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1. Safety profile of pembrolizumab monotherapy based on an aggregate safety evaluation of 8937 patients.

Author

Brahmer, Julie, Long, Georgina, Hamid, Omid, Garon, Edward, Herbst, Roy, Andre, Thierry, Armand, Philippe, Bajorin, Dean, Bellmunt, Joaquim, Burtness, Barbara, Choueiri, Toni, Cohen, Ezra, Diaz, Luis, Shitara, Kohei, Kulkarni, Girish, McDermott, David, Shah, Manish, Tabernero, Josep, Vogel, Arndt, Zinzani, Pier, Jafari, Niusha, Bird, Steven, Snyder, Ellen, Gause, Christine, Bracco, Oswaldo, Pietanza, M, Gruber, Todd, and Ribas, Antoni

Subjects
Neoplasms, Pembrolizumab, Programmed cell death 1 receptor, Safety, Humans, Carcinoma, Non-Small-Cell Lung, Lung Neoplasms, Antibodies, Monoclonal, Humanized, Melanoma
Abstract

BACKGROUND: Pembrolizumab has a manageable safety profile as described in its label, which was primarily based on 2799 patients who participated in clinical trials for melanoma or non-small cell lung cancer. Here, we evaluated the safety of pembrolizumab in a broader population of patients from 31 advanced cancer clinical trials across 19 cancer types. METHODS: Safety was analyzed in patients who received at least one dose of pembrolizumab (200 mg every 3 weeks [Q3W], 10 mg/kg Q2W or Q3W, or 2 mg/kg Q3W). Adverse events (AEs) and immune-mediated AEs and infusion reactions were evaluated. RESULTS: Safety data from 8937 patients in 31 trials of pembrolizumab monotherapy were pooled (median, seven administrations; range, 1-59). Median duration on treatment was 4.1 months (range, 0.03-40.1). AEs occurred in 96.6% of patients. Grade 3-5 AEs occurred in 50.6% of patients. AEs led to pembrolizumab discontinuation in 12.7% of patients and death in 5.9%. Immune-mediated AEs and infusion reactions occurred in 23.7% of patients (4.6% experienced multiple immune-mediated AEs/infusion reactions) and led to pembrolizumab discontinuation in 3.6% and death in 0.2%. Grade 3-5 immune-mediated AEs occurred in 6.3% of patients. Serious immune-mediated AEs and infusion reactions occurred in 6.0% of patients. Median time to immune-mediated AE onset was 85 days (range, 13-163). Of 2657 immune-mediated AEs, 22.3% were initially treated with prednisone ≥ 40 mg/day or equivalent, and 8.3% were initially treated with lower steroid doses. CONCLUSIONS: This pooled analysis of 31 clinical trials showed that pembrolizumab has a consistent safety profile across indications.

Published
2024

6. Perioperative nivolumab versus observation in patients with renal cell carcinoma undergoing nephrectomy (PROSPER ECOG-ACRIN EA8143): an open-label, randomised, phase 3 study

Author

Allaf, Mohamad E, Kim, Se-Eun, Master, Viraj, McDermott, David F, Harshman, Lauren C, Cole, Suzanne M, Drake, Charles G, Signoretti, Sabina, Akgul, Mahmut, Baniak, Nicholas, Li-Ning, Elsa, Palmer, Matthew B, Emamekhoo, Hamid, Adra, Nabil, Kaimakliotis, Hristos, Ged, Yasser, Pierorazio, Phillip M, Abel, E Jason, Bilen, Mehmet A, Ogan, Kenneth, Moon, Helen H, Ramaswamy, Krishna A, Singer, Eric A, Mayer, Tina M, Lohrey, Jay, Margulis, Vitaly, Gills, Jessie, Delacroix, Scott E, Waples, Mark J, James, Andrew C, Wang, Peng, Choueiri, Toni, Michaelson, M Dror, Kapoor, Anil, Heng, Daniel Y, Shuch, Brian, Leibovich, Bradley C, Lara, Primo N, Manola, Judith, Maskens, Deborah, Battle, Dena, Uzzo, Robert, Bratslavsky, Gennady, Haas, Naomi B, and Carducci, Michael A

Published
2024
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8. Validation of the Lung Immune Prognostic Index (LIPI) as a prognostic biomarker in metastatic renal cell carcinoma

