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3. Cost-effectiveness of treating advanced melanoma with tumor-infiltrating lymphocytes based on an international randomized phase 3 clinical trial

Author

HEE, Regenerative Medicine and Stem Cells, MS Urologische Oncologie, Ten Ham, Renske M T, Rohaan, Maartje W, Jedema, Inge, Kessels, Rob, Stegeman, Wim, Scheepmaker, Walter, Nuijen, Bastiaan, Nijenhuis, Cynthia, Lindenberg, Melanie, Borch, Troels Holz, Monberg, Tine, Donia, Marco, Marie Svane, Inge, van Harten, Wim, Haanen, John, Retel, Valesca P, HEE, Regenerative Medicine and Stem Cells, MS Urologische Oncologie, Ten Ham, Renske M T, Rohaan, Maartje W, Jedema, Inge, Kessels, Rob, Stegeman, Wim, Scheepmaker, Walter, Nuijen, Bastiaan, Nijenhuis, Cynthia, Lindenberg, Melanie, Borch, Troels Holz, Monberg, Tine, Donia, Marco, Marie Svane, Inge, van Harten, Wim, Haanen, John, and Retel, Valesca P

Published
2024

4. Cost-effectiveness of treating advanced melanoma with tumor-infiltrating lymphocytes based on an international randomized phase 3 clinical trial

Author

Ten Ham, Renske M.T., Rohaan, Maartje W., Jedema, Inge, Kessels, Rob, Stegeman, Wim, Scheepmaker, Walter, Nuijen, Bastiaan, Nijenhuis, Cynthia, Lindenberg, Melanie, Borch, Troels Holz, Monberg, Tine, Donia, Marco, Marie Svane, Inge, van Harten, Wim, Haanen, John, Retel, Valesca P., Ten Ham, Renske M.T., Rohaan, Maartje W., Jedema, Inge, Kessels, Rob, Stegeman, Wim, Scheepmaker, Walter, Nuijen, Bastiaan, Nijenhuis, Cynthia, Lindenberg, Melanie, Borch, Troels Holz, Monberg, Tine, Donia, Marco, Marie Svane, Inge, van Harten, Wim, Haanen, John, and Retel, Valesca P.

Abstract

INTRODUCTION: In a multicenter, open-label randomized phase 3 clinical trial conducted in the Netherlands and Denmark, treatment with ex vivo-expanded tumor-infiltrating lymphocytes (TIL-NKI/CCIT) from autologous melanoma tumor compared with ipilimumab improved progression-free survival in patients with unresectable stage IIIC-IV melanoma after failure of first-line or second-line treatment. Based on this trial, we conducted a cost-utility analysis. METHODS: A Markov decision model was constructed to estimate expected costs (expressed in 2021€) and outcomes (quality-adjusted life years (QALYs)) of TIL-NKI/CCIT versus ipilimumab in the Netherlands. The Danish setting was assessed in a scenario analysis. A modified societal perspective was applied over a lifetime horizon. TIL-NKI/CCIT production costs were estimated via activity-based costing. Through sensitivity analyses, uncertainties and their impact on the incremental cost-effectiveness ratio (ICER) were assessed. RESULTS: Mean total undiscounted lifetime benefits were 4.47 life years (LYs) and 3.52 QALYs for TIL-NKI/CCIT and 3.33 LYs and 2.46 QALYs for ipilimumab. Total lifetime undiscounted costs in the Netherlands were €347,168 for TIL-NKI/CCIT (including €67,547 for production costs) compared with €433,634 for ipilimumab. Undiscounted lifetime cost in the Danish scenario were €337,309 and €436,135, respectively. This resulted in a dominant situation for TIL-NKI/CCIT compared with ipilimumab in both countries, meaning incremental QALYs were gained at lower costs. Survival probabilities, and utility in progressive disease affected the ICER most. CONCLUSION: Based on the data of a randomized phase 3 trial, treatment with TIL-NKI/CCIT in patients with unresectable stage IIIC-IV melanoma is cost-effective and cost-saving, both in the current Dutch and Danish setting. These findings led to inclusion of TIL-NKI/CCIT as insured care and treatment guidelines. Publicly funded development of the TIL-NKI/CCIT cell ther

Published
2024

5. Ex vivo modulation of intact tumor fragments with anti-PD-1 and anti-CTLA-4 influences the expansion and specificity of tumor-infiltrating lymphocytes.

Author

Hulen, Thomas Morgan, Friese, Christina, Kristensen, Nikolaj Pagh, Granhøj, Joachim Stoltenborg, Borch, Troels Holz, Peeters, Marlies J. W., Donia, Marco, Andersen, Mads Hald, Hadrup, Sine Reker, Svane, Inge Marie, and Met, Özcan

Subjects
TUMOR antigens, TUMOR-infiltrating immune cells, DEATH receptors, GENETIC barcoding, CELLULAR therapy
Abstract

Checkpoint inhibition (CPI) therapy and adoptive cell therapy with autologous tumor-infiltrating lymphocytes (TIL-based ACT) are the two most effective immunotherapies for the treatment of metastatic melanoma. While CPI has been the dominating therapy in the past decade, TIL-based ACT is beneficial for individuals even after progression on previous immunotherapies. Given that notable differences in response have been made when used as a subsequent treatment, we investigated how the qualities of TILs changed when the ex vivo microenvironment of intact tumor fragments were modulated with checkpoint inhibitors targeting programmed death receptor 1 (PD-1) and cytotoxic Tlymphocyte-associated protein 4 (CTLA-4). Initially, we show that unmodified TILs from CPI-resistant individuals can be produced, are overwhelmingly terminally differentiated, and are capable of responding to tumor. We then investigate these properties in ex vivo checkpoint modulated TILs finding that that they retain these qualities. Lastly, we confirmed the specificity of the TILs to the highest responding tumor antigens, and identified this reactivity resides largely in CD39+CD69+ terminally differentiated populations. Overall, we found that anti-PD-1 will alter the proliferative capacity while anti-CTLA4 will influence breadth of antigen specificity. [ABSTRACT FROM AUTHOR]

Published
2024
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7. Cost-effectiveness of treating advanced melanoma with tumor-infiltrating lymphocytes based on an international randomized phase 3 clinical trial

Author

ten Ham, Renske M T, primary, Rohaan, Maartje W, additional, Jedema, Inge, additional, Kessels, Rob, additional, Stegeman, Wim, additional, Scheepmaker, Walter, additional, Nuijen, Bastiaan, additional, Nijenhuis, Cynthia, additional, Lindenberg, Melanie, additional, Borch, Troels Holz, additional, Monberg, Tine, additional, Donia, Marco, additional, Marie Svane, Inge, additional, van Harten, Wim, additional, Haanen, John, additional, and Retel, Valesca P, additional

Published
2024
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10. Ex vivo modulation of intact tumor fragments with anti-PD-1 and anti-CTLA-4 influences the expansion and specificity of tumor-infiltrating lymphocytes

Author

Hulen, Thomas Morgan, primary, Friese, Christina, additional, Kristensen, Nikolaj Pagh, additional, Granhøj, Joachim Stoltenborg, additional, Borch, Troels Holz, additional, Peeters, Marlies J. W., additional, Donia, Marco, additional, Andersen, Mads Hald, additional, Hadrup, Sine Reker, additional, Svane, Inge Marie, additional, and Met, Özcan, additional

Published
2023
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11. Ex vivo modulation of intact tumor fragments with anti-PD-1 and anti-CTLA-4 influences the expansion and specificity of tumor-infiltrating lymphocytes

Author

Hulen, Thomas Morgan, Friese, Christina, Kristensen, Nikolaj Pagh, Granhøj, Joachim Stoltenborg, Borch, Troels Holz, Peeters, Marlies J.W., Donia, Marco, Andersen, Mads Hald, Hadrup, Sine Reker, Svane, Inge Marie, Met, Özcan, Hulen, Thomas Morgan, Friese, Christina, Kristensen, Nikolaj Pagh, Granhøj, Joachim Stoltenborg, Borch, Troels Holz, Peeters, Marlies J.W., Donia, Marco, Andersen, Mads Hald, Hadrup, Sine Reker, Svane, Inge Marie, and Met, Özcan

Abstract

Checkpoint inhibition (CPI) therapy and adoptive cell therapy with autologous tumor-infiltrating lymphocytes (TIL-based ACT) are the two most effective immunotherapies for the treatment of metastatic melanoma. While CPI has been the dominating therapy in the past decade, TIL-based ACT is beneficial for individuals even after progression on previous immunotherapies. Given that notable differences in response have been made when used as a subsequent treatment, we investigated how the qualities of TILs changed when the ex vivo microenvironment of intact tumor fragments were modulated with checkpoint inhibitors targeting programmed death receptor 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). Initially, we show that unmodified TILs from CPI-resistant individuals can be produced, are overwhelmingly terminally differentiated, and are capable of responding to tumor. We then investigate these properties in ex vivo checkpoint modulated TILs finding that that they retain these qualities. Lastly, we confirmed the specificity of the TILs to the highest responding tumor antigens, and identified this reactivity resides largely in CD39+CD69+ terminally differentiated populations. Overall, we found that anti-PD-1 will alter the proliferative capacity while anti-CTLA4 will influence breadth of antigen specificity.

Published
2023

12. of intact tumor fragments with anti-PD-1 and anti-CTLA-4 influences the expansion and specificity of tumor-infiltrating lymphocytes

Author

Hulen, Thomas Morgan, Friese, Christina, Kristensen, Nikolaj Pagh, Granhøj, Joachim Stoltenborg, Borch, Troels Holz, Peeters, Marlies J.W., Donia, Marco, Andersen, Mads Hald, Hadrup, Sine Reker, Svane, Inge Marie, Met, Özcan, Hulen, Thomas Morgan, Friese, Christina, Kristensen, Nikolaj Pagh, Granhøj, Joachim Stoltenborg, Borch, Troels Holz, Peeters, Marlies J.W., Donia, Marco, Andersen, Mads Hald, Hadrup, Sine Reker, Svane, Inge Marie, and Met, Özcan

Abstract

Checkpoint inhibition (CPI) therapy and adoptive cell therapy with autologous tumor-infiltrating lymphocytes (TIL-based ACT) are the two most effective immunotherapies for the treatment of metastatic melanoma. While CPI has been the dominating therapy in the past decade, TIL-based ACT is beneficial for individuals even after progression on previous immunotherapies. Given that notable differences in response have been made when used as a subsequent treatment, we investigated how the qualities of TILs changed when the ex vivo microenvironment of intact tumor fragments were modulated with checkpoint inhibitors targeting programmed death receptor 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). Initially, we show that unmodified TILs from CPI-resistant individuals can be produced, are overwhelmingly terminally differentiated, and are capable of responding to tumor. We then investigate these properties in ex vivo checkpoint modulated TILs finding that that they retain these qualities. Lastly, we confirmed the specificity of the TILs to the highest responding tumor antigens, and identified this reactivity resides largely in CD39+CD69+ terminally differentiated populations. Overall, we found that anti-PD-1 will alter the proliferative capacity while anti-CTLA4 will influence breadth of antigen specificity.

Published
2023

13. Supplementary Figures 1-6 and Supplementary Table 1 from Long-Lasting Complete Responses in Patients with Metastatic Melanoma after Adoptive Cell Therapy with Tumor-Infiltrating Lymphocytes and an Attenuated IL2 Regimen

Author

Andersen, Rikke, primary, Donia, Marco, primary, Ellebaek, Eva, primary, Borch, Troels Holz, primary, Kongsted, Per, primary, Iversen, Trine Zeeberg, primary, Hölmich, Lisbet Rosenkrantz, primary, Hendel, Helle Westergren, primary, Met, Özcan, primary, Andersen, Mads Hald, primary, thor Straten, Per, primary, and Svane, Inge Marie, primary

Published
2023
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14. “One more chance to survive”The experiences of patients with advanced melanoma and their partners with Tumor-infiltrating Lymphocyte Therapy: a qualitative study and recommendations for future care

Author

Egeler, Mees, primary, Boomstra, Eva, additional, Rohaan, Maartje, additional, Heuvel, Noelle Van den, additional, Fraterman, Itske, additional, Delfos, Marjolein, additional, de Poll-Franse, Lonneke van, additional, Borch, Troels Holz, additional, Svane, Inge Marie, additional, Haanen, John, additional, Retèl, Valesca, additional, and Boekhout, Annelies, additional

Published
2023
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18. Adoptive cell therapy with tumor-infiltrating lymphocytes supported by checkpoint inhibition across multiple solid cancer types

Author

Kverneland, Anders Handrup, primary, Chamberlain, Christopher Aled, additional, Borch, Troels Holz, additional, Nielsen, Morten, additional, Mørk, Sofie Kirial, additional, Kjeldsen, Julie Westerlin, additional, Lorentzen, Cathrine Lund, additional, Jørgensen, Lise Pyndt, additional, Riis, Lene Buhl, additional, Yde, Christina Westmose, additional, Met, Özcan, additional, Donia, Marco, additional, and Marie Svane, Inge, additional

Published
2021
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19. Clinical efficacy of T-cell therapy after short-term BRAF-inhibitor priming in patients with checkpoint inhibitor-resistant metastatic melanoma

Author

Borch, Troels Holz, primary, Harbst, Katja, additional, Rana, Aynal Haque, additional, Andersen, Rikke, additional, Martinenaite, Evelina, additional, Kongsted, Per, additional, Pedersen, Magnus, additional, Nielsen, Morten, additional, Kjeldsen, Julie Westerlin, additional, Kverneland, Anders Handrup, additional, Lauss, Martin, additional, Hölmich, Lisbet Rosenkrantz, additional, Hendel, Helle, additional, Met, Özcan, additional, Jönsson, Göran, additional, Donia, Marco, additional, and Marie Svane, Inge, additional

Published
2021
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20. Clinical efficacy of T-cell therapy after short-term BRAF-inhibitor priming in patients with checkpoint inhibitor-resistant metastatic melanoma

Author

Borch, Troels Holz, Harbst, Katja, Rana, Aynal Haque, Andersen, Rikke, Martinenaite, Evelina, Kongsted, Per, Pedersen, Magnus, Nielsen, Morten, Kjeldsen, Julie Westerlin, Kverneland, Anders Handrup, Lauss, Martin, Hölmich, Lisbet Rosenkrantz, Hendel, Helle, Met, Özcan, Jönsson, Göran, Donia, Marco, Marie Svane, Inge, Borch, Troels Holz, Harbst, Katja, Rana, Aynal Haque, Andersen, Rikke, Martinenaite, Evelina, Kongsted, Per, Pedersen, Magnus, Nielsen, Morten, Kjeldsen, Julie Westerlin, Kverneland, Anders Handrup, Lauss, Martin, Hölmich, Lisbet Rosenkrantz, Hendel, Helle, Met, Özcan, Jönsson, Göran, Donia, Marco, and Marie Svane, Inge

Abstract

PURPOSE: Despite impressive response rates following adoptive transfer of autologous tumor-infiltrating lymphocytes (TILs) in patients with metastatic melanoma, improvement is needed to increase the efficacy and broaden the applicability of this treatment. We evaluated the use of vemurafenib, a small-molecule BRAF inhibitor with immunomodulatory properties, as priming before TIL harvest and adoptive T cell therapy in a phase I/II clinical trial. METHODS: 12 patients were treated with vemurafenib for 7 days before tumor excision and during the following weeks until TIL infusion. TILs were grown from tumor fragments, expanded in vitro and reinfused to the patient preceded by a lymphodepleting chemotherapy regimen and followed by interleukin-2 infusion. Extensive immune monitoring, tumor profiling and T cell receptor sequencing were performed. RESULTS: No unexpected toxicity was observed, and treatment was well tolerated. Of 12 patients, 1 achieved a complete response, 8 achieved partial response and 3 achieved stable disease. A PR and the CR are ongoing for 23 and 43 months, respectively. In vitro anti-tumor reactivity was found in TILs from 10 patients, including all patients achieving objective response. Serum and tumor biomarker analyses indicate that baseline cytokine levels and the number of T cell clones may predict response to TIL therapy. Further, TCR sequencing suggested skewing of TCR repertoire during in vitro expansion, promoting certain low frequency clonotypes. CONCLUSIONS: Priming with vemurafenib before infusion of TILs was safe and feasible, and induced objective clinical responses in this cohort of patients with checkpoint inhibitor-resistant metastatic melanoma. In this trial, vemurafenib treatment seemed to decrease attrition and could be considered to bridge the waiting time while TILs are prepared.

Published
2021

22. CTLA-4 blockade boosts the expansion of tumor-reactive CD8+ tumor-infiltrating lymphocytes in ovarian cancer

Author

Friese, Christina, Harbst, Katja, Borch, Troels Holz, Westergaard, Marie Christine Wulff, Pedersen, Magnus, Kverneland, Anders, Jönsson, Göran, Donia, Marco, Svane, Inge Marie, Met, Özcan, Friese, Christina, Harbst, Katja, Borch, Troels Holz, Westergaard, Marie Christine Wulff, Pedersen, Magnus, Kverneland, Anders, Jönsson, Göran, Donia, Marco, Svane, Inge Marie, and Met, Özcan

Abstract

Adoptive cell therapy (ACT) with autologous tumor-infiltrating lymphocytes (TILs) can induce durable complete tumor regression in patients with advanced melanoma. Efforts are currently underway to expand this treatment modality to other cancer types. In the microenvironment of ovarian cancer, the engagement of co-inhibitory immune checkpoint molecules such as CTLA-4 can lead to the inactivation of TILs. Thus, approaches that directly manipulate co-inhibitory pathways within the tumor microenvironment might improve the expansion of tumor-reactive TILs. The initial expansion of TILs for ACT from tumor fragments provides a window of opportunity to manipulate an intact tumor microenvironment and improve CD8+ T-cell output and TIL tumor reactivity. To exploit this, we used a CTLA-4-blocking antibody, added during the initial TIL culture, and found that the blockade of CTLA-4 favored the propagation of CD8+ TILs from ovarian tumor fragments. Interestingly, adding the CTLA-4 blocking antibody in the initial phase of the TIL culture resulted in more potent anti-tumor TILs in comparison to standard TIL cultures. This phenotype was preserved during the rapid expansion phase. Thus, targeting CTLA-4 within the intact tumor microenvironment of tumor fragments enriches tumor-reactive TILs and may improve clinical outcome of TIL-based ACT in ovarian cancer.

Published
2020

23. Changes in the tumor immune microenvironment during disease progression in patients with ovarian cancer

Author

Westergaard, Marie Christine Wulff, Milne, Katy, Pedersen, Magnus, Hasselager, Thomas, Olsen, Lars Rønn, Anglesio, Michael S., Borch, Troels Holz, Kennedy, Mia, Briggs, Gillian, Ledoux, Stacey, Kreuzinger, Caroline, von der Decken, Isabel, Donia, Marco, Castillo-Tong, Dan Cacsire, Nelson, Brad H., Svane, Inge Marie, Westergaard, Marie Christine Wulff, Milne, Katy, Pedersen, Magnus, Hasselager, Thomas, Olsen, Lars Rønn, Anglesio, Michael S., Borch, Troels Holz, Kennedy, Mia, Briggs, Gillian, Ledoux, Stacey, Kreuzinger, Caroline, von der Decken, Isabel, Donia, Marco, Castillo-Tong, Dan Cacsire, Nelson, Brad H., and Svane, Inge Marie

Abstract

Anti-PD1/PDL1 therapy has proven efficacious against many cancers but only reached modest objective response rates against recurrent ovarian cancer. A deeper understanding of the tumor microenvironment (TME) may reveal other immunosuppressive mechanisms that warrant investigation as immunotherapeutic targets for this challenging disease. Matched primary and recurrent tumors from patients with high-grade serous ovarian carcinoma (HGSC) were analyzed by multicolor immunohistochemistry/immunofluorescence for the presence of T cells, B cells, macrophages, and for the expression of immunosuppressive and HLA molecules. Cancer-and immune-related gene expression was assessed by NanoString analysis. Recurrent tumors showed increased infiltration by immune cells, displayed higher expression of PDL1, IDO, and HLA molecules, and contained more stromal tissue. NanoString analysis demonstrated increased expression of gene signatures related to chemokines and T cell functions in recurrent tumors. The ovarian tumors showed high gene expression of LAG3 and HAVCR2 (TIM3) and enhanced levels of TIGIT and CTLA4 in recurrent tumors compared to primary tumors. The majority of HGSC developed into a more inflamed phenotype during progression from primary to recurrent disease, including indications of adaptive immune resistance. This suggests that recurrent tumors may be particularly sensitive to inhibition of adaptive immune resistance mechanisms.

Published
2020

24. Adoptive cell therapy in combination with checkpoint inhibitors in ovarian cancer

Author

Kverneland, Anders Handrup, Pedersen, Magnus, Westergaard, Marie Christine Wulff, Nielsen, Morten, Borch, Troels Holz, Olsen, Lars Rønn, Aasbjerg, Gitte, Santegoets, Saskia J., van der Burg, Sjoerd H., Milne, Katy, Nelson, Brad H., Met, Özcan, Donia, Marco, Svane, Inge Marie, Kverneland, Anders Handrup, Pedersen, Magnus, Westergaard, Marie Christine Wulff, Nielsen, Morten, Borch, Troels Holz, Olsen, Lars Rønn, Aasbjerg, Gitte, Santegoets, Saskia J., van der Burg, Sjoerd H., Milne, Katy, Nelson, Brad H., Met, Özcan, Donia, Marco, and Svane, Inge Marie

Abstract

Immune therapy is a promising field within oncology but has been unsuccessful in ovarian cancer (OC). Still, there is rationale and evidence supporting immune therapy in OC. We investigated the potential for adoptive cell therapy (ACT) from in vitro expanded tumor-infiltrating lymphocytes (TILs) in combination with checkpoint inhibitors (ICI) and conducted immunological testing of ex vivo expanded TILs (REP-TILs). Six patients with late-stage metastatic high-grade serous OC were treated with immune therapy consisting of ipilimumab followed by surgery to obtain TILs and infusion of REP-TILs, low-dose IL-2 and nivolumab. One patient achieved a partial response and 5 others experienced disease stabilization for up to 12 months. Analysis of the REP-TILs with flow- and mass-cytometry show primarily activated and differentiated effector memory T cells. REP-TILs showed in vitro reactivity and expression of inhibitory receptors, such as LAG-3 and PD-1. Furthermore, our data indicate that addition of ipilimumab therapy improves the T cell fold expansion during production, increase the level of CD8 T cell tumor reactivity, and favorably affect the T cell phenotype. We show that the combination of ICI and ACT is feasible and safe. With one partial response and one long-lasting SD, we demonstrated the potential of ACT in OC.

Published
2020

25. Future role for adoptive T-cell therapy in checkpoint inhibitor-resistant metastatic melanoma

Author

Borch, Troels Holz, Andersen, Rikke, Ellebaek, Eva, Met, Özcan, Donia, Marco, Marie Svane, Inge, Borch, Troels Holz, Andersen, Rikke, Ellebaek, Eva, Met, Özcan, Donia, Marco, and Marie Svane, Inge

Abstract

Personalized cell therapy targeting tumor antigens with expanded tumor-infiltrating lymphocytes (TILs) has shown great promise in metastatic melanoma (MM) since the 90s. However, MM was first-in line to benefit from the wave of checkpoint inhibitors (CPI), which shifted the focus of immunotherapy almost fully to immune CPI. Still, the majority of patients fail to benefit from CPI treatment, raising the intriguing question on how TIL therapy may fit into the changing landscape of melanoma treatment. We took advantage of data from a unique cohort of patients with MM treated with T-cell therapy in consecutive clinical trials at our institution across the last 10 years. Based on detailed data on patient characteristics, pre-TIL and post-TIL treatments and long-term follow-up, we were able to address the important issue of how TIL therapy can be positioned in the current CPI era. We found that previous progression on anticytotoxic T-lymphocyte-associated protein 4 do not seem to harm neither rate nor duration of response to TIL therapy. Importantly, even in the hard-to-treat population of patients who progressed on antiprogrammed cell death protein 1 (anti-PD-1), an objective response rate of 32% was achieved, including durable responses. Yet, median progression-free survival was reduced in this anti-PD-1 refractory population. Trial registration number: ClinicalTrials.gov ID: NCT00937625, NCT02379195 and NCT02354690.

Published
2020

26. Qualitative analysis of tumor-infiltrating lymphocytes across human tumor types reveals a higher proportion of bystander CD8+ T cells in non-melanoma cancers compared to melanoma

Author

Gokuldass, Aishwarya, Draghi, Arianna, Papp, Krisztian, Borch, Troels Holz, Nielsen, Morten, Westergaard, Marie Christine Wulff, Andersen, Rikke, Schina, Aimilia, Bol, Kalijn Fredrike, Chamberlain, Christopher Aled, Presti, Mario, Met, Özcan, Harbst, Katja, Lauss, Martin, Soraggi, Samuele, Csabai, Istvan, Szállási, Zoltán, Jönsson, Göran, Svane, Inge Marie, Donia, Marco, Gokuldass, Aishwarya, Draghi, Arianna, Papp, Krisztian, Borch, Troels Holz, Nielsen, Morten, Westergaard, Marie Christine Wulff, Andersen, Rikke, Schina, Aimilia, Bol, Kalijn Fredrike, Chamberlain, Christopher Aled, Presti, Mario, Met, Özcan, Harbst, Katja, Lauss, Martin, Soraggi, Samuele, Csabai, Istvan, Szállási, Zoltán, Jönsson, Göran, Svane, Inge Marie, and Donia, Marco

Abstract

Background: Human intratumoral T cell infiltrates can be defined by quantitative or qualitative features, such as their ability to recognize autologous tumor antigens. In this study, we reproduced the tumor-T cell interactions of individual patients to determine and compared the qualitative characteristics of intratumoral T cell infiltrates across multiple tumor types. Methods: We employed 187 pairs of unselected tumor-infiltrating lymphocytes (TILs) and autologous tumor cells from patients with melanoma, renal-, ovarian-cancer or sarcoma, and single-cell RNA sequencing data from a pooled cohort of 93 patients with melanoma or epithelial cancers. Measures of TIL quality including the proportion of tumor-reactive CD8+ and CD4+ TILs, and TIL response polyfunctionality were determined. Results: Tumor-specific CD8+ and CD4+ TIL responses were detected in over half of the patients in vitro, and greater CD8+ TIL responses were observed in melanoma, regardless of previous anti-PD-1 treatment, compared to renal cancer, ovarian cancer and sarcoma. The proportion of tumor-reactive CD4+ TILs was on average lower and the differences less pronounced across tumor types. Overall, the proportion of tumor-reactive TILs in vitro was remarkably low, implying a high fraction of TILs to be bystanders, and highly variable within the same tumor type. In situ analyses, based on eight single-cell RNA-sequencing datasets encompassing melanoma and five epithelial cancers types, corroborated the results obtained in vitro. Strikingly, no strong correlation between the proportion of CD8+ and CD4+ tumor-reactive TILs was detected, suggesting the accumulation of these responses in the tumor microenvironment to follow non-overlapping biological pathways. Additionally, no strong correlation between TIL responses and tumor mutational burden (TMB) in melanoma was observed, indicating that TMB was not a major dri

Published
2020

27. Changes in the Tumor Immune Microenvironment during Disease Progression in Patients with Ovarian Cancer

Author

Westergaard, Marie Christine Wulff, primary, Milne, Katy, additional, Pedersen, Magnus, additional, Hasselager, Thomas, additional, Olsen, Lars Rønn, additional, Anglesio, Michael S., additional, Borch, Troels Holz, additional, Kennedy, Mia, additional, Briggs, Gillian, additional, Ledoux, Stacey, additional, Kreuzinger, Caroline, additional, Decken, Isabel von der, additional, Donia, Marco, additional, Castillo-Tong, Dan Cacsire, additional, Nelson, Brad H., additional, and Svane, Inge Marie, additional

Published
2020
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28. Qualitative Analysis of Tumor-Infiltrating Lymphocytes across Human Tumor Types Reveals a Higher Proportion of Bystander CD8+ T Cells in Non-Melanoma Cancers Compared to Melanoma

Author

Gokuldass, Aishwarya, primary, Draghi, Arianna, additional, Papp, Krisztian, additional, Borch, Troels Holz, additional, Nielsen, Morten, additional, Westergaard, Marie Christine Wulff, additional, Andersen, Rikke, additional, Schina, Aimilia, additional, Bol, Kalijn Fredrike, additional, Chamberlain, Christopher Aled, additional, Presti, Mario, additional, Met, Özcan, additional, Harbst, Katja, additional, Lauss, Martin, additional, Soraggi, Samuele, additional, Csabai, Istvan, additional, Szállási, Zoltán, additional, Jönsson, Göran, additional, Svane, Inge Marie, additional, and Donia, Marco, additional

Published
2020
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30. Adoptive cell therapy in combination with checkpoint inhibitors in ovarian cancer

Author

Kverneland, Anders Handrup, primary, Pedersen, Magnus, additional, Westergaard, Marie Christine Wulff, additional, Nielsen, Morten, additional, Borch, Troels Holz, additional, Olsen, Lars Rønn, additional, Aasbjerg, Gitte, additional, Santegoets, Saskia J., additional, Burg, Sjoerd H. van der, additional, Milne, Katy, additional, Nelson, Brad H., additional, Met, Özcan, additional, Donia, Marco, additional, and Svane, Inge Marie, additional

Published
2020
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32. Differential effects of corticosteroids and anti-TNF on tumor-specific immune responses:implications for the management of irAEs

Author

Draghi, Arianna, Borch, Troels Holz, Radic, Haja Dominike, Chamberlain, Christopher Aled, Gokuldass, Aishwarya, Svane, Inge Marie, Donia, Marco, Draghi, Arianna, Borch, Troels Holz, Radic, Haja Dominike, Chamberlain, Christopher Aled, Gokuldass, Aishwarya, Svane, Inge Marie, and Donia, Marco

Abstract

Up to 60% of patients treated with cancer immunotherapy develop severe or life threatening immune-related adverse events (irAEs). Immunosuppression with high dose corticosteroids, or tumor necrosis factor (TNF) antagonists in refractory cases, is the mainstay of treatment for irAEs. It is currently unknown what impact corticosteroids and anti-TNF have on the activity of antitumor T cells. In our study, the influence of clinically relevant doses of dexamethasone (corresponding to an oral dose of 10–125 mg prednisolone) and infliximab (anti-TNF) on the activation and killing ability of tumor-infiltrating lymphocytes (TILs) was tested in vitro. Overall, dexamethasone at low or intermediate/high doses impaired the activation (−46 and −62%, respectively) and tumor-killing ability (−48 and −53%, respectively) of tumor-specific TILs. In contrast, a standard clinical dose of infliximab only had a minor effect on T cell activation (−20%) and tumor killing (−10%). A 72-hr resting period after withdrawal of dexamethasone was sufficient to rescue the in vitro activity of TILs, while a short withdrawal did not result in a full rescue. In conclusion, clinically relevant doses of infliximab only had a minor influence on the activity of tumor-specific TILs in vitro, whereas even low doses of corticosteroids markedly impaired the antitumor activity of TILs. However, the activity of TILs could be restored after withdrawal of steroids. These data indirectly support steroid-sparing strategies and early initiation of anti-TNF therapy for the treatment of irAEs in immuno-oncology.

Published
2019

35. Adoptive cell therapy with tumor-infiltrating lymphocytes in patients with metastatic ovarian cancer:a pilot study

Author

Pedersen, Magnus, Westergaard, Marie Christine Wulff, Milne, Katy, Nielsen, Morten, Borch, Troels Holz, Poulsen, Lars Grønlund, Hendel, Helle Westergren, Kennedy, Mia, Briggs, Gillian, Ledoux, Stacey, Nøttrup, Trine Jakobi, Andersen, Pernille, Hasselager, Thomas, Met, Özcan, Nelson, Brad H, Donia, Marco, Svane, Inge Marie, Pedersen, Magnus, Westergaard, Marie Christine Wulff, Milne, Katy, Nielsen, Morten, Borch, Troels Holz, Poulsen, Lars Grønlund, Hendel, Helle Westergren, Kennedy, Mia, Briggs, Gillian, Ledoux, Stacey, Nøttrup, Trine Jakobi, Andersen, Pernille, Hasselager, Thomas, Met, Özcan, Nelson, Brad H, Donia, Marco, and Svane, Inge Marie

Abstract

Objective:Ovarian cancer (OC) is often diagnosed at an advanced stage with two thirds of patients experiencing recurrent disease with a poor prognosis. Adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TIL) has shown curative potential in malignant melanoma, but has only been investigated scarcely in other cancers. In this pilot study, we tested TIL based ACT in patients with metastatic OC. Methods:Six patients with progressive platinum-resistant metastatic OC were treated with an infusion of TIL preceded by standard lymphodepleting chemotherapy and followed by decrescendo intravenous interleukin-2 (IL-2). Primarily, the feasibility and tolerability of the treatment was assessed. Secondarily, disease control rate was described and immune responses against tumor cells were monitored. Results:Treatment was well tolerated with manageable toxicities. Four patients had stable disease for three months and two patients for five months with five patients having a decrease in target lesions. Progression was primarily due to new lesions while target lesions in general remained stable or in regression. Antitumor reactivity was observed in TIL infusion products from five patients but no antitumor reactivity was detectable in peripheral blood lymphocytes collected after treatment. High numbers of infused TIL expressed exhaustion markers including LAG3 and PD-1, and immunostaining of tumor tissue demonstrated substantial MHCII and PD-L1 expression. Conclusions:ACT with TIL in combination with decrescendo IL-2 is feasible in patients with metastatic OC. Early indications of clinical activity were found. However, TIL ACT efficacy was incomplete with possible involvement of the inhibitory immune checkpoint pathways LAG3/MHCII and PD1/PD-L1.

Published
2018

37. Adoptive cell therapy with tumor-infiltrating lymphocytes in patients with metastatic ovarian cancer: a pilot study

Author

Pedersen, Magnus, primary, Westergaard, Marie Christine Wulff, additional, Milne, Katy, additional, Nielsen, Morten, additional, Borch, Troels Holz, additional, Poulsen, Lars Grønlund, additional, Hendel, Helle Westergren, additional, Kennedy, Mia, additional, Briggs, Gillian, additional, Ledoux, Stacey, additional, Nøttrup, Trine Jakobi, additional, Andersen, Pernille, additional, Hasselager, Thomas, additional, Met, Özcan, additional, Nelson, Brad H., additional, Donia, Marco, additional, and Svane, Inge Marie, additional

Published
2018
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38. Dendritic cell vaccination in combination with docetaxel for patients with metastatic castration-resistant prostate cancer:A randomized phase II study

Author

Kongsted, Per, Borch, Troels Holz, Ellebaek, Eva, Iversen, Trine Zeeberg, Andersen, Rikke, Met, Özcan, Hansen, Morten, Lindberg, Henriette, Sengeløv, Lisa, Svane, Inge Marie, Kongsted, Per, Borch, Troels Holz, Ellebaek, Eva, Iversen, Trine Zeeberg, Andersen, Rikke, Met, Özcan, Hansen, Morten, Lindberg, Henriette, Sengeløv, Lisa, and Svane, Inge Marie

Abstract

Background aims We investigated whether the addition of an autologous dendritic cell–based cancer vaccine (DCvac) induces an immune response in patients with metastatic castration-resistant prostate cancer treated with docetaxel. Methods Forty-three patients were randomized 1:1 to receive up to 10 cycles of docetaxel alone, 75 mg/m2 every 3 weeks or in combination with DCvac. Monocytes were harvested following a leukapheresis procedure, matured ex vivo and subsequently transfected with messenger RNA encoding multiple tumor-associated antigens (TAAs). DCvac was administered intradermally twice through treatment cycles 1–4 and once through treatment cycles 5–10. Immune cell composition and antigen-specific responses were analyzed using flow cytometry, ELISpot and delayed type hypersensitivity (DTH) tests. Toxicity was graded according to Common Terminology Criteria for Adverse Events version 3.0. Progression-free survival (PFS) and disease-specific survival (DSS) was calculated using the Kaplan-Meier method. Results Prostate-specific antigen responses were similar in patients treated with docetaxel alone and combination therapy (58% versus 38%; P = 0.21). PFS and DSS were comparable: 5.5 versus 5.7 months (P = 0.62, log rank) and 21.9 versus 25.1 months (P = 0.60, log rank). Nine (50%) and 14 (78%) patients treated with docetaxel and DCvac had a TAA-specific or vaccine-specific immune response in the ELISpot and DTH analysis, respectively. Vaccine induced toxicity was limited to local reactions. Decline in myeloid-derived suppressor cells at the third treatment cycle was found to be an independent predictor of DSS. Conclusions The addition of DCvac was safe. Immune responses were detected in approximately half of the patients investigated.

Published
2017

39. Immune monitoring using mRNA-transfected dendritic cells

Author

Borch, Troels Holz, Svane, Inge Marie, Met, Özcan, Borch, Troels Holz, Svane, Inge Marie, and Met, Özcan

Abstract

Dendritic cells are known to be the most potent antigen presenting cell in the immune system and are used as cellular adjuvants in therapeutic anticancer vaccines using various tumor-associated antigens or their derivatives. One way of loading antigen into the dendritic cells is by mRNA electroporation, ensuring presentation of antigen through major histocompatibility complex I and potentially activating T cells, enabling them to kill the tumor cells. Despite extensive research in the field, only one dendritic cell-based vaccine has been approved. There is therefore a great need to elucidate and understand the immunological impact of dendritic cell vaccination in order to improve clinical benefit. In this chapter, we describe a method for performing immune monitoring using peripheral blood mononuclear cells and autologous dendritic cells transfected with tumor-associated antigen-encoding mRNA.

Published
2016

40. Long-Lasting Complete Responses in Patients with Metastatic Melanoma after Adoptive Cell Therapy with Tumor-Infiltrating Lymphocytes and an Attenuated IL2 Regimen

Author

Andersen, Rikke, Donia, Marco, Ellebæk, Eva, Borch, Troels Holz, Kongsted, Per, Iversen, Trine Zeeberg, Hølmich, Lisbet Rosenkrantz, Hendel, Helle Westergren, Met, Özcan, Andersen, Mads Hald, Thor Straten, Eivind Per, Svane, Inge Marie, Andersen, Rikke, Donia, Marco, Ellebæk, Eva, Borch, Troels Holz, Kongsted, Per, Iversen, Trine Zeeberg, Hølmich, Lisbet Rosenkrantz, Hendel, Helle Westergren, Met, Özcan, Andersen, Mads Hald, Thor Straten, Eivind Per, and Svane, Inge Marie

Abstract

PURPOSE: Adoptive cell transfer therapy (ACT) based on autologous tumor-infiltrating lymphocytes (TIL) has achieved impressive clinical results in several phase I and II trials performed outside of Europe. Although transient, the toxicities associated with high-dose (HD) bolus IL2 classically administered together with TILs are severe. To further scrutinize whether similar results can be achieved with lower doses of IL2, we have carried out a phase I/II trial of TIL transfer after classical lymphodepleting chemotherapy followed by an attenuated IL2 regimen.EXPERIMENTAL DESIGN: Twenty-five patients with progressive treatment-refractory metastatic melanoma, good clinical performance, age < 70 years, and at least one resectable metastasis were eligible. TIL infusion was preceded by standard lymphodepleting chemotherapy and followed by attenuated doses of IL2 administered in an intravenous, continuous decrescendo regimen (ClinicalTrials.gov Identifier: NCT00937625).RESULTS: Classical IL2-related toxicities were observed but patients were manageable in a general oncology ward without the need for intervention from the intensive care unit. RECIST 1.0 evaluation displayed three complete responses and seven partial responses (ORR 42%). Median overall survival was 21.8 months. Tumor regression was associated with a higher absolute number of infused tumor-reactive T cells. Moreover, induction and persistence of antimelanoma T-cell responses in the peripheral blood was strongly correlated to clinical response to treatment.CONCLUSIONS: TIL-ACT with a reduced IL2 decrescendo regimen results in long-lasting complete responses in patients with treatment-refractory melanoma. Larger randomized trials are needed to elucidate whether clinical efficacy is comparable with TIL-ACT followed by HD bolus IL2. Clin Cancer Res; 22(15); 3734-45. ©2016 AACR.

Published
2016

41. PD-L1 peptide co-stimulation increases immunogenicity of a dendritic cell-based cancer vaccine

Author

Munir Ahmad, Shamaila, Martinenaite, Evelina, Hansen, Morten, Junker, Niels, Borch, Troels Holz, Met, Özcan, Donia, Marco, Svane, Inge Marie, Andersen, Mads Hald, Munir Ahmad, Shamaila, Martinenaite, Evelina, Hansen, Morten, Junker, Niels, Borch, Troels Holz, Met, Özcan, Donia, Marco, Svane, Inge Marie, and Andersen, Mads Hald

Abstract

We recently described naturally occurring PD-L1-specific T cells that recognize PD-L1-expressing immune cells as well as malignant cells. In the present study, we investigated whether the immunogenicity of a dendritic cell (DC)-based vaccine could be influenced by co-stimulation with a known PD-L1-derived epitope. We incubated a PD-L1-derived peptide epitope (19 amino acids long) or a control peptide (an irrelevant HIV epitope) with peripheral blood mononuclear cells from patients with malignant melanoma who had received a DC-based vaccine. We observed a significantly higher number of T cells that reacted to the vaccine in cultures that had been co-stimulated with the PD-L1 peptide epitope compared to cultures incubated with control peptide. Next, we characterized a novel PD-L1-derived epitope (23 amino acids long) and found that co-stimulation with both PD-L1 epitopes boosted the immune response elicited by the DC vaccine even further. Consequently, we observed a significant increase in the number of vaccine-reacting T cells in vitro. In conclusion, activation of PD-L1-specific T cells may directly modulate immunogenicity of DC vaccines. Addition of PD-L1 epitopes may thus be an easily applicable and attractive option to augment the effectiveness of cancer vaccines and other immunotherapeutic agents.

Published
2016

42. Long-Lasting Complete Responses in Patients with Metastatic Melanoma after Adoptive Cell Therapy with Tumor-Infiltrating Lymphocytes and an Attenuated IL2 Regimen

Author

Andersen, Rikke, primary, Donia, Marco, additional, Ellebaek, Eva, additional, Borch, Troels Holz, additional, Kongsted, Per, additional, Iversen, Trine Zeeberg, additional, Hölmich, Lisbet Rosenkrantz, additional, Hendel, Helle Westergren, additional, Met, Özcan, additional, Andersen, Mads Hald, additional, thor Straten, Per, additional, and Svane, Inge Marie, additional

Published
2016
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45. Randomized phase III study comparing non-myeloablative lymphocyte depleting regimen of chemotherapy followed by infusion of tumor-infiltrating lymphocytes and interleukin-2 to standard ipilimumab treatment in metastatic melanoma.

Author

Geukes Foppen, MarnixMarnix Heimen, primary, Donia, Marco, additional, Borch, Troels Holz, additional, Met, Özcan, additional, Blank, Christian U., additional, Pronk, Loes, additional, Van Thienen, Johannes V., additional, Svane, Inge Marie, additional, and Haanen, John B. A. G., additional

Published
2016
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48. 31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016): part one: National Harbor, MD, USA. 9-13 November 2016

Author

Lundqvist, Andreas, van Hoef, Vincent, Zhang, Xiaonan, Wennerberg, Erik, Lorent, Julie, Witt, Kristina, Sanz, Laia Masvidal, Liang, Shuo, Murray, Shannon, Larsson, Ola, Kiessling, Rolf, Mao, Yumeng, Sidhom, John-William, Bessell, Catherine A., Havel, Jonathan, Schneck, Jonathan, Chan, Timothy A., Sachsenmeier, Eliot, Woods, David, Berglund, Anders, Ramakrishnan, Rupal, Sodre, Andressa, Weber, Jeffrey, Zappasodi, Roberta, Li, Yanyun, Qi, Jingjing, Wong, Philip, Sirard, Cynthia, Postow, Michael, Newman, Walter, Koon, Henry, Velcheti, Vamsidhar, Callahan, Margaret K., Wolchok, Jedd D., Merghoub, Taha, Lum, Lawrence G., Choi, Minsig, Thakur, Archana, Deol, Abhinav, Dyson, Gregory, Shields, Anthony, Haymaker, Cara, Uemura, Marc, Murthy, Ravi, James, Marihella, Wang, Daqing, Brevard, Julie, Monaghan, Catherine, Swann, Suzanne, Geib, James, Cornfeld, Mark, Chunduru, Srinivas, Agrawal, Sudhir, Yee, Cassian, Wargo, Jennifer, Patel, Sapna P., Amaria, Rodabe, Tawbi, Hussein, Glitza, Isabella, Woodman, Scott, Hwu, Wen-Jen, Davies, Michael A., Hwu, Patrick, Overwijk, Willem W., Bernatchez, Chantale, Diab, Adi, Massarelli, Erminia, Segal, Neil H., Ribrag, Vincent, Melero, Ignacio, Gangadhar, Tara C., Urba, Walter, Schadendorf, Dirk, Ferris, Robert L., Houot, Roch, Morschhauser, Franck, Logan, Theodore, Luke, Jason J., Sharfman, William, Barlesi, Fabrice, Ott, Patrick A., Mansi, Laura, Kummar, Shivaani, Salles, Gilles, Carpio, Cecilia, Meier, Roland, Krishnan, Suba, McDonald, Dan, Maurer, Matthew, Gu, Xuemin, Neely, Jaclyn, Suryawanshi, Satyendra, Levy, Ronald, Khushalani, Nikhil, Wu, Jennifer, Zhang, Jinyu, Basher, Fahmin, Rubinstein, Mark, Bucsek, Mark, Qiao, Guanxi, MacDonald, Cameron, Hylander, Bonnie, Repasky, Elizabeth, Chatterjee, Shilpak, Daenthanasanmak, Anusara, Chakraborty, Paramita, Toth, Kyle, Meek, Megan, Garrett-Mayer, Elizabeth, Nishimura, Michael, Paulos, Chrystal, Beeson, Craig, Yu, Xuezhong, Mehrotra, Shikhar, Zhao, Fei, Evans, Kathy, Xiao, Christine, Holtzhausen, Alisha, Hanks, Brent A., Scharping, Nicole, Menk, Ashley V., Moreci, Rebecca, Whetstone, Ryan, Dadey, Rebekah, Watkins, Simon, Ferris, Robert, Delgoffe, Greg M., Peled, Jonathan, Devlin, Sean, Staffas, Anna, Lumish, Melissa, Rodriguez, Kori Porosnicu, Ahr, Katya, Perales, Miguel, Giralt, Sergio, Taur, Ying, Pamer, Eric, van den Brink, Marcel R. M., Jenq, Robert, Annels, Nicola, Pandha, Hardev, Simpson, Guy, Mostafid, Hugh, Harrington, Kevin, Melcher, Alan, Grose, Mark, Davies, Bronwyn, Au, Gough, Karpathy, Roberta, Shafren, Darren, Ricca, Jacob, Zamarin, Dmitriy, Batista, Luciana, Marliot, Florence, Vasaturo, Angela, Carpentier, Sabrina, Poggionovo, Cécile, Frayssinet, Véronique, Fieschi, Jacques, Van den Eynde, Marc, Pagès, Franck, Galon, Jérôme, Hermitte, Fabienne, Smith, Sean G., Nguyen, Khue, Ravindranathan, Sruthi, Koppolu, Bhanu, Zaharoff, David, Schvartsman, Gustavo, Bassett, Roland, McQuade, Jennifer L., Haydu, Lauren E., Kline, Douglas, Chen, Xiufen, Fosco, Dominick, Kline, Justin, Overacre, Abigail, Chikina, Maria, Brunazzi, Erin, Shayan, Gulidanna, Horne, William, Kolls, Jay, Bruno, Tullia C., Workman, Creg, Vignali, Dario, Adusumilli, Prasad S., Ansa-Addo, Ephraim A, Li, Zihai, Gerry, Andrew, Sanderson, Joseph P., Howe, Karen, Docta, Roslin, Gao, Qian, Bagg, Eleanor A. L., Tribble, Nicholas, Maroto, Miguel, Betts, Gareth, Bath, Natalie, Melchiori, Luca, Lowther, Daniel E., Ramachandran, Indu, Kari, Gabor, Basu, Samik, Binder-Scholl, Gwendolyn, Chagin, Karen, Pandite, Lini, Holdich, Tom, Amado, Rafael, Zhang, Hua, Glod, John, Bernstein, Donna, Jakobsen, Bent, Mackall, Crystal, Wong, Ryan, Silk, Jonathan D., Adams, Katherine, Hamilton, Garth, Bennett, Alan D., Brett, Sara, Jing, Junping, Quattrini, Adriano, Saini, Manoj, Wiedermann, Guy, Brewer, Joanna, Duong, MyLinh, Lu, An, Chang, Peter, Mahendravada, Aruna, Shinners, Nicholas, Slawin, Kevin, Spencer, David M., Foster, Aaron E., Bayle, J. Henri, Bergamaschi, Cristina, Ng, Sinnie Sin Man, Nagy, Bethany, Jensen, Shawn, Hu, Xintao, Alicea, Candido, Fox, Bernard, Felber, Barbara, Pavlakis, George, Chacon, Jessica, Yamamoto, Tori, Garrabrant, Thomas, Cortina, Luis, Powell, Daniel J., Donia, Marco, Kjeldsen, Julie Westerlin, Andersen, Rikke, Westergaard, Marie Christine Wulff, Bianchi, Valentina, Legut, Mateusz, Attaf, Meriem, Dolton, Garry, Szomolay, Barbara, Ott, Sascha, Lyngaa, Rikke, Hadrup, Sine Reker, Sewell, Andrew Kelvin, Svane, Inge Marie, Fan, Aaron, Kumai, Takumi, Celis, Esteban, Frank, Ian, Stramer, Amanda, Blaskovich, Michelle A., Wardell, Seth, Fardis, Maria, Bender, James, Lotze, Michael T., Goff, Stephanie L., Zacharakis, Nikolaos, Assadipour, Yasmine, Prickett, Todd D., Gartner, Jared J., Somerville, Robert, Black, Mary, Xu, Hui, Chinnasamy, Harshini, Kriley, Isaac, Lu, Lily, Wunderlich, John, Robbins, Paul F., Rosenberg, Steven, Feldman, Steven A., Trebska-McGowan, Kasia, Malekzadeh, Parisa, Payabyab, Eden, Sherry, Richard, Gokuldass, Aishwarya, Kopits, Charlene, Rabinovich, Brian, Green, Daniel S., Kamenyeva, Olena, Zoon, Kathryn C., Annunziata, Christina M., Hammill, Joanne, Helsen, Christopher, Aarts, Craig, Bramson, Jonathan, Harada, Yui, Yonemitsu, Yoshikazu, Mwawasi, Kenneth, Denisova, Galina, Giri, Rajanish, Jin, Benjamin, Campbell, Tracy, Draper, Lindsey M., Stevanovic, Sanja, Yu, Zhiya, Weissbrich, Bianca, Restifo, Nicholas P., Trimble, Cornelia L., Hinrichs, Christian S., Tsang, Kwong, Fantini, Massimo, Hodge, James W., Fujii, Rika, Fernando, Ingrid, Jochems, Caroline, Heery, Christopher, Gulley, James, Soon-Shiong, Patrick, Schlom, Jeffrey, Jing, Weiqing, Gershan, Jill, Blitzer, Grace, Weber, James, McOlash, Laura, Johnson, Bryon D., Kiany, Simin, Gangxiong, Huang, Kleinerman, Eugenie S., Klichinsky, Michael, Ruella, Marco, Shestova, Olga, Kenderian, Saad, Kim, Miriam, Scholler, John, June, Carl H., Gill, Saar, Moogk, Duane, Zhong, Shi, Liadi, Ivan, Rittase, William, Fang, Victoria, Dougherty, Janna, Perez-Garcia, Arianne, Osman, Iman, Zhu, Cheng, Varadarajan, Navin, Frey, Alan, Krogsgaard, Michelle, Landi, Daniel, Fousek, Kristen, Mukherjee, Malini, Shree, Ankita, Joseph, Sujith, Bielamowicz, Kevin, Byrd, Tiara, Ahmed, Nabil, Hegde, Meenakshi, Lee, Sylvia, Byrd, David, Thompson, John, Bhatia, Shailender, Tykodi, Scott, Delismon, Judy, Chu, Liz, Abdul-Alim, Siddiq, Ohanian, Arpy, DeVito, Anna Marie, Riddell, Stanley, Margolin, Kim, Magalhaes, Isabelle, Mattsson, Jonas, Uhlin, Michael, Nemoto, Satoshi, Villarroel, Patricio Pérez, Nakagawa, Ryosuke, Mule, James J., Mailloux, Adam W., Mata, Melinda, Nguyen, Phuong, Gerken, Claudia, DeRenzo, Christopher, Gottschalk, Stephen, Mathieu, Mélissa, Pelletier, Sandy, Stagg, John, Turcotte, Simon, Minutolo, Nicholas, Sharma, Prannda, Tsourkas, Andrew, Mockel-Tenbrinck, Nadine, Mauer, Daniela, Drechsel, Katharina, Barth, Carola, Freese, Katharina, Kolrep, Ulrike, Schult, Silke, Assenmacher, Mario, Kaiser, Andrew, Mullinax, John, Hall, MacLean, Le, Julie, Kodumudi, Krithika, Royster, Erica, Richards, Allison, Gonzalez, Ricardo, Sarnaik, Amod, Pilon-Thomas, Shari, Nielsen, Morten, Krarup-Hansen, Anders, Hovgaard, Dorrit, Petersen, Michael Mørk, Loya, Anand Chainsukh, Junker, Niels, Rivas, Charlotte, Parihar, Robin, Rooney, Cliona M., Qin, Haiying, Nguyen, Sang, Su, Paul, Burk, Chad, Duncan, Brynn, Kim, Bong-Hyun, Kohler, M. Eric, Fry, Terry, Rao, Arjun A., Teyssier, Noam, Pfeil, Jacob, Sgourakis, Nikolaos, Salama, Sofie, Haussler, David, Richman, Sarah A., Nunez-Cruz, Selene, Gershenson, Zack, Mourelatos, Zissimos, Barrett, David, Grupp, Stephan, Milone, Michael, Rodriguez-Garcia, Alba, Robinson, Matthew K., Adams, Gregory P., Santos, João, Havunen, Riikka, Siurala, Mikko, Cervera-Carrascón, Víctor, Parviainen, Suvi, Antilla, Marjukka, Hemminki, Akseli, Sethuraman, Jyothi, Santiago, Laurelis, Chen, Jie Qing, Dai, Zhimin, Sha, Huizi, Su, Shu, Ding, Naiqing, Liu, Baorui, Pasetto, Anna, Helman, Sarah R., Rosenberg, Steven A., Burgess, Melissa, Zhang, Hui, Lee, Tien, Klingemann, Hans, Nghiem, Paul, Kirkwood, John M., Rossi, John M., Sherman, Marika, Xue, Allen, Shen, Yueh-wei, Navale, Lynn, Kochenderfer, James N., Bot, Adrian, Veerapathran, Anandaraman, Wiener, Doris, Waller, Edmund K., Li, Jian-Ming, Petersen, Christopher, Blazar, Bruce R., Li, Jingxia, Giver, Cynthia R., Wang, Ziming, Grossenbacher, Steven K., Sturgill, Ian, Canter, Robert J., Murphy, William J., Zhang, Congcong, Burger, Michael C., Jennewein, Lukas, Waldmann, Anja, Mittelbronn, Michel, Tonn, Torsten, Steinbach, Joachim P., Wels, Winfried S., Williams, Jason B., Zha, Yuanyuan, Gajewski, Thomas F., Williams, LaTerrica C., Krenciute, Giedre, Kalra, Mamta, Louis, Chrystal, Xin, Gang, Schauder, David, Jiang, Aimin, Joshi, Nikhil, Cui, Weiguo, Zeng, Xue, Zhao, Zeguo, Hamieh, Mohamad, Eyquem, Justin, Gunset, Gertrude, Bander, Neil, Sadelain, Michel, Askmyr, David, Abolhalaj, Milad, Lundberg, Kristina, Greiff, Lennart, Lindstedt, Malin, Angell, Helen K., Kim, Kyoung-Mee, Kim, Seung-Tae, Kim, Sung, Sharpe, Alan D., Ogden, Julia, Davenport, Anna, Hodgson, Darren R., Barrett, Carl, Lee, Jeeyun, Kilgour, Elaine, Hanson, Jodi, Caspell, Richard, Karulin, Alexey, Lehmann, Paul, Ansari, Tameem, Schiller, Annemarie, Sundararaman, Srividya, Roen, Diana, Ayers, Mark, Levitan, Diane, Arreaza, Gladys, Liu, Fang, Mogg, Robin, Bang, Yung-Jue, O’Neil, Bert, Cristescu, Razvan, Friedlander, Philip, Wassman, Karl, Kyi, Chrisann, Oh, William, Bhardwaj, Nina, Bornschlegl, Svetlana, Gustafson, Michael P., Gastineau, Dennis A., Parney, Ian F., Dietz, Allan B., Carvajal-Hausdorf, Daniel, Mani, Nikita, Schalper, Kurt, Rimm, David, Chang, Serena, Kurland, John, Ahlers, Christoph Matthias, Jure-Kunkel, Maria, Cohen, Lewis, Maecker, Holden, Kohrt, Holbrook, Chen, Shuming, Crabill, George, Pritchard, Theresa, McMiller, Tracee, Pardoll, Drew, Pan, Fan, Topalian, Suzanne, Danaher, Patrick, Warren, Sarah, Dennis, Lucas, White, Andrew M., D’Amico, Leonard, Geller, Melissa, Disis, Mary L., Beechem, Joseph, Odunsi, Kunle, Fling, Steven, Derakhshandeh, Roshanak, Webb, Tonya J., Dubois, Sigrid, Conlon, Kevin, Bryant, Bonita, Hsu, Jennifer, Beltran, Nancy, Müller, Jürgen, Waldmann, Thomas, Duhen, Rebekka, Duhen, Thomas, Thompson, Lucas, Montler, Ryan, Weinberg, Andrew, Kates, Max, Early, Brandon, Yusko, Erik, Schreiber, Taylor H., Bivalacqua, Trinity J., Lunceford, Jared, Nebozhyn, Michael, Murphy, Erin, Loboda, Andrey, Kaufman, David R., Albright, Andrew, Cheng, Jonathan, Kang, S. Peter, Shankaran, Veena, Piha-Paul, Sarina A., Yearley, Jennifer, Seiwert, Tanguy, Ribas, Antoni, McClanahan, Terrill K., Sher, Xinwei, Liu, Xiao Qiao, Joe, Andrew, Plimack, Elizabeth, Forrest-Hay, Alex, Guyre, Cheryl A., Narumiya, Kohei, Delcommenne, Marc, Hirsch, Heather A., Deshpande, Amit, Reeves, Jason, Shu, Jenny, Zi, Tong, Michaelson, Jennifer, Law, Debbie, Trehu, Elizabeth, Sathyanaryanan, Sriram, Hodkinson, Brendan P., Hutnick, Natalie A., Schaffer, Michael E., Gormley, Michael, Hulett, Tyler, Ballesteros-Merino, Carmen, Dubay, Christopher, Afentoulis, Michael, Reddy, Ashok, David, Larry, Jayant, Kumar, Agrawal, Swati, Agrawal, Rajendra, Jeyakumar, Ghayathri, Kim, Seongho, Kim, Heejin, Silski, Cynthia, Suisham, Stacey, Heath, Elisabeth, Vaishampayan, Ulka, Vandeven, Natalie, Viller, Natasja Nielsen, O’Connor, Alison, Chen, Hui, Bossen, Bolette, Sievers, Eric, Uger, Robert, Johnson, Lisa, Kao, Hsiang-Fong, Hsiao, Chin-Fu, Lai, Shu-Chuan, Wang, Chun-Wei, Ko, Jenq-Yuh, Lou, Pei-Jen, Lee, Tsai-Jan, Liu, Tsang-Wu, Hong, Ruey-Long, Kearney, Staci J., Black, Joshua C., Landis, Benjamin J., Koegler, Sally, Hirsch, Brooke, Gianani, Roberto, Kim, Jeffrey, He, Ming-Xiao, Zhang, Bingqing, Su, Nan, Luo, Yuling, Ma, Xiao-Jun, Park, Emily, Kim, Dae Won, Copploa, Domenico, Kothari, Nishi, doo Chang, Young, Kim, Richard, Kim, Namyong, Lye, Melvin, Wan, Ee, Knaus, Hanna A., Berglund, Sofia, Hackl, Hubert, Karp, Judith E., Gojo, Ivana, Luznik, Leo, Hong, Henoch S., Koch, Sven D., Scheel, Birgit, Gnad-Vogt, Ulrike, Kallen, Karl-Josef, Wiegand, Volker, Backert, Linus, Kohlbacher, Oliver, Hoerr, Ingmar, Fotin-Mleczek, Mariola, Billingsley, James M., Koguchi, Yoshinobu, Conrad, Valerie, Miller, William, Gonzalez, Iliana, Poplonski, Tomasz, Meeuwsen, Tanisha, Howells-Ferreira, Ana, Rattray, Rogan, Campbell, Mary, Bifulco, Carlo, Bahjat, Keith, Curti, Brendan, Vetsika, E-K, Kallergi, G., Aggouraki, Despoina, Lyristi, Z., Katsarlinos, P., Koinis, Filippos, Georgoulias, V., Kotsakis, Athanasios, Martin, Nathan T., Aeffner, Famke, Cerkovnik, Logan, Pratte, Luke, Kim, Rebecca, Krueger, Joseph, Martínez-Usatorre, Amaia, Jandus, Camilla, Donda, Alena, Carretero-Iglesia, Laura, Speiser, Daniel E., Zehn, Dietmar, Rufer, Nathalie, Romero, Pedro, Panda, Anshuman, Mehnert, Janice, Hirshfield, Kim M., Riedlinger, Greg, Damare, Sherri, Saunders, Tracie, Sokol, Levi, Stein, Mark, Poplin, Elizabeth, Rodriguez-Rodriguez, Lorna, Silk, Ann, Chan, Nancy, Frankel, Melissa, Kane, Michael, Malhotra, Jyoti, Aisner, Joseph, Kaufman, Howard L., Ali, Siraj, Ross, Jeffrey, White, Eileen, Bhanot, Gyan, Ganesan, Shridar, Monette, Anne, Bergeron, Derek, Amor, Amira Ben, Meunier, Liliane, Caron, Christine, Morou, Antigoni, Kaufmann, Daniel, Liberman, Moishe, Jurisica, Igor, Mes-Masson, Anne-Marie, Hamzaoui, Kamel, Lapointe, Rejean, Mongan, Ann, Ku, Yuan-Chieh, Tom, Warren, Sun, Yongming, Pankov, Alex, Looney, Tim, Au-Young, Janice, Hyland, Fiona, Conroy, Jeff, Morrison, Carl, Glenn, 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Savoldo, Barbara, Dotti, Gianpietro, Höglund, Martin, Brenner, Malcolm K., Hagberg, Hans, Loskog, Angelica, Bernett, Matthew J., Moore, Gregory L., Hedvat, Michael, Bonzon, Christine, Chu, Seung, Rashid, Rumana, Avery, Kendra N., Muchhal, Umesh, Desjarlais, John, Kraman, Matthew, Kmiecik, Katarzyna, Allen, Natalie, Faroudi, Mustapha, Zimarino, Carlo, Wydro, Mateusz, Doody, Jacqueline, Srinivasa, Sreesha P., Govindappa, Nagaraja, Reddy, Praveen, Dubey, Aparajita, Periyasamy, Sankar, Adekandi, Madhukara, Dey, Chaitali, Joy, Mary, van Loo, Pieter Fokko, Veninga, Henrike, Shamsili, Setareh, Throsby, Mark, Dolstra, Harry, Bakker, Lex, Alva, Ajjai, Gschwendt, Juergen, Loriot, Yohann, Bellmunt, Joaquim, Feng, Dai, Poehlein, Christian, Powles, Thomas, Antonarakis, Emmanuel S., Drake, Charles G., Wu, Haiyan, De Bono, Johann, Bannerji, Rajat, Byrd, John, Gregory, Gareth, Opat, Stephen, Shortt, Jake, Yee, Andrew J., Raje, Noopur, Thompson, Seth, Balakumaran, Arun, Kumar, Shaji, Rini, Brian I., Choueiri, Toni K., Mariani, Mariangela, Albiges, Laurence, Haanen, John B., Larkin, James, Schmidinger, Manuela, Magazzù, Domenico, di Pietro, Alessandra, Motzer, Robert J., Borch, Troels Holz, Kongsted, Per, Pedersen, Magnus, Met, Özcan, Boudadi, Karim, Wang, Hao, Vasselli, James, Baughman, Jan E., Wigginton, Jon, Abdallah, Rehab, Ross, Ashley, Park, Jiwon, Grossenbacher, Steven, Luna, Jesus I., Withers, Sita, Culp, William, Chen, Mingyi, Monjazeb, Arta, Kent, Michael S., Chandran, Smita, Danforth, David, Yang, James, Klebanoff, Christopher, Goff, Stephanie, Paria, Biman, Sabesan, Arvind, Srivastava, Abhishek, Kammula, Udai, Richards, Jon, Faries, Mark, Andtbacka, Robert H. I., Diaz, Luis A., Le, Dung T., Yoshino, Takayuki, André, Thierry, Bendell, Johanna, Koshiji, Minori, Zhang, Yayan, Kang, S Peter, Lam, Bao, Jäger, Dirk, Bauer, Todd M., Wang, Judy S., Lee, Jean K., Manji, Gulam A., Kudchadkar, Ragini, Kauh, John S., Tang, Shande, Laing, Naomi, Falchook, Gerald, Garon, Edward B., Halmos, Balazs, Rina, Hui, Leighl, Natasha, Lee, Sung Sook, Walsh, William, Dragnev, Konstanin, Piperdi, Bilal, Rodriguez, Luis Paz-Ares, Shinwari, Nabeegha, Wei, Ziewn, Maas, Mary L, Deeds, Michael, Armstrong, Adam, Peterson, Tim, Steinmetz, Sue, Herzog, Thomas, Backes, Floor J., Copeland, Larry, Del Pilar Estevez Diz, Maria, Hare, Thomas W., Huh, Warner, Kim, Byoung-Gie, Moore, Kathleen M., Oaknin, Ana, Small, William, Tewari, Krishnansu S., Monk, Bradley J., Kamat, Ashish M., Nam, Kijoeng, De Santis, Maria, Dreicer, Robert, Hahn, Noah M., Perini, Rodolfo, Siefker-Radtke, Arlene, Sonpavde, Guru, de Wit, Ronald, Witjes, J. Alfred, Keefe, Stephen, Bajorin, Dean, Armand, Philippe, Kuruvilla, John, Moskowitz, Craig, Hamadani, Mehdi, Zinzani, Pier Luigi, Chlosta, Sabine, Bartlett, Nancy, Sabado, Rachel, Saenger, Yvonne, William, Loging, Donovan, Michael Joseph, Sacris, Erlinda, Mandeli, John, Salazar, Andres M., Powderly, John, Brody, Joshua, Nemunaitis, John, Emens, Leisha, Patnaik, Amita, McCaffery, Ian, Miller, Richard, Laport, Ginna, Coveler, Andrew L., Smith, David C., Grilley-Olson, Juneko E., Goel, Sanjay, Gardai, Shyra J., Law, Che-Leung, Means, Gary, Manley, Thomas, Marrone, Kristen A., Rosner, Gary, Anagnostou, Valsamo, Riemer, Joanne, Wakefield, Jessica, Zanhow, Cynthia, Baylin, Stephen, Gitlitz, Barbara, Brahmer, Julie, Signoretti, Sabina, Li, Wenting, Schloss, Charles, Michot, Jean-Marie, Ding, Wei, Christian, Beth, Marinello, Patricia, Shipp, Margaret, Najjar, Yana G., Lin, Butterfield, Lisa H., Tarhini, Ahmad A., Davar, Diwakar, Zarour, Hassane, Rush, Elizabeth, Sander, Cindy, Fu, Siqing, Bauer, Todd, Molineaux, Chris, Bennett, Mark K., Orford, Keith W., Papadopoulos, Kyriakos P., Padda, Sukhmani K., Shah, Sumit A., Colevas, A Dimitrios, Narayanan, Sujata, Fisher, George A., Supan, Dana, Wakelee, Heather A., Aoki, Rhonda, Pegram, Mark D., Villalobos, Victor M., Liu, Jie, Takimoto, Chris H., Chao, Mark, Volkmer, Jens-Peter, Majeti, Ravindra, Weissman, Irving L., Sikic, Branimir I., Yu, Wendy, Conlin, Alison, Ruzich, Janet, Lewis, Stacy, Acheson, Anupama, Kemmer, Kathleen, Perlewitz, Kelly, Moxon, Nicole M., Mellinger, Staci, McArthur, Heather, Juhler-Nøttrup, Trine, Desai, Jayesh, Markman, Ben, Sandhu, Shahneen, Gan, Hui, Friedlander, Michael L., Tran, Ben, Meniawy, Tarek, Lundy, Joanne, Colyer, Duncan, Ameratunga, Malaka, Norris, Christie, Yang, Jason, Li, Kang, Wang, Lai, Luo, Lusong, Qin, Zhen, Mu, Song, Tan, Xuemei, Song, James, Millward, Michael, Katz, Matthew H. G., Bauer, Todd W., Varadhachary, Gauri R., Acquavella, Nicolas, Merchant, Nipun, Petroni, Gina, Rahma, Osama E., Chen, Mei, Song, Yang, Puhlmann, Markus, Khattri, Arun, Brisson, Ryan, Harvey, Christopher, Shah, Jatin, Mateos, Maria Victoria, Matsumoto, Morio, Blacklock, Hilary, Rocafiguera, Albert Oriol, Goldschmidt, Hartmut, Iida, Shinsuke, Yehuda, Dina Ben, Ocio, Enrique, Rodríguez-Otero, Paula, Jagannath, Sundar, Lonial, Sagar, Kher, Uma, San-Miguel, Jesus, de Oliveira, Moacyr Ribeiro, Yimer, Habte, Rifkin, Robert, Schjesvold, Fredrik, Ghori, Razi, Spreafico, Anna, Lee, Victor, Ngan, Roger K. C., To, Ka Fai, Ahn, Myung Ju, Ng, Quan Sing, Lin, Jin-Ching, Swaby, Ramona F., Gause, Christine, Saraf, Sanatan, Chan, Anthony T. C., Lam, Elaine, Tannir, Nizar M., Meric-Bernstam, Funda, Gross, Matt, MacKinnon, Andy, Whiting, Sam, Voss, Martin, Yu, Evan Y., Albertini, Mark R., Ranheim, Erik A., Hank, Jacquelyn A., Zuleger, Cindy, McFarland, Thomas, Collins, Jennifer, Clements, Erin, Weber, Sharon, Weigel, Tracey, Neuman, Heather, Hartig, Greg, Mahvi, David, Henry, MaryBeth, Gan, Jacek, Yang, Richard, Carmichael, Lakeesha, Kim, KyungMann, Gillies, Stephen D., Sondel, Paul M., Subbiah, Vivek, Noffsinger, Lori, Hendricks, Kyle, Bosch, Marnix, Lee, Jay M., Lee, Mi-Heon, Goldman, Jonathan W., Baratelli, Felicita E., Schaue, Dorthe, Wang, Gerald, Rosen, Frances, Yanagawa, Jane, Walser, Tonya C., Lin, Ying Q., Adams, Sharon, Marincola, Franco M., Tumeh, Paul C., Abtin, Fereidoun, Suh, Robert, Reckamp, Karen, Wallace, William D., Zeng, Gang, Elashoff, David A., Sharma, Sherven, Dubinett, Steven M., Pavlick, Anna C., Gastman, Brian, Hanks, Brent, Keler, Tibor, Davis, Tom, Vitale, Laura A., Sharon, Elad, Morishima, Chihiro, Cheever, Martin, Heery, Christopher R., Kim, Joseph W., Lamping, Elizabeth, Marte, Jennifer, McMahon, Sheri, Cordes, Lisa, Fakhrejahani, Farhad, Madan, Ravi, Salazar, Rachel, Zhang, Maggie, Helwig, Christoph, Gulley, James L, Li, Roger, Amrhein, John, Cohen, Zvi, Champagne, Monique, Kamat, Ashish, Aznar, M. Angela, Labiano, Sara, Diaz-Lagares, Angel, Esteller, Manel, Sandoval, Juan, Barbee, Susannah D., Bellovin, David I., Timmer, John C., Wondyfraw, Nebiyu, Johnson, Susan, Park, Johanna, Chen, Amanda, Mkrtichyan, Mikayel, Razai, Amir S., Jones, Kyle S., Hata, Chelsie Y., Gonzalez, Denise, Deveraux, Quinn, Eckelman, Brendan P., Borges, Luis, Bhardwaj, Rukmini, Puri, Raj K., Suzuki, Akiko, Leland, Pamela, Joshi, Bharat H., Bartkowiak, Todd, Jaiswal, Ashvin, Ager, Casey, Ai, Midan, Budhani, Pratha, Chin, Renee, Hong, David, Curran, Michael, Hastings, William D., Pinzon-Ortiz, Maria, Murakami, Masato, Dobson, Jason R., Quinn, David, Wagner, Joel P., Rong, Xianhui, Shaw, Pamela, Dammassa, Ernesta, Guan, Wei, Dranoff, Glenn, Cao, Alexander, Fulton, Ross B., Leonardo, Steven, Fraser, Kathryn, Kangas, Takashi O., Ottoson, Nadine, Bose, Nandita, Huhn, Richard D., Graff, Jeremy, Lowe, Jamie, Gorden, Keith, Uhlik, Mark, O’Neill, Thomas, Widger, Jenifer, Crocker, Andrea, He, Li-Zhen, Weidlick, Jeffrey, Sundarapandiyan, Karuna, Ramakrishna, Venky, Storey, James, Thomas, Lawrence J., Goldstein, Joel, Marsh, Henry C., Grailer, Jamison, Gilden, Julia, Stecha, Pete, Garvin, Denise, Hartnett, Jim, Fan, Frank, Cong, Mei, Cheng, Zhi-jie Jey, Hinner, Marlon J., Aiba, Rachida-Siham Bel, Schlosser, Corinna, Jaquin, Thomas, Allersdorfer, Andrea, Berger, Sven, Wiedenmann, Alexander, Matschiner, Gabriele, Schüler, Julia, Moebius, Ulrich, Rothe, Christine, Shane, Olwill A., Horton, Brendan, Spranger, Stefani, Moreira, Dayson, Adamus, Tomasz, Zhao, Xingli, Swiderski, Piotr, Pal, Sumanta, Kortylewski, Marcin, Kosmides, Alyssa, Necochea, Kevin, Mahoney, Kathleen M., Shukla, Sachet A., Patsoukis, Nikolaos, Chaudhri, Apoorvi, Pham, Hung, Hua, Ping, Bu, Xia, Zhu, Baogong, Hacohen, Nir, Wu, Catherine J., Fritsch, Edward, Boussiotis, Vassiliki A., Freeman, Gordon J., Moran, Amy E., Polesso, Fanny, Lukaesko, Lisa, Rådestad, Emelie, Egevad, Lars, Sundberg, Berit, Henningsohn, Lars, Levitsky, Victor, Rafelson, William, Reagan, John L., Fast, Loren, Sasikumar, Pottayil, Sudarshan, Naremaddepalli, Ramachandra, Raghuveer, Gowda, Nagesh, Samiulla, Dodheri, Chandrasekhar, Talapaneni, Adurthi, Sreenivas, Mani, Jiju, Nair, Rashmi, Dhudashia, Amit, Gowda, Nagaraj, Ramachandra, Murali, Sankin, Alexander, Gartrell, Benjamin, Cumberbatch, Kerwin, Huang, Hongying, Stern, Joshua, Schoenberg, Mark, Zang, Xingxing, Swanson, Ryan, Kornacker, Michael, Evans, Lawrence, Rickel, Erika, Wolfson, Martin, Valsesia-Wittmann, Sandrine, Shekarian, Tala, Simard, François, Nailo, Rodrigo, Dutour, Aurélie, Jallas, Anne-Catherine, Caux, Christophe, and Marabelle, Aurélien

Published
2016
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49. Qualitative Analysis of Tumor-Infiltrating Lymphocytes across Human Tumor Types Reveals a Higher Proportion of Bystander CD8 + T Cells in Non-Melanoma Cancers Compared to Melanoma.

Author

Gokuldass, Aishwarya, Draghi, Arianna, Papp, Krisztian, Borch, Troels Holz, Nielsen, Morten, Westergaard, Marie Christine Wulff, Andersen, Rikke, Schina, Aimilia, Bol, Kalijn Fredrike, Chamberlain, Christopher Aled, Presti, Mario, Met, Özcan, Harbst, Katja, Lauss, Martin, Soraggi, Samuele, Csabai, Istvan, Szállási, Zoltán, Jönsson, Göran, Svane, Inge Marie, and Donia, Marco

Subjects
ANTIGENS, CELL physiology, GENE expression, MELANOMA, T cells, T-test (Statistics), QUALITATIVE research, DATA analysis software, DESCRIPTIVE statistics, SEQUENCE analysis, MANN Whitney U Test
Abstract

Simple Summary: Human tumors are often infiltrated by T cells; however, it remains unclear what proportion of T cells infiltrating tumors are bystander and non-tumor specific. We have investigated qualitative characteristics of these tumor-infiltrating lymphocytes (TILs) based on their gene-expression in the tumor-microenvironment or on their response to autologous tumor cells in vitro. Despite a considerable inter-sample variability, we found the overall proportion of bystander (non-tumor reactive) TILs to be remarkably high. Importantly, we observed a higher proportion of bystander TILs in non-melanoma tumors, compared to melanoma. This study suggests that immunotherapeutic strategies, especially when applied to non-melanoma tumors, should be tailored to reinvigorate the small proportion of tumor-reactive T cells infiltrating the tumor-microenvironment. Background: Human intratumoral T cell infiltrates can be defined by quantitative or qualitative features, such as their ability to recognize autologous tumor antigens. In this study, we reproduced the tumor-T cell interactions of individual patients to determine and compared the qualitative characteristics of intratumoral T cell infiltrates across multiple tumor types. Methods: We employed 187 pairs of unselected tumor-infiltrating lymphocytes (TILs) and autologous tumor cells from patients with melanoma, renal-, ovarian-cancer or sarcoma, and single-cell RNA sequencing data from a pooled cohort of 93 patients with melanoma or epithelial cancers. Measures of TIL quality including the proportion of tumor-reactive CD8+ and CD4+ TILs, and TIL response polyfunctionality were determined. Results: Tumor-specific CD8+ and CD4+ TIL responses were detected in over half of the patients in vitro, and greater CD8+ TIL responses were observed in melanoma, regardless of previous anti-PD-1 treatment, compared to renal cancer, ovarian cancer and sarcoma. The proportion of tumor-reactive CD4+ TILs was on average lower and the differences less pronounced across tumor types. Overall, the proportion of tumor-reactive TILs in vitro was remarkably low, implying a high fraction of TILs to be bystanders, and highly variable within the same tumor type. In situ analyses, based on eight single-cell RNA-sequencing datasets encompassing melanoma and five epithelial cancers types, corroborated the results obtained in vitro. Strikingly, no strong correlation between the proportion of CD8+ and CD4+ tumor-reactive TILs was detected, suggesting the accumulation of these responses in the tumor microenvironment to follow non-overlapping biological pathways. Additionally, no strong correlation between TIL responses and tumor mutational burden (TMB) in melanoma was observed, indicating that TMB was not a major driving force of response. No substantial differences in polyfunctionality across tumor types were observed. Conclusions: These analyses shed light on the functional features defining the quality of TIL infiltrates in cancer. A significant proportion of TILs across tumor types, especially non-melanoma, are bystander T cells. These results highlight the need to develop strategies focused on the tumor-reactive TIL subpopulation. [ABSTRACT FROM AUTHOR]

Published
2020
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50. 31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016): part one

Author

Lundqvist, Andreas, van Hoef, Vincent, Zhang, Xiaonan, Wennerberg, Erik, Lorent, Julie, Witt, Kristina, Sanz, Laia Masvidal, Liang, Shuo, Murray, Shannon, Larsson, Ola, Kiessling, Rolf, Mao, Yumeng, Sidhom, John-William, Bessell, Catherine A., Havel, Jonathan, Schneck, Jonathan, Chan, Timothy A., Sachsenmeier, Eliot, Woods, David, Berglund, Anders, Ramakrishnan, Rupal, Sodre, Andressa, Weber, Jeffrey, Zappasodi, Roberta, Li, Yanyun, Qi, Jingjing, Wong, Philip, Sirard, Cynthia, Postow, Michael, Newman, Walter, Koon, Henry, Velcheti, Vamsidhar, Callahan, Margaret K., Wolchok, Jedd D., Merghoub, Taha, Lum, Lawrence G., Choi, Minsig, Thakur, Archana, Deol, Abhinav, Dyson, Gregory, Shields, Anthony, Haymaker, Cara, Uemura, Marc, Murthy, Ravi, James, Marihella, Wang, Daqing, Brevard, Julie, Monaghan, Catherine, Swann, Suzanne, Geib, James, Cornfeld, Mark, Chunduru, Srinivas, Agrawal, Sudhir, Yee, Cassian, Wargo, Jennifer, Patel, Sapna P., Amaria, Rodabe, Tawbi, Hussein, Glitza, Isabella, Woodman, Scott, Hwu, Wen-Jen, Davies, Michael A., Hwu, Patrick, Overwijk, Willem W., Bernatchez, Chantale, Diab, Adi, Massarelli, Erminia, Segal, Neil H., Ribrag, Vincent, Melero, Ignacio, Gangadhar, Tara C., Urba, Walter, Schadendorf, Dirk, Ferris, Robert L., Houot, Roch, Morschhauser, Franck, Logan, Theodore, Luke, Jason J., Sharfman, William, Barlesi, Fabrice, Ott, Patrick A., Mansi, Laura, Kummar, Shivaani, Salles, Gilles, Carpio, Cecilia, Meier, Roland, Krishnan, Suba, McDonald, Dan, Maurer, Matthew, Gu, Xuemin, Neely, Jaclyn, Suryawanshi, Satyendra, Levy, Ronald, Khushalani, Nikhil, Wu, Jennifer, Zhang, Jinyu, Basher, Fahmin, Rubinstein, Mark, Bucsek, Mark, Qiao, Guanxi, MacDonald, Cameron, Hylander, Bonnie, Repasky, Elizabeth, Chatterjee, Shilpak, Daenthanasanmak, Anusara, Chakraborty, Paramita, Toth, Kyle, Meek, Megan, Garrett-Mayer, Elizabeth, Nishimura, Michael, Paulos, Chrystal, Beeson, Craig, Yu, Xuezhong, Mehrotra, Shikhar, Zhao, Fei, Evans, Kathy, Xiao, Christine, Holtzhausen, Alisha, Hanks, Brent A., Scharping, Nicole, Menk, Ashley V., Moreci, Rebecca, Whetstone, Ryan, Dadey, Rebekah, Watkins, Simon, Ferris, Robert, Delgoffe, Greg M., Peled, Jonathan, Devlin, Sean, Staffas, Anna, Lumish, Melissa, Rodriguez, Kori Porosnicu, Ahr, Katya, Perales, Miguel, Giralt, Sergio, Taur, Ying, Pamer, Eric, van den Brink, Marcel R. M., Jenq, Robert, Annels, Nicola, Pandha, Hardev, Simpson, Guy, Mostafid, Hugh, Harrington, Kevin, Melcher, Alan, Grose, Mark, Davies, Bronwyn, Au, Gough, Karpathy, Roberta, Shafren, Darren, Ricca, Jacob, Zamarin, Dmitriy, Batista, Luciana, Marliot, Florence, Vasaturo, Angela, Carpentier, Sabrina, Poggionovo, Cécile, Frayssinet, Véronique, Fieschi, Jacques, Van den Eynde, Marc, Pagès, Franck, Galon, Jérôme, Hermitte, Fabienne, Smith, Sean G., Nguyen, Khue, Ravindranathan, Sruthi, Koppolu, Bhanu, Zaharoff, David, Schvartsman, Gustavo, Bassett, Roland, McQuade, Jennifer L., Haydu, Lauren E., Kline, Douglas, Chen, Xiufen, Fosco, Dominick, Kline, Justin, Overacre, Abigail, Chikina, Maria, Brunazzi, Erin, Shayan, Gulidanna, Horne, William, Kolls, Jay, Bruno, Tullia C., Workman, Creg, Vignali, Dario, Adusumilli, Prasad S., Ansa-Addo, Ephraim A, Li, Zihai, Gerry, Andrew, Sanderson, Joseph P., Howe, Karen, Docta, Roslin, Gao, Qian, Bagg, Eleanor A. L., Tribble, Nicholas, Maroto, Miguel, Betts, Gareth, Bath, Natalie, Melchiori, Luca, Lowther, Daniel E., Ramachandran, Indu, Kari, Gabor, Basu, Samik, Binder-Scholl, Gwendolyn, Chagin, Karen, Pandite, Lini, Holdich, Tom, Amado, Rafael, Zhang, Hua, Glod, John, Bernstein, Donna, Jakobsen, Bent, Mackall, Crystal, Wong, Ryan, Silk, Jonathan D., Adams, Katherine, Hamilton, Garth, Bennett, Alan D., Brett, Sara, Jing, Junping, Quattrini, Adriano, Saini, Manoj, Wiedermann, Guy, Brewer, Joanna, Duong, MyLinh, Lu, An, Chang, Peter, Mahendravada, Aruna, Shinners, Nicholas, Slawin, Kevin, Spencer, David M., Foster, Aaron E., Bayle, J. Henri, Bergamaschi, Cristina, Ng, Sinnie Sin Man, Nagy, Bethany, Jensen, Shawn, Hu, Xintao, Alicea, Candido, Fox, Bernard, Felber, Barbara, Pavlakis, George, Chacon, Jessica, Yamamoto, Tori, Garrabrant, Thomas, Cortina, Luis, Powell, Daniel J., Donia, Marco, Kjeldsen, Julie Westerlin, Andersen, Rikke, Westergaard, Marie Christine Wulff, Bianchi, Valentina, Legut, Mateusz, Attaf, Meriem, Dolton, Garry, Szomolay, Barbara, Ott, Sascha, Lyngaa, Rikke, Hadrup, Sine Reker, Sewell, Andrew Kelvin, Svane, Inge Marie, Fan, Aaron, Kumai, Takumi, Celis, Esteban, Frank, Ian, Stramer, Amanda, Blaskovich, Michelle A., Wardell, Seth, Fardis, Maria, Bender, James, Lotze, Michael T., Goff, Stephanie L., Zacharakis, Nikolaos, Assadipour, Yasmine, Prickett, Todd D., Gartner, Jared J., Somerville, Robert, Black, Mary, Xu, Hui, Chinnasamy, Harshini, Kriley, Isaac, Lu, Lily, Wunderlich, John, Robbins, Paul F., Rosenberg, Steven, Feldman, Steven A., Trebska-McGowan, Kasia, Malekzadeh, Parisa, Payabyab, Eden, Sherry, Richard, Gokuldass, Aishwarya, Kopits, Charlene, Rabinovich, Brian, Green, Daniel S., Kamenyeva, Olena, Zoon, Kathryn C., Annunziata, Christina M., Hammill, Joanne, Helsen, Christopher, Aarts, Craig, Bramson, Jonathan, Harada, Yui, Yonemitsu, Yoshikazu, Mwawasi, Kenneth, Denisova, Galina, Giri, Rajanish, Jin, Benjamin, Campbell, Tracy, Draper, Lindsey M., Stevanovic, Sanja, Yu, Zhiya, Weissbrich, Bianca, Restifo, Nicholas P., Trimble, Cornelia L., Hinrichs, Christian S., Tsang, Kwong, Fantini, Massimo, Hodge, James W., Fujii, Rika, Fernando, Ingrid, Jochems, Caroline, Heery, Christopher, Gulley, James, Soon-Shiong, Patrick, Schlom, Jeffrey, Jing, Weiqing, Gershan, Jill, Blitzer, Grace, Weber, James, McOlash, Laura, Johnson, Bryon D., Kiany, Simin, Gangxiong, Huang, Kleinerman, Eugenie S., Klichinsky, Michael, Ruella, Marco, Shestova, Olga, Kenderian, Saad, Kim, Miriam, Scholler, John, June, Carl H., Gill, Saar, Moogk, Duane, Zhong, Shi, Liadi, Ivan, Rittase, William, Fang, Victoria, Dougherty, Janna, Perez-Garcia, Arianne, Osman, Iman, Zhu, Cheng, Varadarajan, Navin, Frey, Alan, Krogsgaard, Michelle, Landi, Daniel, Fousek, Kristen, Mukherjee, Malini, Shree, Ankita, Joseph, Sujith, Bielamowicz, Kevin, Byrd, Tiara, Ahmed, Nabil, Hegde, Meenakshi, Lee, Sylvia, Byrd, David, Thompson, John, Bhatia, Shailender, Tykodi, Scott, Delismon, Judy, Chu, Liz, Abdul-Alim, Siddiq, Ohanian, Arpy, DeVito, Anna Marie, Riddell, Stanley, Margolin, Kim, Magalhaes, Isabelle, Mattsson, Jonas, Uhlin, Michael, Nemoto, Satoshi, Villarroel, Patricio Pérez, Nakagawa, Ryosuke, Mule, James J., Mailloux, Adam W., Mata, Melinda, Nguyen, Phuong, Gerken, Claudia, DeRenzo, Christopher, Gottschalk, Stephen, Mathieu, Mélissa, Pelletier, Sandy, Stagg, John, Turcotte, Simon, Minutolo, Nicholas, Sharma, Prannda, Tsourkas, Andrew, Mockel-Tenbrinck, Nadine, Mauer, Daniela, Drechsel, Katharina, Barth, Carola, Freese, Katharina, Kolrep, Ulrike, Schult, Silke, Assenmacher, Mario, Kaiser, Andrew, Mullinax, John, Hall, MacLean, Le, Julie, Kodumudi, Krithika, Royster, Erica, Richards, Allison, Gonzalez, Ricardo, Sarnaik, Amod, Pilon-Thomas, Shari, Nielsen, Morten, Krarup-Hansen, Anders, Hovgaard, Dorrit, Petersen, Michael Mørk, Loya, Anand Chainsukh, Junker, Niels, Rivas, Charlotte, Parihar, Robin, Rooney, Cliona M., Qin, Haiying, Nguyen, Sang, Su, Paul, Burk, Chad, Duncan, Brynn, Kim, Bong-Hyun, Kohler, M. Eric, Fry, Terry, Rao, Arjun A., Teyssier, Noam, Pfeil, Jacob, Sgourakis, Nikolaos, Salama, Sofie, Haussler, David, Richman, Sarah A., Nunez-Cruz, Selene, Gershenson, Zack, Mourelatos, Zissimos, Barrett, David, Grupp, Stephan, Milone, Michael, Rodriguez-Garcia, Alba, Robinson, Matthew K., Adams, Gregory P., Santos, João, Havunen, Riikka, Siurala, Mikko, Cervera-Carrascón, Víctor, Parviainen, Suvi, Antilla, Marjukka, Hemminki, Akseli, Sethuraman, Jyothi, Santiago, Laurelis, Chen, Jie Qing, Dai, Zhimin, Sha, Huizi, Su, Shu, Ding, Naiqing, Liu, Baorui, Pasetto, Anna, Helman, Sarah R., Rosenberg, Steven A., Burgess, Melissa, Zhang, Hui, Lee, Tien, Klingemann, Hans, Nghiem, Paul, Kirkwood, John M., Rossi, John M., Sherman, Marika, Xue, Allen, Shen, Yueh-wei, Navale, Lynn, Kochenderfer, James N., Bot, Adrian, Veerapathran, Anandaraman, Wiener, Doris, Waller, Edmund K., Li, Jian-Ming, Petersen, Christopher, Blazar, Bruce R., Li, Jingxia, Giver, Cynthia R., Wang, Ziming, Grossenbacher, Steven K., Sturgill, Ian, Canter, Robert J., Murphy, William J., Zhang, Congcong, Burger, Michael C., Jennewein, Lukas, Waldmann, Anja, Mittelbronn, Michel, Tonn, Torsten, Steinbach, Joachim P., Wels, Winfried S., Williams, Jason B., Zha, Yuanyuan, Gajewski, Thomas F., Williams, LaTerrica C., Krenciute, Giedre, Kalra, Mamta, Louis, Chrystal, Xin, Gang, Schauder, David, Jiang, Aimin, Joshi, Nikhil, Cui, Weiguo, Zeng, Xue, Zhao, Zeguo, Hamieh, Mohamad, Eyquem, Justin, Gunset, Gertrude, Bander, Neil, Sadelain, Michel, Askmyr, David, Abolhalaj, Milad, Lundberg, Kristina, Greiff, Lennart, Lindstedt, Malin, Angell, Helen K., Kim, Kyoung-Mee, Kim, Seung-Tae, Kim, Sung, Sharpe, Alan D., Ogden, Julia, Davenport, Anna, Hodgson, Darren R., Barrett, Carl, Lee, Jeeyun, Kilgour, Elaine, Hanson, Jodi, Caspell, Richard, Karulin, Alexey, Lehmann, Paul, Ansari, Tameem, Schiller, Annemarie, Sundararaman, Srividya, Roen, Diana, Ayers, Mark, Levitan, Diane, Arreaza, Gladys, Liu, Fang, Mogg, Robin, Bang, Yung-Jue, O’Neil, Bert, Cristescu, Razvan, Friedlander, Philip, Wassman, Karl, Kyi, Chrisann, Oh, William, Bhardwaj, Nina, Bornschlegl, Svetlana, Gustafson, Michael P., Gastineau, Dennis A., Parney, Ian F., Dietz, Allan B., Carvajal-Hausdorf, Daniel, Mani, Nikita, Schalper, Kurt, Rimm, David, Chang, Serena, Kurland, John, Ahlers, Christoph Matthias, Jure-Kunkel, Maria, Cohen, Lewis, Maecker, Holden, Kohrt, Holbrook, Chen, Shuming, Crabill, George, Pritchard, Theresa, McMiller, Tracee, Pardoll, Drew, Pan, Fan, Topalian, Suzanne, Danaher, Patrick, Warren, Sarah, Dennis, Lucas, White, Andrew M., D’Amico, Leonard, Geller, Melissa, Disis, Mary L., Beechem, Joseph, Odunsi, Kunle, Fling, Steven, Derakhshandeh, Roshanak, Webb, Tonya J., Dubois, Sigrid, Conlon, Kevin, Bryant, Bonita, Hsu, Jennifer, Beltran, Nancy, Müller, Jürgen, Waldmann, Thomas, Duhen, Rebekka, Duhen, Thomas, Thompson, Lucas, Montler, Ryan, Weinberg, Andrew, Kates, Max, Early, Brandon, Yusko, Erik, Schreiber, Taylor H., Bivalacqua, Trinity J., Lunceford, Jared, Nebozhyn, Michael, Murphy, Erin, Loboda, Andrey, Kaufman, David R., Albright, Andrew, Cheng, Jonathan, Kang, S. Peter, Shankaran, Veena, Piha-Paul, Sarina A., Yearley, Jennifer, Seiwert, Tanguy, Ribas, Antoni, McClanahan, Terrill K., Sher, Xinwei, Liu, Xiao Qiao, Joe, Andrew, Plimack, Elizabeth, Forrest-Hay, Alex, Guyre, Cheryl A., Narumiya, Kohei, Delcommenne, Marc, Hirsch, Heather A., Deshpande, Amit, Reeves, Jason, Shu, Jenny, Zi, Tong, Michaelson, Jennifer, Law, Debbie, Trehu, Elizabeth, Sathyanaryanan, Sriram, Hodkinson, Brendan P., Hutnick, Natalie A., Schaffer, Michael E., Gormley, Michael, Hulett, Tyler, Ballesteros-Merino, Carmen, Dubay, Christopher, Afentoulis, Michael, Reddy, Ashok, David, Larry, Jayant, Kumar, Agrawal, Swati, Agrawal, Rajendra, Jeyakumar, Ghayathri, Kim, Seongho, Kim, Heejin, Silski, Cynthia, Suisham, Stacey, Heath, Elisabeth, Vaishampayan, Ulka, Vandeven, Natalie, Viller, Natasja Nielsen, O’Connor, Alison, Chen, Hui, Bossen, Bolette, Sievers, Eric, Uger, Robert, Johnson, Lisa, Kao, Hsiang-Fong, Hsiao, Chin-Fu, Lai, Shu-Chuan, Wang, Chun-Wei, Ko, Jenq-Yuh, Lou, Pei-Jen, Lee, Tsai-Jan, Liu, Tsang-Wu, Hong, Ruey-Long, Kearney, Staci J., Black, Joshua C., Landis, Benjamin J., Koegler, Sally, Hirsch, Brooke, Gianani, Roberto, Kim, Jeffrey, He, Ming-Xiao, Zhang, Bingqing, Su, Nan, Luo, Yuling, Ma, Xiao-Jun, Park, Emily, Kim, Dae Won, Copploa, Domenico, Kothari, Nishi, doo Chang, Young, Kim, Richard, Kim, Namyong, Lye, Melvin, Wan, Ee, Knaus, Hanna A., Berglund, Sofia, Hackl, Hubert, Karp, Judith E., Gojo, Ivana, Luznik, Leo, Hong, Henoch S., Koch, Sven D., Scheel, Birgit, Gnad-Vogt, Ulrike, Kallen, Karl-Josef, Wiegand, Volker, Backert, Linus, Kohlbacher, Oliver, Hoerr, Ingmar, Fotin-Mleczek, Mariola, Billingsley, James M., Koguchi, Yoshinobu, Conrad, Valerie, Miller, William, Gonzalez, Iliana, Poplonski, Tomasz, Meeuwsen, Tanisha, Howells-Ferreira, Ana, Rattray, Rogan, Campbell, Mary, Bifulco, Carlo, Bahjat, Keith, Curti, Brendan, Vetsika, E-K, Kallergi, G., Aggouraki, Despoina, Lyristi, Z., Katsarlinos, P., Koinis, Filippos, Georgoulias, V., Kotsakis, Athanasios, Martin, Nathan T., Aeffner, Famke, Cerkovnik, Logan, Pratte, Luke, Kim, Rebecca, Krueger, Joseph, Martínez-Usatorre, Amaia, Jandus, Camilla, Donda, Alena, Carretero-Iglesia, Laura, Speiser, Daniel E., Zehn, Dietmar, Rufer, Nathalie, Romero, Pedro, Panda, Anshuman, Mehnert, Janice, Hirshfield, Kim