Journal Articles

Tumor micro-environment

Composition, function and interactions of the tumor immune environment and strategies to modulate the tumor immune environment; Immune biomarkers

Modulating Tumor Immunology by Inhibiting Indoleamine 2,3-Dioxygenase (IDO): Recent Developments and First Clinical Experiences

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Indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) catalyze the first rate-limiting step in the oxidative metabolism of compounds containing indole rings, including the transformation of the essential amino acid L-tryptophan to N-formyl-L-kynurenine. Through direct and indirect means, IDO exerts both tolerogenic and pro-inflammatory effects and has a profound immunoregulatory role in the tumor microenvironment. Although the role of IDO in mediating peripheral acquired immunologic tolerance has been known for some time, its role in tumorigenesis and the subversion of anti-tumor immunity have only recently been appreciated. Small-molecule inhibitors of IDO1 and TDO are being evaluated as single agents and in combination with immune checkpoint blockade in a host of advanced cancers. In this review, we delineate the tolerogenic and pro-inflammatory effects of IDO as it relates to immune escape and discuss current clinical progress in this area.

Author Info: (1) Department of Medicine, Division of Hematology-Oncology, University of Pittsburgh Medical Center, 5117 Centre Avenue, Pittsburgh, PA, 15232, USA. (2) Department of Medicine, Division of

Author Info: (1) Department of Medicine, Division of Hematology-Oncology, University of Pittsburgh Medical Center, 5117 Centre Avenue, Pittsburgh, PA, 15232, USA. (2) Department of Medicine, Division of Hematology-Oncology, University of Pittsburgh Medical Center, 5117 Centre Avenue, Pittsburgh, PA, 15232, USA. baharyn@upmc.edu.

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Bevacizumab-mediated tumor vasculature remodelling improves tumor infiltration and antitumor efficacy of GD2-CAR T cells in a human neuroblastoma preclinical model

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GD2-redirected chimeric antigen receptor (CAR) T lymphocytes represent a promising therapeutic option for immunotherapy of neuroblastoma (NB). However, despite the encouraging therapeutic effects observed in some hematological malignancies, clinical results of CAR T cell immunotherapy in solid tumors are still modest. Tumor driven neo-angiogenesis supports an immunosuppressive microenvironment that influences treatment responses and is amenable to targeting with antiangiogenic drugs. The latter agents promote lymphocyte tumor infiltration by transiently reprogramming tumor vasculature, and may represent a valid combinatorial approach with CAR T cell immunotherapy. In light of these considerations, we investigated the anti-NB activity of GD2-CAR T cells combined with bevacizumab (BEV) in an orthotopic xenograft model of human NB. Two weeks after tumor implantation, mice received BEV or GD2-CAR T cells or both by single intravenous administration. GD2-CAR T cells exerted a significant anti-NB activity only in combination with BEV, even at the lowest concentration tested, which per se did not inhibit tumor growth. When combined with BEV, GD2-CAR T cells massively infiltrated tumor mass where they produced interferon-gamma (IFN-gamma), which, in turn, induced expression of CXCL10 by NB cells. IFN-gamma, and possibly other cytokines, upregulated NB cell expression of PD-L1, while tumor infiltrating GD2-CAR T cells expressed PD-1. Thus, the PD-1/PD-L1 axis can limit the anti-tumor efficacy of the GD2-CAR T cell/BEV association. This study provides a strong rationale for testing the combination of GD2-CAR T cells with BEV in a clinical trial enrolling NB patients. PD-L1 silencing or blocking strategies may further enhance the efficacy of such combination.

Author Info: (1) Laboratory of Oncology, Dep. of Translational Research, IRCCS Istituto G. Gaslini, Genova, Italy. (2) Anatomic Pathology and Molecular Medicine, Dep. of Medicine and Sciences

Author Info: (1) Laboratory of Oncology, Dep. of Translational Research, IRCCS Istituto G. Gaslini, Genova, Italy. (2) Anatomic Pathology and Molecular Medicine, Dep. of Medicine and Sciences of Aging, "G. d'Annunzio" University, Chieti, Italy. Ce. S. I.-MeT, Aging Research Center, Pathological Anatomy and Immuno-Oncology Unit, "G. d'Annunzio" University, Chieti, Italy. (3) Laboratory of Cell and Gene Therapy of Pediatric Tumors, Dep. of Hematology/Oncology, IRCCS Ospedale Pediatrico Bambino Gesu, Roma, Italy. (4) S.S.D. Animal Facility, Ospedale Policlinico San Martino, IRCCS per l'Oncologia, Genova, Italy. (5) S.S.D. Animal Facility, Ospedale Policlinico San Martino, IRCCS per l'Oncologia, Genova, Italy. (6) Laboratory of Cell and Gene Therapy of Pediatric Tumors, Dep. of Hematology/Oncology, IRCCS Ospedale Pediatrico Bambino Gesu, Roma, Italy. (7) Laboratory of Cell and Gene Therapy of Pediatric Tumors, Dep. of Hematology/Oncology, IRCCS Ospedale Pediatrico Bambino Gesu, Roma, Italy. Dipartimento di Medicina Clinica e Chirurgia, Universita degli Studi di Napoli Federico II, Napoli, Italy. (8) Laboratory of Oncology, Dep. of Translational Research, IRCCS Istituto G. Gaslini, Genova, Italy. (9) Laboratory of Oncology, Dep. of Translational Research, IRCCS Istituto G. Gaslini, Genova, Italy. (10) Laboratory of Oncology, Dep. of Translational Research, IRCCS Istituto G. Gaslini, Genova, Italy. (11) Laboratory of Cell and Gene Therapy of Pediatric Tumors, Dep. of Hematology/Oncology, IRCCS Ospedale Pediatrico Bambino Gesu, Roma, Italy. Department of Pediatrics, Universita di Pavia, Pavia, Italy. (12) Immunology Area, IRCCS Ospedale Pediatrico Bambino Gesu, Roma, Italy. (13) Laboratory of Oncology, Dep. of Translational Research, IRCCS Istituto G. Gaslini, Genova, Italy.

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Mutation load and an effector T-cell gene signature may distinguish immunologically distinct and clinically relevant lymphoma subsets

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Identifying follicular lymphoma (FL) patients with preexisting antitumor immunity will inform precision medicine strategies for novel cancer immunotherapies. Using clinical and genomic data from 249 FL patients, we determined the clinical impact of mutation load and an effector T-cell (Teff) gene signature as proxies for the likelihood of a functional immune response. The FL mutation load estimate varied between 0 and 33 mutations per Mb (median, 6.6), and 92% of FL patients with a high mutation load had high Teff gene expression (P = .001). The mutation load was associated with a benefit from rituximab maintenance: FL patients with low mutation loads experienced a profound benefit from rituximab maintenance (hazard ratio [HR], 0.29; 95% confidence interval [CI], 0.15-0.54; P < .001). The Teff gene signature was prognostic as a continuous predictor (P = .008), and was used to separate FL patients into 2 groups, an "inflamed" subset (Teff-high; n = 74) and an "uninflamed" subset (Teff-low; n = 75), with longer progression-free survival (PFS) in the inflamed FL subset (PFS HR, 0.39; 95% CI, 0.21-0.70; P = .002). Furthermore, the subset of inflamed FL tumors demonstrated high expression of other T-cell signatures and counterregulatory genes, which also correlate with PFS. Mutation load and Teff gene expression may help identify immunologically distinct lymphoma subsets relevant for modern immunotherapies.

Author Info: (1) Bioinformatics and. (2) Oncology Biomarker Development, Genentech, South San Francisco, CA. (3) Laboratory of Hematology, Lyon-Sud Hospital Center, Pierre-Benite, France. Cancer Research Center of

Author Info: (1) Bioinformatics and. (2) Oncology Biomarker Development, Genentech, South San Francisco, CA. (3) Laboratory of Hematology, Lyon-Sud Hospital Center, Pierre-Benite, France. Cancer Research Center of Lyon, INSERM U1052, Unite Mixte de Recherche Centre National de la Recherche Scientifique 5286, Lyon, France. (4) Foundation Medicine, Inc, Cambridge, MA. (5) Bioinformatics and. (6) Henri Becquerel Center, Rouen, France. (7) Gustave Roussy Institute, Villejuif, France; and. (8) Oncology Biomarker Development, Genentech, South San Francisco, CA. (9) Oncology Biomarker Development, Genentech, South San Francisco, CA. (10) Department of Bio-Pathology, Hematology, and Tumor Immunology, and. Paoli-Calmettes Institute, Aix-Marseille University, Marseille, France. (11) Laboratory of Hematology, Lyon-Sud Hospital Center, Pierre-Benite, France. Cancer Research Center of Lyon, INSERM U1052, Unite Mixte de Recherche Centre National de la Recherche Scientifique 5286, Lyon, France. (12) Laboratory of Hematology, Lyon-Sud Hospital Center, Pierre-Benite, France. Cancer Research Center of Lyon, INSERM U1052, Unite Mixte de Recherche Centre National de la Recherche Scientifique 5286, Lyon, France. (13) Oncology Biomarker Development, Genentech, South San Francisco, CA.

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Immunotherapy for glioblastoma: on the sidelines or in the game

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The successful eradication of multiple tumor types, often in a durable manner, has recently validated the bona fide potential of an effectively mobilized immune response as a cancer therapy. Critical questions at present, therefore, include deciphering why some patients respond while others do not, as well as why certain cancers respond while others like glioblastoma do not. Glioblastoma remains a major unmet need in medical oncology and is considered incurable with less than 10% of patients surviving five years from diagnosis. Hallmark phenotypic features of glioblastoma including aberrantly activated cell proliferation, survival, invasion, angiogenesis, and treatment resistance are linked with multiple adaptive and supportive mechanisms culminating in formidable heterogeneity across and within individual tumors. Similarly, the complex adaptive abilities of glioblastoma tumors to abrogate anti-tumor immune responses are multifaceted yet integrated. Not unexpectedly, results of recent advanced clinical trials with single-agent immunotherapeutics for glioblastoma have been negative although some early stage studies and anecdotal cases have generated encouraging results. The application of immunotherapies for glioblastoma currently finds itself therefore at a pivotal crossroads. Critical to mapping a path forward will be the systematic characterization of the immunobiology of glioblastoma tumors utilizing currently available, state of the art technologies. Therapeutic approaches aimed at driving effector immune cells into the glioblastoma microenvironment as well as overcoming immunosuppressive myeloid cells, physical factors, and cytokines, as well as limiting the potentially detrimental, iatrogenic impact of dexamethasone, will likely be required for the potential of anti-tumor immune responses to be realized for glioblastoma.

Author Info: (1) Center of Neuro-Oncology, Dana-Farber/Brigham and Women's Cancer Center, Boston, MA 02215, USA. Department of Medical Oncology, Dana-Farber/Brigham and Women's Cancer Center, Boston, MA 02215

Author Info: (1) Center of Neuro-Oncology, Dana-Farber/Brigham and Women's Cancer Center, Boston, MA 02215, USA. Department of Medical Oncology, Dana-Farber/Brigham and Women's Cancer Center, Boston, MA 02215, USA. (2) Department of Cancer Immunology and Virology, Dana-Farber/Brigham and Women's Cancer Center, Boston, MA 02215, USA. (3) Department of Neurosurgery, Dana-Farber/Brigham and Women's Cancer Center, Boston, MA 02215, USA.