Author

Carril-Ajuria, Lucia, Lavaud, Pernelle, Dalban, Cecile, Negrier, Sylvie, Gravis, Gwénaëlle, Motzer, Robert J., Chevreau, Christine, Tannir, Nizar M., Oudard, Stéphane, McDermott, David F., Laguerre, Brigitte, Hammers, Hans J., Barthelemy, Philippe, Plimack, Elizabeth R., Borchiellini, Delphine, Gross-Goupil, Marine, Jiang, Ruiyun, Lee, Chung-Wei, de Silva, Heshani, Rini, Brian I., Escudier, Bernard, and Albigès, Laurence

Published
2024
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9. Perturbations of the T-cell receptor repertoire in response to SARS-CoV-2 in immunocompetent and immunocompromised individuals

Author

Delmonte, Ottavia M., Oguz, Cihan, Dobbs, Kerry, Myint-Hpu, Katherine, Palterer, Boaz, Abers, Michael S., Draper, Deborah, Truong, Meng, Kaplan, Ian M., Gittelman, Rachel M., Zhang, Yu, Rosen, Lindsey B., Snow, Andrew L., Dalgard, Clifton L., Burbelo, Peter D., Imberti, Luisa, Sottini, Alessandra, Quiros-Roldan, Eugenia, Castelli, Francesco, Rossi, Camillo, Brugnoni, Duilio, Biondi, Andrea, Bettini, Laura Rachele, D’Angio, Mariella, Bonfanti, Paolo, Anderson, Megan V., Saracino, Annalisa, Chironna, Maria, Di Stefano, Mariantonietta, Fiore, Jose Ramon, Santantonio, Teresa, Castagnoli, Riccardo, Marseglia, Gian Luigi, Magliocco, Mary, Bosticardo, Marita, Pala, Francesca, Shaw, Elana, Matthews, Helen, Weber, Sarah E., Xirasagar, Sandhya, Barnett, Jason, Oler, Andrew J., Dimitrova, Dimana, Bergerson, Jenna R.E., McDermott, David H., Rao, V. Koneti, Murphy, Philip M., Holland, Steven M., Lisco, Andrea, Su, Helen C., Lionakis, Michail S., Cohen, Jeffrey I., Freeman, Alexandra F., Snyder, Thomas M., Lack, Justin, and Notarangelo, Luigi D.

Published
2024
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10. Safety profile of pembrolizumab monotherapy based on an aggregate safety evaluation of 8937 patients

Author

Brahmer, Julie R., Long, Georgina V., Hamid, Omid, Garon, Edward B., Herbst, Roy S., Andre, Thierry, Armand, Philippe, Bajorin, Dean, Bellmunt, Joaquim, Burtness, Barbara, Choueiri, Toni K., Cohen, Ezra E.W., Diaz, Luis A., Jr, Shitara, Kohei, Kulkarni, Girish, McDermott, David, Shah, Manish, Tabernero, Josep, Vogel, Arndt, Zinzani, Pier Luigi, Jafari, Niusha, Bird, Steven, Snyder, Ellen, Gause, Christine, Bracco, Oswaldo L., Pietanza, M. Catherine, Gruber, Todd, and Ribas, Antoni

Published
2024
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13. WHIM Syndrome-linked CXCR4 mutations drive osteoporosis

Author

Anginot, Adrienne, Nguyen, Julie, Abou Nader, Zeina, Rondeau, Vincent, Bonaud, Amélie, Kalogeraki, Maria, Boutin, Antoine, Lemos, Julia P., Bisio, Valeria, Koenen, Joyce, Hanna Doumit Sakr, Lea, Picart, Amandine, Coudert, Amélie, Provot, Sylvain, Dulphy, Nicolas, Aurrand-Lions, Michel, Mancini, Stéphane J. C., Lazennec, Gwendal, McDermott, David H., Guidez, Fabien, Blin-Wakkach, Claudine, Murphy, Philip M., Cohen-Solal, Martine, Espéli, Marion, Rouleau, Matthieu, and Balabanian, Karl

Published
2023
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16. Salvage Ipilimumab and Nivolumab in Patients With Metastatic Renal Cell Carcinoma After Prior Immune Checkpoint Inhibitors.