M., Riedlinger, Greg, Damare, Sherri, Saunders, Tracie, Sokol, Levi, Stein, Mark, Poplin, Elizabeth, Rodriguez-Rodriguez, Lorna, Silk, Ann, Chan, Nancy, Frankel, Melissa, Kane, Michael, Malhotra, Jyoti, Aisner, Joseph, Kaufman, Howard L., Ali, Siraj, Ross, Jeffrey, White, Eileen, Bhanot, Gyan, Ganesan, Shridar, Monette, Anne, Bergeron, Derek, Amor, Amira Ben, Meunier, Liliane, Caron, Christine, Morou, Antigoni, Kaufmann, Daniel, Liberman, Moishe, Jurisica, Igor, Mes-Masson, Anne-Marie, Hamzaoui, Kamel, Lapointe, Rejean, Mongan, Ann, Ku, Yuan-Chieh, Tom, Warren, Sun, Yongming, Pankov, Alex, Looney, Tim, Au-Young, Janice, Hyland, Fiona, Conroy, Jeff, Morrison, Carl, Glenn, Sean, Burgher, Blake, Ji, He, Gardner, Mark, Omilian, Angela R., Bshara, Wiam, Angela, Omilian, Obeid, Joseph M., Erdag, Gulsun, Smolkin, Mark E., Deacon, Donna H., Patterson, James W., Chen, Lieping, Bullock, Timothy N., Slingluff, Craig L., Loffredo, John T., Vuyyuru, Raja, Beyer, Sophie, Spires, Vanessa M., Fox, Maxine, Ehrmann, Jon M., Taylor, Katrina A., Korman, Alan J., Graziano, Robert F., Page, David, Sanchez, Katherine, Martel, Maritza, De Macedo, Mariana Petaccia, Qin, Yong, Reuben, Alex, Spencer, Christine, Guindani, Michele, Racolta, Adriana, Kelly, Brian, Jones, Tobin, Polaske, Nathan, Theiss, Noah, Robida, Mark, Meridew, Jeffrey, Habensus, Iva, Zhang, Liping, Pestic-Dragovich, Lidija, Tang, Lei, Sullivan, Ryan J., Olencki, Thomas, Hutson, Thomas, Roder, Joanna, Blackmon, Shauna, Roder, Heinrich, Stewart, John, Amin, Asim, Ernstoff, Marc S., Clark, Joseph I., Atkins, Michael B., Sosman, Jeffrey, McDermott, David F., Kluger, Harriet, Halaban, Ruth, Snzol, Mario, Asmellash, Senait, Steingrimsson, Arni, Wang, Chichung, Roman, Kristin, Clement, Amanda, Downing, Sean, Hoyt, Clifford, Harder, Nathalie, Schmidt, Guenter, Schoenmeyer, Ralf, Brieu, Nicolas, Yigitsoy, Mehmet, Madonna, Gabriele, Botti, Gerardo, Grimaldi, Antonio, Ascierto, Paolo A., Huss, Ralf, Athelogou, Maria, Hessel, Harald, Buchner, Alexander, Stief, Christian, Binnig, Gerd, Kirchner, Thomas, Sellappan, Shankar, Thyparambil, Sheeno, Schwartz, Sarit, Cecchi, Fabiola, Nguyen, Andrew, Vaske, Charles, Hembrough, Todd, Spacek, Jan, Vocka, Michal, Zavadova, Eva, Skalova, Helena, Dundr, Pavel, Petruzelka, Lubos, Francis, Nicole, Tilman, Rau T., Hartmann, Arndt, Netikova, Irena, Stump, Julia, Tufman, Amanda, Berger, Frank, Neuberger, Michael, Hatz, Rudolf, Lindner, Michael, Sanborn, Rachel E., Handy, John, Huber, Rudolf M., Winter, Hauke, Reu, Simone, Sun, Cheng, Xiao, Weihua, Tian, Zhigang, Arora, Kshitij, Desai, Niyati, Kulkarni, Anupriya, Rajurkar, Mihir, Rivera, Miguel, Deshpande, Vikram, Ting, David, Tsai, Katy, Nosrati, Adi, Goldinger, Simone, Hamid, Omid, Algazi, Alain, Tumeh, Paul, Hwang, Jimmy, Liu, Jacqueline, Chen, Lawrence, Dummer, Reinhard, Rosenblum, Michael, Daud, Adil, Tsao, Tsu-Shuen, Ashworth-Sharpe, Julia, Johnson, Donald, Bhaumik, Srabani, Bieniarz, Christopher, Couto, Joseph, Farrell, Michael, Ghaffari, Mahsa, Hubbard, Antony, Kosmeder, Jerome, Lee, Cleo, Marner, Erin, Uribe, Diana, Zhang, Hongjun, Zhang, Jian, Zhang, Wenjun, Zhu, Yifei, Morrison, Larry, Tsujikawa, Takahiro, Borkar, Rohan N., Azimi, Vahid, Kumar, Sushil, Thibault, Guillaume, Mori, Motomi, El Rassi, Edward, Clayburgh, Daniel R., Kulesz-Martin, Molly F., Flint, Paul W., Coussens, Lisa M., Villabona, Lisa, Masucci, Giuseppe V., Geiss, Gary, Birditt, Brian, Mei, Qian, Huang, Alan, Eagan, Maribeth A., Ignacio, Eduardo, Elliott, Nathan, Dunaway, Dwayne, Jung, Jaemyeong, Merritt, Chris, Sprague, Isaac, Webster, Philippa, Liang, Yan, Wenthe, Jessica, Enblad, Gunilla, Karlsson, Hannah, Essand, Magnus, Savoldo, Barbara, Dotti, Gianpietro, Höglund, Martin, Brenner, Malcolm K., Hagberg, Hans, Loskog, Angelica, Bernett, Matthew J., Moore, Gregory L., Hedvat, Michael, Bonzon, Christine, Chu, Seung, Rashid, Rumana, Avery, Kendra N., Muchhal, Umesh, Desjarlais, John, Kraman, Matthew, Kmiecik, Katarzyna, Allen, Natalie, Faroudi, Mustapha, Zimarino, Carlo, Wydro, Mateusz, Doody, Jacqueline, Srinivasa, Sreesha P., Govindappa, Nagaraja, Reddy, Praveen, Dubey, Aparajita, Periyasamy, Sankar, Adekandi, Madhukara, Dey, Chaitali, Joy, Mary, van Loo, Pieter Fokko, Veninga, Henrike, Shamsili, Setareh, Throsby, Mark, Dolstra, Harry, Bakker, Lex, Alva, Ajjai, Gschwendt, Juergen, Loriot, Yohann, Bellmunt, Joaquim, Feng, Dai, Poehlein, Christian, Powles, Thomas, Antonarakis, Emmanuel S., Drake, Charles G., Wu, Haiyan, De Bono, Johann, Bannerji, Rajat, Byrd, John, Gregory, Gareth, Opat, Stephen, Shortt, Jake, Yee, Andrew J., Raje, Noopur, Thompson, Seth, Balakumaran, Arun, Kumar, Shaji, Rini, Brian I., Choueiri, Toni K., Mariani, Mariangela, Albiges, Laurence, Haanen, John B., Larkin, James, Schmidinger, Manuela, Magazzù, Domenico, di Pietro, Alessandra, Motzer, Robert J., Borch, Troels Holz, Kongsted, Per, Pedersen, Magnus, Met, Özcan, Boudadi, Karim, Wang, Hao, Vasselli, James, Baughman, Jan E., Wigginton, Jon, Abdallah, Rehab, Ross, Ashley, Park, Jiwon, Grossenbacher, Steven, Luna, Jesus I., Withers, Sita, Culp, William, Chen, Mingyi, Monjazeb, Arta, Kent, Michael S., Chandran, Smita, Danforth, David, Yang, James, Klebanoff, Christopher, Goff, Stephanie, Paria, Biman, Sabesan, Arvind, Srivastava, Abhishek, Kammula, Udai, Richards, Jon, Faries, Mark, Andtbacka, Robert H. I., Diaz, Luis A., Le, Dung T., Yoshino, Takayuki, André, Thierry, Bendell, Johanna, Koshiji, Minori, Zhang, Yayan, Kang, S Peter, Lam, Bao, Jäger, Dirk, Bauer, Todd M., Wang, Judy S., Lee, Jean K., Manji, Gulam A., Kudchadkar, Ragini, Kauh, John S., Tang, Shande, Laing, Naomi, Falchook, Gerald, Garon, Edward B., Halmos, Balazs, Rina, Hui, Leighl, Natasha, Lee, Sung Sook, Walsh, William, Dragnev, Konstanin, Piperdi, Bilal, Rodriguez, Luis Paz-Ares, Shinwari, Nabeegha, Wei, Ziewn, Maas, Mary L, Deeds, Michael, Armstrong, Adam, Peterson, Tim, Steinmetz, Sue, Herzog, Thomas, Backes, Floor J., Copeland, Larry, Del Pilar Estevez Diz, Maria, Hare, Thomas W., Huh, Warner, Kim, Byoung-Gie, Moore, Kathleen M., Oaknin, Ana, Small, William, Tewari, Krishnansu S., Monk, Bradley J., Kamat, Ashish M., Nam, Kijoeng, De Santis, Maria, Dreicer, Robert, Hahn, Noah M., Perini, Rodolfo, Siefker-Radtke, Arlene, Sonpavde, Guru, de Wit, Ronald, Witjes, J. Alfred, Keefe, Stephen, Bajorin, Dean, Armand, Philippe, Kuruvilla, John, Moskowitz, Craig, Hamadani, Mehdi, Zinzani, Pier Luigi, Chlosta, Sabine, Bartlett, Nancy, Sabado, Rachel, Saenger, Yvonne, William, Loging, Donovan, Michael Joseph, Sacris, Erlinda, Mandeli, John, Salazar, Andres M., Powderly, John, Brody, Joshua, Nemunaitis, John, Emens, Leisha, Patnaik, Amita, McCaffery, Ian, Miller, Richard, Laport, Ginna, Coveler, Andrew L., Smith, David C., Grilley-Olson, Juneko E., Goel, Sanjay, Gardai, Shyra J., Law, Che-Leung, Means, Gary, Manley, Thomas, Marrone, Kristen A., Rosner, Gary, Anagnostou, Valsamo, Riemer, Joanne, Wakefield, Jessica, Zanhow, Cynthia, Baylin, Stephen, Gitlitz, Barbara, Brahmer, Julie, Signoretti, Sabina, Li, Wenting, Schloss, Charles, Michot, Jean-Marie, Ding, Wei, Christian, Beth, Marinello, Patricia, Shipp, Margaret, Najjar, Yana G., Lin, Butterfield, Lisa H., Tarhini, Ahmad A., Davar, Diwakar, Zarour, Hassane, Rush, Elizabeth, Sander, Cindy, Fu, Siqing, Bauer, Todd, Molineaux, Chris, Bennett, Mark K., Orford, Keith W., Papadopoulos, Kyriakos P., Padda, Sukhmani K., Shah, Sumit A., Colevas, A Dimitrios, Narayanan, Sujata, Fisher, George A., Supan, Dana, Wakelee, Heather A., Aoki, Rhonda, Pegram, Mark D., Villalobos, Victor M., Liu, Jie, Takimoto, Chris H., Chao, Mark, Volkmer, Jens-Peter, Majeti, Ravindra, Weissman, Irving L., Sikic, Branimir I., Yu, Wendy, Conlin, Alison, Ruzich, Janet, Lewis, Stacy, Acheson, Anupama, Kemmer, Kathleen, Perlewitz, Kelly, Moxon, Nicole M., Mellinger, Staci, McArthur, Heather, Juhler-Nøttrup, Trine, Desai, Jayesh, Markman, Ben, Sandhu, Shahneen, Gan, Hui, Friedlander, Michael L., Tran, Ben, Meniawy, Tarek, Lundy, Joanne, Colyer, Duncan, Ameratunga, Malaka, Norris, Christie, Yang, Jason, Li, Kang, Wang, Lai, Luo, Lusong, Qin, Zhen, Mu, Song, Tan, Xuemei, Song, James, Millward, Michael, Katz, Matthew H. G., Bauer, Todd W., Varadhachary, Gauri R., Acquavella, Nicolas, Merchant, Nipun, Petroni, Gina, Rahma, Osama E., Chen, Mei, Song, Yang, Puhlmann, Markus, Khattri, Arun, Brisson, Ryan, Harvey, Christopher, Shah, Jatin, Mateos, Maria Victoria, Matsumoto, Morio, Blacklock, Hilary, Rocafiguera, Albert Oriol, Goldschmidt, Hartmut, Iida, Shinsuke, Yehuda, Dina Ben, Ocio, Enrique, Rodríguez-Otero, Paula, Jagannath, Sundar, Lonial, Sagar, Kher, Uma, San-Miguel, Jesus, de Oliveira, Moacyr Ribeiro, Yimer, Habte, Rifkin, Robert, Schjesvold, Fredrik, Ghori, Razi, Spreafico, Anna, Lee, Victor, Ngan, Roger K. C., To, Ka Fai, Ahn, Myung Ju, Ng, Quan Sing, Lin, Jin-Ching, Swaby, Ramona F., Gause, Christine, Saraf, Sanatan, Chan, Anthony T. C., Lam, Elaine, Tannir, Nizar M., Meric-Bernstam, Funda, Gross, Matt, MacKinnon, Andy, Whiting, Sam, Voss, Martin, Yu, Evan Y., Albertini, Mark R., Ranheim, Erik A., Hank, Jacquelyn A., Zuleger, Cindy, McFarland, Thomas, Collins, Jennifer, Clements, Erin, Weber, Sharon, Weigel, Tracey, Neuman, Heather, Hartig, Greg, Mahvi, David, Henry, MaryBeth, Gan, Jacek, Yang, Richard, Carmichael, Lakeesha, Kim, KyungMann, Gillies, Stephen D., Sondel, Paul M., Subbiah, Vivek, Noffsinger, Lori, Hendricks, Kyle, Bosch, Marnix, Lee, Jay M., Lee, Mi-Heon, Goldman, Jonathan W., Baratelli, Felicita E., Schaue, Dorthe, Wang, Gerald, Rosen, Frances, Yanagawa, Jane, Walser, Tonya C., Lin, Ying Q., Adams, Sharon, Marincola, Franco M., Tumeh, Paul C., Abtin, Fereidoun, Suh, Robert, Reckamp, Karen, Wallace, William D., Zeng, Gang, Elashoff, David A., Sharma, Sherven, Dubinett, Steven M., Pavlick, Anna C., Gastman, Brian, Hanks, Brent, Keler, Tibor, Davis, Tom, Vitale, Laura A., Sharon, Elad, Morishima, Chihiro, Cheever, Martin, Heery, Christopher R., Kim, Joseph W., Lamping, Elizabeth, Marte, Jennifer, McMahon, Sheri, Cordes, Lisa, Fakhrejahani, Farhad, Madan, Ravi, Salazar, Rachel, Zhang, Maggie, Helwig, Christoph, Gulley, James L, Li, Roger, Amrhein, John, Cohen, Zvi, Champagne, Monique, Kamat, Ashish, Aznar, M. Angela, Labiano, Sara, Diaz-Lagares, Angel, Esteller, Manel, Sandoval, Juan, Barbee, Susannah D., Bellovin, David I., Timmer, John C., Wondyfraw, Nebiyu, Johnson, Susan, Park, Johanna, Chen, Amanda, Mkrtichyan, Mikayel, Razai, Amir S., Jones, Kyle S., Hata, Chelsie Y., Gonzalez, Denise, Deveraux, Quinn, Eckelman, Brendan P., Borges, Luis, Bhardwaj, Rukmini, Puri, Raj K., Suzuki, Akiko, Leland, Pamela, Joshi, Bharat H., Bartkowiak, Todd, Jaiswal, Ashvin, Ager, Casey, Ai, Midan, Budhani, Pratha, Chin, Renee, Hong, David, Curran, Michael, Hastings, William D., Pinzon-Ortiz, Maria, Murakami, Masato, Dobson, Jason R., Quinn, David, Wagner, Joel P., Rong, Xianhui, Shaw, Pamela, Dammassa, Ernesta, Guan, Wei, Dranoff, Glenn, Cao, Alexander, Fulton, Ross B., Leonardo, Steven, Fraser, Kathryn, Kangas, Takashi O., Ottoson, Nadine, Bose, Nandita, Huhn, Richard D., Graff, Jeremy, Lowe, Jamie, Gorden, Keith, Uhlik, Mark, O’Neill, Thomas, Widger, Jenifer, Crocker, Andrea, He, Li-Zhen, Weidlick, Jeffrey, Sundarapandiyan, Karuna, Ramakrishna, Venky, Storey, James, Thomas, Lawrence J., Goldstein, Joel, Marsh, Henry C., Grailer, Jamison, Gilden, Julia, Stecha, Pete, Garvin, Denise, Hartnett, Jim, Fan, Frank, Cong, Mei, Cheng, Zhi-jie Jey, Hinner, Marlon J., Aiba, Rachida-Siham Bel, Schlosser, Corinna, Jaquin, Thomas, Allersdorfer, Andrea, Berger, Sven, Wiedenmann, Alexander, Matschiner, Gabriele, Schüler, Julia, Moebius, Ulrich, Rothe, Christine, Shane, Olwill A., Horton, Brendan, Spranger, Stefani, Moreira, Dayson, Adamus, Tomasz, Zhao, Xingli, Swiderski, Piotr, Pal, Sumanta, Kortylewski, Marcin, Kosmides, Alyssa, Necochea, Kevin, Mahoney, Kathleen M., Shukla, Sachet A., Patsoukis, Nikolaos, Chaudhri, Apoorvi, Pham, Hung, Hua, Ping, Bu, Xia, Zhu, Baogong, Hacohen, Nir, Wu, Catherine J., Fritsch, Edward, Boussiotis, Vassiliki A., Freeman, Gordon J., Moran, Amy E., Polesso, Fanny, Lukaesko, Lisa, Rådestad, Emelie, Egevad, Lars, Sundberg, Berit, Henningsohn, Lars, Levitsky, Victor, Rafelson, William, Reagan, John L., Fast, Loren, Sasikumar, Pottayil, Sudarshan, Naremaddepalli, Ramachandra, Raghuveer, Gowda, Nagesh, Samiulla, Dodheri, Chandrasekhar, Talapaneni, Adurthi, Sreenivas, Mani, Jiju, Nair, Rashmi, Dhudashia, Amit, Gowda, Nagaraj, Ramachandra, Murali, Sankin, Alexander, Gartrell, Benjamin, Cumberbatch, Kerwin, Huang, Hongying, Stern, Joshua, Schoenberg, Mark, Zang, Xingxing, Swanson, Ryan, Kornacker, Michael, Evans, Lawrence, Rickel, Erika, Wolfson, Martin, Valsesia-Wittmann, Sandrine, Shekarian, Tala, Simard, François, Nailo, Rodrigo, Dutour, Aurélie, Jallas, Anne-Catherine, Caux, Christophe, and Marabelle, Aurélien

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