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Immunogenic and Non-immunogenic Cell Death in the Tumor Microenvironment

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The host immune system is continuously exposed to dying cells and has evolved to distinguish between cell death events signaling potential threats and physiological apoptosis that should be tolerated. Tumors can use this distinction to their advantage, promoting apoptotic death of cancer cells to induce tolerance and evasion of immunosurveillance. On the other hand, stimuli that cause immunogenic death of cancer cells can induce an effective anti-tumor immune response. In this chapter we discuss different forms of cell death in the tumor microenvironment, and how these interact with host immune cells to impact tumor progression and cancer therapy. We focus on how cancer cells hijack aspects of cell death to promote tumor survival, and how anti-cancer treatments that activate immunogenic death modalities give strong and durable clinical efficacy.

Author Info: (1) Gustave Roussy Cancer Campus, Villejuif, Cedex, France. INSERM U1015, Villejuif, France. Faculte de Medecine, Universite Paris Sud-XI, Le Kremlin Bicetre, France. (2) Gustave Roussy

Author Info: (1) Gustave Roussy Cancer Campus, Villejuif, Cedex, France. INSERM U1015, Villejuif, France. Faculte de Medecine, Universite Paris Sud-XI, Le Kremlin Bicetre, France. (2) Gustave Roussy Cancer Campus, Villejuif, Cedex, France. INSERM U848, Villejuif, France. Metabolomics Platform, Institut Gustave Roussy, Villejuif, France. Equipe 11 labellisee Ligue contre le Cancer, Centre de Recherche des Cordeliers, Paris, France. Pole de Biologie, Hopital Europeen Georges Pompidou, AP-HP, Paris, France. Universite Paris Descartes-V, Sorbonne Paris Cite, Paris, France. (3) Gustave Roussy Cancer Campus, Villejuif, Cedex, France. laurence.zitvogel@gustaveroussy.fr. INSERM U1015, Villejuif, France. laurence.zitvogel@gustaveroussy.fr. Faculte de Medecine, Universite Paris Sud-XI, Le Kremlin Bicetre, France. laurence.zitvogel@gustaveroussy.fr. Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 1428, Villejuif, France. laurence.zitvogel@gustaveroussy.fr.

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The Role of Tumor Microenvironment in Cancer Immunotherapy

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The field of tumor immunology and immunotherapy has undergone a renaissance in the past decade do in large part to a better understanding of the tumor immune microenvironment. After suffering countless successes and setbacks in the twentieth century, immunotherapy has now come to the forefront of cancer research and is recognized as an important tool in the anti-tumor armamentarium. The goal of therapy is to aid the immune system in recognition and destruction of tumor cells by enhancing its ability to react to tumor antigens. This traditionally has been accomplished by induction of adaptive immunity through vaccination or through passive delivery of immunologic effectors as in the case of adoptive cell transfer. The recent discovery of immune "checkpoints" whose purpose is to suppress immune activity and prevent auto-immunity has created a new angle by which reactivity to tumors can be enhanced. Blockers of these checkpoints have yielded impressive clinical results and have recently been approved for use in a wide variety of malignancies. With data showing increasing rates of not only treatment response, but complete remissions, immunotherapy is poised to become an increasingly utilized therapy in the treatment of cancer.

Author Info: (1) Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA. Graduate Programs in Immunology and Tumor Biology, University of Michigan, Ann

Author Info: (1) Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA. Graduate Programs in Immunology and Tumor Biology, University of Michigan, Ann Arbor, MI, USA. (2) Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA. Graduate Programs in Immunology and Tumor Biology, University of Michigan, Ann Arbor, MI, USA. (3) Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA. wzou@med.umich.edu. Graduate Programs in Immunology and Tumor Biology, University of Michigan, Ann Arbor, MI, USA. wzou@med.umich.edu. The University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA. wzou@med.umich.edu.

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Regulation of CTL Infiltration Within the Tumor Microenvironment

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The tumor microenvironment consists of a complex milieu of cells and factors that maintain equilibrium between tumor progression and destruction. Characterization of the immune contexture in primary tumors has consistently shown that T lymphocytes are an integral predictor of improved clinical outcome. This is notably true in colorectal carcinoma where high densities of cytotoxic or memory T lymphocytes in the invasive margin and the center of the primary tumor predict better patient survival, a measure termed Immunoscore. Since a high Immunoscore and pre-existing adaptive immune response are significantly correlated with improved clinical outcome, it is essential to understand the mechanisms underlying functional T lymphocyte infiltration into the tumor. The ability of cytolytic and memory T lymphocytes to migrate into tumors is regulated by multiple strategies including T lymphocyte help, homing factors, cytokines, tumor genotype, angiogenesis, lymphangiogenesis, and neurological signals. This chapter will discuss the predominant factors that mediate T-lymphocyte infiltration into tumors and how analysis of these biomarkers determine patients' disease-related survival and predicts response to cancer therapy.

Author Info: (1) Laboratory of Integrative Cancer Immunology, INSERM, UMRS1138, 15 Rue de l'Ecole de Medecine, Paris, France. church.immunology@gmail.com. Universite Paris Descartes, Paris, France. church.immunology@gmail.com. Cordeliers Research

Author Info: (1) Laboratory of Integrative Cancer Immunology, INSERM, UMRS1138, 15 Rue de l'Ecole de Medecine, Paris, France. church.immunology@gmail.com. Universite Paris Descartes, Paris, France. church.immunology@gmail.com. Cordeliers Research Centre, Universite Pierre et Marie Curie Paris 6, Paris, France. church.immunology@gmail.com. (2) Laboratory of Integrative Cancer Immunology, INSERM, UMRS1138, 15 Rue de l'Ecole de Medecine, Paris, France. Universite Paris Descartes, Paris, France. Cordeliers Research Centre, Universite Pierre et Marie Curie Paris 6, Paris, France.

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Cancer Immunotherapy Targets Based on Understanding the T Cell-Inflamed Versus Non-T Cell-Inflamed Tumor Microenvironment

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Most cancers express tumor antigens that can be recognized by T cells of the host. The fact that cancers become clinically evident nonetheless implies that immune escape must occur. Two major subsets of human melanoma metastases have been identified based on gene expression profiling. One subgroup has a T cell-inflamed phenotype that includes expression of chemokines, T cell markers, and a type I IFN signature. In contrast, the other major subset lacks this phenotype and has been designated as non-T cell-inflamed. The mechanisms of immune escape are likely distinct in these two phenotypes, and therefore the optimal immunotherapeutic interventions necessary to promote clinical responses may be different. The T cell-inflamed tumor microenvironment subset shows the highest expression of negative regulatory factors, including PD-L1, IDO, FoxP3(+) Tregs, and evidence for T cell-intrinsic anergy. Therapeutic strategies to overcome these inhibitory mechanisms are being pursued, and anti-PD-1 mAbs have been FDA approved. The presence of multiple inhibitory mechanisms in the same tumor microenvironment argues that combination therapies may be advantageous, several of which are in clinical testing. A new paradigm may be needed to promote de novo inflammation in cases of the non-T cell-infiltrated tumor microenvironment. Natural innate immune sensing of tumors appears to occur via the host STING pathway, type I IFN production, and cross-priming of T cells via CD8alpha(+) DCs. New strategies are being developed to engage this pathway therapeutically, such as through STING agonists. The molecular mechanisms that mediate the presence or absence of the T cell-inflamed tumor microenvironment are being elucidated using parallel genomics platforms. The first oncogene pathway identified that mediates immune exclusion is the Wnt/beta-catenin pathway, suggesting that new pharmacologic strategies to target this pathway should be developed to restore immune access to the tumor microenvironment.

Author Info: (1) University of Chicago, Chicago, IL, USA. tgajewski@medicine.bsd.uchicago.edu. (2) University of Chicago, Chicago, IL, USA. (3) University of Chicago, Chicago, IL, USA. (4) University of

Author Info: (1) University of Chicago, Chicago, IL, USA. tgajewski@medicine.bsd.uchicago.edu. (2) University of Chicago, Chicago, IL, USA. (3) University of Chicago, Chicago, IL, USA. (4) University of Chicago, Chicago, IL, USA. (5) University of Chicago, Chicago, IL, USA. (6) University of Chicago, Chicago, IL, USA.

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Tumor Immuno-Environment in Cancer Progression and Therapy

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The approvals of Provenge (Sipuleucel-T), Ipilimumab (Yervoy/anti-CTLA-4) and blockers of the PD-1 - PD-L1/PD-L2 pathway, such as nivolumab (Opdivo), pembrolizumab (Keytruda), or atezolizumab (Tecentriq), have established immunotherapy as a key component of comprehensive cancer care. Further, murine mechanistic studies and studies in immunocompromised patients have documented the critical role of immunity in effectiveness of radio- and chemotherapy. However, in addition to the ability of the immune system to control cancer progression, it can also promote tumor growth, via regulatory T cells (Tregs), myeloid-derived dendritic cells (MDSCs) and tumor associated macrophages (TAM), which can enhance survival of cancer cells directly or via the regulation of the tumor stroma.An increasing body of evidence supports a central role for the tumor microenvironment (TME) and the interactions between tumor stroma, infiltrating immune cells and cancer cells during the induction and effector phase of anti-cancer immunity, and the overall effectiveness of immunotherapy and other forms of cancer treatment. In this chapter, we discuss the roles of key TME components during tumor progression, metastatic process and cancer therapy-induced tumor regression, as well as opportunities for their modulation to enhance the overall therapeutic benefit.

Author Info: (1) Department of Medicine and Center for Immunotherapy, Roswell Park Cancer Institute, Buffalo, NY, USA. Pawel.Kalinski@RoswellPark.org. (2) University of Nebraska Medical Center, 986495 Nebraska Medical

Author Info: (1) Department of Medicine and Center for Immunotherapy, Roswell Park Cancer Institute, Buffalo, NY, USA. Pawel.Kalinski@RoswellPark.org. (2) University of Nebraska Medical Center, 986495 Nebraska Medical Center, Omaha, NE, USA.

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Imaging the Tumor Microenvironment

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The tumor microenvironment consists of tumor, stromal, and immune cells, as well as extracellular milieu. Changes in numbers of these cell types and their environments have an impact on cancer growth and metastasis. Non-invasive imaging of aspects of the tumor microenvironment can provide important information on the aggressiveness of the cancer, whether or not it is metastatic, and can also help to determine early response to treatment. This chapter provides an overview on non-invasive in vivo imaging in humans and mouse models of various cell types and physiological parameters that are unique to the tumor microenvironment. Current clinical imaging and research investigation are in the areas of nuclear imaging (positron emission tomography (PET) and single photon emission computed tomography (SPECT)), magnetic resonance imaging (MRI) and optical (near infrared (NIR) fluorescence) imaging. Aspects of the tumor microenvironment that have been imaged by PET, MRI and/or optical imaging are tumor associated inflammation (primarily macrophages and T cells), hypoxia, pH changes, as well as enzymes and integrins that are highly prevalent in tumors, stroma and immune cells. Many imaging agents and strategies are currently available for cancer patients; however, the investigation of novel avenues for targeting aspects of the tumor microenvironment in pre-clinical models of cancer provides the cancer researcher with a means to monitor changes and evaluate novel treatments that can be translated into the clinic.

Author Info: (1) Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA. (2) Department of Radiology, University of Pittsburgh, Pittsburgh, PA, USA. Department of Bioengineering, University of

Author Info: (1) Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA. (2) Department of Radiology, University of Pittsburgh, Pittsburgh, PA, USA. Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA. (3) Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA. andersoncj@upmc.edu. Department of Radiology, University of Pittsburgh, Pittsburgh, PA, USA. andersoncj@upmc.edu. Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA. andersoncj@upmc.edu. Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA. andersoncj@upmc.edu.

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