Author

Gul, Anita, Stewart, Tyler F, Mantia, Charlene M, Shah, Neil J, Gatof, Emily Stern, Long, Ying, Allman, Kimberly D, Ornstein, Moshe C, Hammers, Hans J, McDermott, David F, Atkins, Michael B, Hurwitz, Michael, and Rini, Brian I

Subjects
Kidney Disease, Cancer, Clinical Research, Evaluation of treatments and therapeutic interventions, 6.2 Cellular and gene therapies, Good Health and Well Being, Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols, B7-H1 Antigen, Carcinoma, Renal Cell, Disease Progression, Female, Humans, Immune Checkpoint Inhibitors, Ipilimumab, Kidney Neoplasms, Male, Middle Aged, Nivolumab, Programmed Cell Death 1 Receptor, Progression-Free Survival, Retreatment, Retrospective Studies, Salvage Therapy, Young Adult, Clinical Sciences, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

PurposeImmune checkpoint inhibitors (ICIs) are standard therapy in metastatic renal cell carcinoma (RCC). The safety and activity of the combination of ipilimumab and nivolumab in patients who have received prior ICI targeting the programmed death 1 (PD-1) pathway remains unknown. We evaluated ipilimumab and nivolumab in patients with metastatic RCC after prior treatment with anti-PD-1 pathway-targeted therapy.Patients and methodsPatients with metastatic RCC who received prior anti-PD-1 pathway-targeted therapy and subsequently received ipilimumab and nivolumab were reviewed. Objective response rate and progression-free survival per investigator assessment were recorded. Toxicity of ipilimumab and nivolumab was also assessed.ResultsForty-five patients with metastatic RCC were included. All patients (100%) received prior ICIs targeting the PD-1 pathway. The median age was 62 years (range, 21-82 years). At a median follow-up of 12 months, the objective response rate to ipilimumab and nivolumab was 20%. The median progression-free survival while on ipilimumab and nivolumab was 4 months (range, 0.8-19 months). Immune-related adverse events (irAEs) of any grade with ipilimumab and nivolumab were recorded in 29 (64%) of the 45 patients; grade 3 irAEs were recorded in 6 (13%) of the 45 patients.ConclusionIpilimumab and nivolumab demonstrated antitumor activity with acceptable toxicity in patients with metastatic RCC who had prior treatment with checkpoint inhibition.

Published
2020

17. Discovery of several thousand highly diverse circular DNA viruses

Author

Tisza, Michael J, Pastrana, Diana V, Welch, Nicole L, Stewart, Brittany, Peretti, Alberto, Starrett, Gabriel J, Pang, Yuk-Ying S, Krishnamurthy, Siddharth R, Pesavento, Patricia A, McDermott, David H, Murphy, Philip M, Whited, Jessica L, Miller, Bess, Brenchley, Jason, Rosshart, Stephan P, Rehermann, Barbara, Doorbar, John, Ta'ala, Blake A, Pletnikova, Olga, Troncoso, Juan C, Resnick, Susan M, Bolduc, Ben, Sullivan, Matthew B, Varsani, Arvind, Segall, Anca M, and Buck, Christopher B

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Infectious Diseases, Biotechnology, Aetiology, 2.2 Factors relating to the physical environment, Infection, Animals, Capsid Proteins, DNA Virus Infections, DNA Viruses, DNA, Circular, DNA, Viral, Genome, Viral, Humans, Molecular Sequence Annotation, Software, evolutionary biology, infectious disease, metagenomics, microbiology, microbiome, viral evolution, virus, Biochemistry and Cell Biology, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Although millions of distinct virus species likely exist, only approximately 9000 are catalogued in GenBank's RefSeq database. We selectively enriched for the genomes of circular DNA viruses in over 70 animal samples, ranging from nematodes to human tissue specimens. A bioinformatics pipeline, Cenote-Taker, was developed to automatically annotate over 2500 complete genomes in a GenBank-compliant format. The new genomes belong to dozens of established and emerging viral families. Some appear to be the result of previously undescribed recombination events between ssDNA and ssRNA viruses. In addition, hundreds of circular DNA elements that do not encode any discernable similarities to previously characterized sequences were identified. To characterize these 'dark matter' sequences, we used an artificial neural network to identify candidate viral capsid proteins, several of which formed virus-like particles when expressed in culture. These data further the understanding of viral sequence diversity and allow for high throughput documentation of the virosphere.

Published
2020

19. A phase III randomized crossover trial of plerixafor versus G-CSF for treatment of WHIM syndrome

Author

McDermott, David H., Velez, Daniel, Cho, Elena, Cowen, Edward W., DiGiovanna, John J., Pastrana, Diana V., Buck, Christopher B., Calvo, Katherine R., Gardner, Pamela J., Rosenzweig, Sergio D., Stratton, Pamela, Merideth, Melissa A., