OX40 and GITR agonists to expand and enhance the activated effector populations, and (iii) an IDO inhibitor (IDOi) to enable effector-cell activity in the TME. Flow cytometry, T-cell receptor (TCR) sequencing, and RNA-sequencing (RNA-seq) analyses showed that in the CEA-transgenic murine colon carcinoma (MC38-CEA) tumor model, Ad-CEA + N-803 combination therapy resulted in immune-mediated antitumor effects and promoted the expression of costimulatory molecules on immune subsets, OX40 and GITR, and the inhibitory molecule IDO. Treatment with Ad-CEA + N-803 + OX40 + GITR + IDOi, termed the pentatherapy regimen, resulted in the greatest inhibition of tumor growth and protection from tumor rechallenge without toxicity. Monotherapy with any of the agents had little to no antitumor activity, whereas combining two, three, or four agents had minimal antitumor effects. Immune analyses demonstrated that the pentatherapy combination induced CD4+ and CD8+ T-cell activity in the periphery and tumor, and antitumor activity associated with decreased regulatory T-cell (Treg) immunosuppression in the TME. The pentatherapy combination also inhibited tumor growth and metastatic formation in 4T1 and LL2-CEA murine tumor models. This study provides the rationale for the combination of multimodal immunotherapy agents to engage, enhance, and enable adaptive antitumor immunity.

journal_name

Cancer Immunol Res

authors

Fabian KP,Malamas AS,Padget MR,Solocinski K,Wolfson B,Fujii R,Abdul Sater H,Schlom J,Hodge JW

doi

10.1158/2326-6066.CIR-20-0638

subject

Has Abstract

pub_date

2020-12-22 00:00:00

eissn

2326-6066

issn

2326-6074

pii

2326-6066.CIR-20-0638

pub_type

杂志文章
  • Possible Interaction of Anti-PD-1 Therapy with the Effects of Radiosurgery on Brain Metastases.

    abstract::Delayed radiation-induced vasculitic leukoencephalopathy related to stereotactic radiosurgery (SRS) of brain metastases has been reported to manifest clinically 9 to 18 months after treatment. Immune-modulating therapies have been introduced to treatment regimens for malignancies with metastatic predilection to the br...

    journal_title:Cancer immunology research

    pub_type: 杂志文章

    doi:10.1158/2326-6066.CIR-15-0238

    authors: Alomari AK,Cohen J,Vortmeyer AO,Chiang A,Gettinger S,Goldberg S,Kluger HM,Chiang VL

    更新日期:2016-06-01 00:00:00

  • Pathogen-driven cancers and emerging immune therapeutic strategies.

    abstract::Infectious agents play an etiologic role in approximately 20% of cancer cases worldwide. Eleven pathogens (seven viruses, three parasites, and one bacterium) are known to contribute to oncogenesis either directly via the expression of their protein products or indirectly via chronic inflammation. Although prevention o...

    journal_title:Cancer immunology research

    pub_type: 杂志文章,评审

    doi:10.1158/2326-6066.CIR-13-0179

    authors: Vandeven N,Nghiem P

    更新日期:2014-01-01 00:00:00

  • The Antigen ASB4 on Cancer Stem Cells Serves as a Target for CTL Immunotherapy of Colorectal Cancer.

    abstract::Colorectal cancer consists of a small number of cancer stem cells (CSC) and many non-CSCs. Although rare in number, CSCs are a target for cancer therapy, because they survive conventional chemo- and radiotherapies and perpetuate tumor formation in vivo In this study, we conducted an HLA ligandome analysis to survey HL...

    journal_title:Cancer immunology research

    pub_type: 杂志文章

    doi:10.1158/2326-6066.CIR-17-0518

    authors: Miyamoto S,Kochin V,Kanaseki T,Hongo A,Tokita S,Kikuchi Y,Takaya A,Hirohashi Y,Tsukahara T,Terui T,Ishitani K,Hata F,Takemasa I,Miyazaki A,Hiratsuka H,Sato N,Torigoe T

    更新日期:2018-03-01 00:00:00

  • Tumor Cell-Intrinsic USP22 Suppresses Antitumor Immunity in Pancreatic Cancer.

    abstract::Although immune checkpoint blockade (ICB) improves clinical outcome in several types of malignancies, pancreatic ductal adenocarcinoma (PDA) remains refractory to this therapy. Preclinical studies have demonstrated that the relative abundance of suppressive myeloid cells versus cytotoxic T cells determines the efficac...

    journal_title:Cancer immunology research

    pub_type: 杂志文章

    doi:10.1158/2326-6066.CIR-19-0661

    authors: Li J,Yuan S,Norgard RJ,Yan F,Yamazoe T,Blanco A,Stanger BZ

    更新日期:2020-03-01 00:00:00

  • Insights into Tumor-Associated Tertiary Lymphoid Structures: Novel Targets for Antitumor Immunity and Cancer Immunotherapy.

    abstract::Tertiary lymphoid structures (TLS) are ectopic lymphoid aggregates that phenotypically resemble conventional secondary lymphoid organs and are commonly found at sites of chronic inflammation. They are also found in a wide variety of primary and metastatic human tumors. The presence of tumor-associated TLS (TA-TLS) is ...

    journal_title:Cancer immunology research

    pub_type: 杂志文章,评审

    doi:10.1158/2326-6066.CIR-20-0432

    authors: Rodriguez AB,Engelhard VH

    更新日期:2020-11-01 00:00:00

  • Durable Clinical Benefit in Metastatic Renal Cell Carcinoma Patients Who Discontinue PD-1/PD-L1 Therapy for Immune-Related Adverse Events.

    abstract::The current standard of care for treatment of metastatic renal cell carcinoma (mRCC) patients is PD-1/PD-L1 inhibitors until progression or toxicity. Here, we characterize the clinical outcomes for 19 mRCC patients who experienced an initial clinical response (any degree of tumor shrinkage), but after immune-related a...

    journal_title:Cancer immunology research

    pub_type: 杂志文章

    doi:10.1158/2326-6066.CIR-17-0220

    authors: Martini DJ,Hamieh L,McKay RR,Harshman LC,Brandao R,Norton CK,Steinharter JA,Krajewski KM,Gao X,Schutz FA,McGregor B,Bossé D,Lalani AA,De Velasco G,Michaelson MD,McDermott DF,Choueiri TK

    更新日期:2018-04-01 00:00:00

  • The Clinical Activity of PD-1/PD-L1 Inhibitors in Metastatic Non-Clear Cell Renal Cell Carcinoma.

    abstract::Programmed death 1 (PD-1) and PD ligand 1 (PD-L1) inhibitors have shown activity in metastatic clear cell renal cell carcinoma (ccRCC). Data on the activity of these agents in patients with non-clear cell RCC (nccRCC) or patients with sarcomatoid/rhabdoid differentiation are limited. In this multicenter analysis, we e...

    journal_title:Cancer immunology research

    pub_type: 杂志文章,多中心研究

    doi:10.1158/2326-6066.CIR-17-0475

    authors: McKay RR,Bossé D,Xie W,Wankowicz SAM,Flaifel A,Brandao R,Lalani AA,Martini DJ,Wei XX,Braun DA,Van Allen E,Castellano D,De Velasco G,Wells JC,Heng DY,Fay AP,Schutz FA,Hsu J,Pal SK,Lee JL,Hsieh JJ,Harshman LC,Si

    更新日期:2018-07-01 00:00:00

  • Cancer-testis antigen expression in digestive tract carcinomas: frequent expression in esophageal squamous cell carcinoma and its precursor lesions.

    abstract::Cancer-testis (CT) antigens are attractive tumor antigens for cancer immunotherapy. They comprise a group of proteins normally expressed in germ cells and aberrantly activated in a variety of human cancers. The protein expression of eight cancer-testis antigens [MAGEA, NY-ESO-1, GAGE, MAGEC1 (CT7), MAGEC2 (CT10), CT45...

    journal_title:Cancer immunology research

    pub_type: 杂志文章

    doi:10.1158/2326-6066.CIR-13-0124

    authors: Chen YT,Panarelli NC,Piotti KC,Yantiss RK

    更新日期:2014-05-01 00:00:00

  • Integration of Oncogenes via Sleeping Beauty as a Mouse Model of HPV16+ Oral Tumors and Immunologic Control.

    abstract::Human papillomavirus type 16 (HPV16) is the etiologic factor for cervical cancer and a subset of oropharyngeal cancers. Although several prophylactic HPV vaccines are available, no effective therapeutic strategies to control active HPV diseases exist. Tumor implantation models are traditionally used to study HPV-assoc...

    journal_title:Cancer immunology research

    pub_type: 杂志文章

    doi:10.1158/2326-6066.CIR-16-0358

    authors: Lin YH,Yang MC,Tseng SH,Jiang R,Yang A,Farmer E,Peng S,Henkle T,Chang YN,Hung CF,Wu TC

    更新日期:2018-03-01 00:00:00

  • Adenovirus Improves the Efficacy of Adoptive T-cell Therapy by Recruiting Immune Cells to and Promoting Their Activity at the Tumor.

    abstract::Despite the rapid progress in the development of novel adoptive T-cell therapies, the clinical benefits in treatment of established tumors have remained modest. Several immune evasion mechanisms hinder T-cell entry into tumors and their activity within the tumor. Of note, oncolytic adenoviruses are intrinsically immun...

    journal_title:Cancer immunology research

    pub_type: 杂志文章

    doi:10.1158/2326-6066.CIR-14-0220-T

    authors: Tähtinen S,Grönberg-Vähä-Koskela S,Lumen D,Merisalo-Soikkeli M,Siurala M,Airaksinen AJ,Vähä-Koskela M,Hemminki A

    更新日期:2015-08-01 00:00:00

  • Constitutive IDO1 Expression in Human Tumors Is Driven by Cyclooxygenase-2 and Mediates Intrinsic Immune Resistance.

    abstract::Tumors use various mechanisms to avoid immune destruction. Cyclooxygenase-2 (COX-2) expression may be a driver of immune suppression in melanoma, but the mechanisms involved remain elusive. Here, we show that COX-2 expression drives constitutive expression of indoleamine 2,3-dioxygenase 1 (IDO1) in human tumor cells. ...

    journal_title:Cancer immunology research

    pub_type: 杂志文章

    doi:10.1158/2326-6066.CIR-16-0400

    authors: Hennequart M,Pilotte L,Cane S,Hoffmann D,Stroobant V,Plaen E,Van den Eynde BJ

    更新日期:2017-08-01 00:00:00

  • Increasing Tumor-Infiltrating T Cells through Inhibition of CXCL12 with NOX-A12 Synergizes with PD-1 Blockade.

    abstract::Immune checkpoint inhibitors promote T cell-mediated killing of cancer cells; however, only a subset of patients benefit from the treatment. A possible reason for this limitation may be that the tumor microenvironment (TME) is immune privileged, which may exclude cytotoxic T cells from the vicinity of cancer cells. Th...

    journal_title:Cancer immunology research

    pub_type: 杂志文章

    doi:10.1158/2326-6066.CIR-16-0303

    authors: Zboralski D,Hoehlig K,Eulberg D,Frömming A,Vater A

    更新日期:2017-11-01 00:00:00

  • IL15 Infusion of Cancer Patients Expands the Subpopulation of Cytotoxic CD56bright NK Cells and Increases NK-Cell Cytokine Release Capabilities.

    abstract::The cytokine IL15 is required for survival and activation of natural killer (NK) cells as well as expansion of NK-cell populations. Here, we compare the effects of continuous IL15 infusions on NK-cell subpopulations in cancer patients. Infusions affected the CD56bright NK-cell subpopulation in that the expansion rates...

    journal_title:Cancer immunology research

    pub_type: 杂志文章

    doi:10.1158/2326-6066.CIR-17-0279

    authors: Dubois S,Conlon KC,Müller JR,Hsu-Albert J,Beltran N,Bryant BR,Waldmann TA

    更新日期:2017-10-01 00:00:00

  • An RNA Aptamer-Based Biomarker Platform Demonstrates High Soluble CD25 Occupancy by IL2 in the Serum of Follicular Lymphoma Patients.

    abstract::Ligand-receptor complexes play a central role in mediating a range of processes in immunology and cancer biology. The ability to directly quantify the fraction of receptors occupied by a ligand in a given biospecimen, as opposed to assessing the concentration of ligand and receptor separately, could provide an additio...

    journal_title:Cancer immunology research

    pub_type: 杂志文章

    doi:10.1158/2326-6066.CIR-18-0821

    authors: Veeramani S,Blackwell SE,Thiel WH,Yang ZZ,Ansell SM,Giangrande PH,Weiner GJ

    更新日期:2019-09-01 00:00:00

  • CCR2-Dependent Recruitment of Tregs and Monocytes Following Radiotherapy Is Associated with TNFα-Mediated Resistance.

    abstract::Radiotherapy (RT) represents one of the main anticancer approaches for the treatment of solid tumors. Beyond the expected direct effects of RT on tumor cells, evidence supporting the importance of an immune response to RT is growing. The balance between RT-mediated immunogenic and tolerogenic activity is ill-defined a...

    journal_title:Cancer immunology research

    pub_type: 杂志文章

    doi:10.1158/2326-6066.CIR-18-0633

    authors: Mondini M,Loyher PL,Hamon P,Gerbé de Thoré M,Laviron M,Berthelot K,Clémenson C,Salomon BL,Combadière C,Deutsch E,Boissonnas A

    更新日期:2019-03-01 00:00:00

  • Somatic Mutations and Neoepitope Homology in Melanomas Treated with CTLA-4 Blockade.

    abstract::Immune checkpoint inhibitors are promising treatments for patients with a variety of malignancies. Toward understanding the determinants of response to immune checkpoint inhibitors, it was previously demonstrated that the presence of somatic mutations is associated with benefit from checkpoint inhibition. A hypothesis...

    journal_title:Cancer immunology research

    pub_type: 杂志文章

    doi:10.1158/2326-6066.CIR-16-0019

    authors: Nathanson T,Ahuja A,Rubinsteyn A,Aksoy BA,Hellmann MD,Miao D,Van Allen E,Merghoub T,Wolchok JD,Snyder A,Hammerbacher J

    更新日期:2017-01-01 00:00:00

  • Dietary Consumption of Black Raspberries or Their Anthocyanin Constituents Alters Innate Immune Cell Trafficking in Esophageal Cancer.

    abstract::Freeze-dried black raspberries (BRB), their component anthocyanins (AC), and a metabolite of BRB ACs, protocatechuic acid (PCA), inhibit the development of esophageal cancer in rats induced by the carcinogen, N-nitrosomethylbenzylamine (NMBA). All three components reduce inflammation in the esophagus and in plasma. Th...

    journal_title:Cancer immunology research

    pub_type: 杂志文章

    doi:10.1158/2326-6066.CIR-15-0091

    authors: Peiffer DS,Wang LS,Zimmerman NP,Ransom BW,Carmella SG,Kuo CT,Chen JH,Oshima K,Huang YW,Hecht SS,Stoner GD

    更新日期:2016-01-01 00:00:00

  • Tumor MHC class I expression improves the prognostic value of T-cell density in resected colorectal liver metastases.

    abstract::Tumor-infiltrating lymphocytes (TIL) in colorectal cancer liver metastases (CLM) have been associated with more favorable patient outcomes, but whether MHC class I (MHC-I) expression on cancer cells affects prognosis is uncertain. Immunohistochemistry was performed on a tissue microarray of 158 patients with CLM, who ...

    journal_title:Cancer immunology research

    pub_type: 杂志文章

    doi:10.1158/2326-6066.CIR-13-0180

    authors: Turcotte S,Katz SC,Shia J,Jarnagin WR,Kingham TP,Allen PJ,Fong Y,D'Angelica MI,DeMatteo RP

    更新日期:2014-06-01 00:00:00

  • Environmental and Genetic Activation of Hypothalamic BDNF Modulates T-cell Immunity to Exert an Anticancer Phenotype.

    abstract::Macroenvironmental factors, including a patient's physical and social environment, play a role in cancer risk and progression. Our previous studies show that living in an enriched environment (EE) providing complex stimuli confers an anticancer phenotype in mice mediated, in part by a specific neuroendocrine axis, wit...

    journal_title:Cancer immunology research

    pub_type: 杂志文章

    doi:10.1158/2326-6066.CIR-15-0297

    authors: Xiao R,Bergin SM,Huang W,Slater AM,Liu X,Judd RT,Lin ED,Widstrom KJ,Scoville SD,Yu J,Caligiuri MA,Cao L

    更新日期:2016-06-01 00:00:00

  • T Cells Specific for an Unconventional Natural Antigen Fail to Recognize Leukemic Cells.

    abstract::MHC-bound peptides from aberrant proteins may be a specific immunotherapeutic target on cancer cells. Because of difficulties in identifying such antigens, viral or model antigens have so far been used to study their biological relevance. We here identify a naturally existing human T-cell epitope derived from a trunca...

    journal_title:Cancer immunology research

    pub_type: 杂志文章

    doi:10.1158/2326-6066.CIR-18-0137

    authors: Pont MJ,Oostvogels R,van Bergen CAM,van der Meijden ED,Honders MW,Bliss S,Jongsma MLM,Lokhorst HM,Falkenburg JHF,Mutis T,Griffioen M,Spaapen RM

    更新日期:2019-05-01 00:00:00

  • Translating Science into Survival: Report on the Second International Cancer Immunotherapy Conference.

    abstract::On September 25-28, 2016, in New York City, the Second International Cancer Immunotherapy Conference was cohosted by the Cancer Research Institute, the American Association for Cancer Research, the Association for Cancer Immunotherapy, and the European Academy of Tumor Immunology. This exciting conference brought toge...

    journal_title:Cancer immunology research

    pub_type:

    doi:10.1158/2326-6066.CIR-16-0276

    authors: Brodsky AN,Hubbard-Lucey VM

    更新日期:2016-12-01 00:00:00

  • Improved Antitumor Efficacy of Chimeric Antigen Receptor T Cells that Secrete Single-Domain Antibody Fragments.

    abstract::Chimeric antigen receptor (CAR) T-cell therapy is effective in the treatment of cancers of hematopoietic origin. In the immunosuppressive solid tumor environment, CAR T cells encounter obstacles that compromise their efficacy. We developed a strategy to address these barriers by having CAR T cells secrete single-domai...

    journal_title:Cancer immunology research

    pub_type: 杂志文章

    doi:10.1158/2326-6066.CIR-19-0734

    authors: Xie YJ,Dougan M,Ingram JR,Pishesha N,Fang T,Momin N,Ploegh HL

    更新日期:2020-04-01 00:00:00

  • Systemic GM-CSF Recruits Effector T Cells into the Tumor Microenvironment in Localized Prostate Cancer.

    abstract::Granulocytic-macrophage colony-stimulating factor (GM-CSF) is used as an adjuvant in cancer vaccine trials and has the potential to enhance antitumor efficacy with immunotherapy; however, its immunologic effects are not fully understood. Here, we report results from a phase I study of neoadjuvant GM-CSF in patients wi...

    journal_title:Cancer immunology research

    pub_type: 杂志文章

    doi:10.1158/2326-6066.CIR-16-0042

    authors: Wei XX,Chan S,Kwek S,Lewis J,Dao V,Zhang L,Cooperberg MR,Ryan CJ,Lin AM,Friedlander TW,Rini B,Kane C,Simko JP,Carroll PR,Small EJ,Fong L

    更新日期:2016-11-01 00:00:00

  • Combination of CD40 Agonism and CSF-1R Blockade Reconditions Tumor-Associated Macrophages and Drives Potent Antitumor Immunity.

    abstract::Efficacious antitumor immune responses must overcome multiple suppressive mechanisms in the tumor microenvironment to control cancer progression. In this study, we demonstrate that dual targeting of suppressive myeloid populations by inhibiting CSF-1/CSF-1R signaling and activation of antigen-presenting cells with ago...

    journal_title:Cancer immunology research

    pub_type: 杂志文章

    doi:10.1158/2326-6066.CIR-17-0258

    authors: Wiehagen KR,Girgis NM,Yamada DH,Smith AA,Chan SR,Grewal IS,Quigley M,Verona RI

    更新日期:2017-12-01 00:00:00

  • Untreated stage IV melanoma patients exhibit abnormal monocyte phenotypes and decreased functional capacity.

    abstract::Monocytes may contribute to tumor progression in part by mediating tumor-induced immunosuppression. Alterations to the monocyte populations and functions in untreated patients with late-stage melanoma are not fully understood. To characterize these alterations, we compared the frequency, phenotype, and functional capa...

    journal_title:Cancer immunology research

    pub_type: 杂志文章

    doi:10.1158/2326-6066.CIR-13-0094

    authors: Chavan R,Salvador D,Gustafson MP,Dietz AB,Nevala W,Markovic SN

    更新日期:2014-03-01 00:00:00

  • Quantification of Early-Stage Myeloid-Derived Suppressor Cells in Cancer Requires Excluding Basophils.

    abstract::Myeloid derived suppressor cells (MDSC) are a heterogeneous group of immature cells that accumulate in the peripheral blood and tumor microenvironment and are barriers to cancer therapy. MDSCs serve as prognostic biomarkers and are targets for therapy. On the basis of surface markers, three subsets of MDSCs have been ...

    journal_title:Cancer immunology research

    pub_type: 杂志文章

    doi:10.1158/2326-6066.CIR-19-0556

    authors: Khan ANH,Emmons TR,Wong JT,Alqassim E,Singel KL,Mark J,Smith BE,Tario JD,Eng KH,Moysich KB,Odunsi K,Abrams SI,Segal BH

    更新日期:2020-06-01 00:00:00

  • Concurrent radiotherapy and ipilimumab immunotherapy for patients with melanoma.

    abstract::Ipilimumab and radiotherapy are commonly used to treat unresectable and metastatic melanoma. Results from preclinical studies and case reports suggest a biologic interaction between these two treatments. To understand the clinical implications of the interaction, we carried out a retrospective study reviewing records ...

    journal_title:Cancer immunology research

    pub_type: 杂志文章,评审

    doi:10.1158/2326-6066.CIR-13-0082

    authors: Barker CA,Postow MA,Khan SA,Beal K,Parhar PK,Yamada Y,Lee NY,Wolchok JD

    更新日期:2013-08-01 00:00:00

  • NK Cells Expressing a Chimeric Activating Receptor Eliminate MDSCs and Rescue Impaired CAR-T Cell Activity against Solid Tumors.

    abstract::Solid tumors are refractory to cellular immunotherapies in part because they contain suppressive immune effectors such as myeloid-derived suppressor cells (MDSCs) that inhibit cytotoxic lymphocytes. Strategies to reverse the suppressive tumor microenvironment (TME) should also attract and activate immune effectors wit...

    journal_title:Cancer immunology research

    pub_type: 杂志文章

    doi:10.1158/2326-6066.CIR-18-0572

    authors: Parihar R,Rivas C,Huynh M,Omer B,Lapteva N,Metelitsa LS,Gottschalk SM,Rooney CM

    更新日期:2019-03-01 00:00:00

  • Disruption of IFN-I Signaling Promotes HER2/Neu Tumor Progression and Breast Cancer Stem Cells.

    abstract::Type I interferon (IFN-I) is a class of antiviral immunomodulatory cytokines involved in many stages of tumor initiation and progression. IFN-I acts directly on tumor cells to inhibit cell growth and indirectly by activating immune cells to mount antitumor responses. To understand the role of endogenous IFN-I in spont...

    journal_title:Cancer immunology research

    pub_type: 杂志文章

    doi:10.1158/2326-6066.CIR-17-0675

    authors: Castiello L,Sestili P,Schiavoni G,Dattilo R,Monque DM,Ciaffoni F,Iezzi M,Lamolinara A,Sistigu A,Moschella F,Pacca AM,Macchia D,Ferrantini M,Zeuner A,Biffoni M,Proietti E,Belardelli F,Aricò E

    更新日期:2018-06-01 00:00:00

  • Subacute CNS Demyelination after Treatment with Nivolumab for Melanoma.

    abstract::Immunotherapy with monoclonal antibodies targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4) or programmed cell death 1 (PD-1) has improved the survival of patients with metastatic melanoma. These agents carry a certain risk of adverse immune-related events. We present a patient with widely metastatic melanoma who was...

    journal_title:Cancer immunology research

    pub_type: 杂志文章

    doi:10.1158/2326-6066.CIR-15-0141

    authors: Maurice C,Schneider R,Kiehl TR,Bavi P,Roehrl MH,Mason WP,Hogg D

    更新日期:2015-12-01 00:00:00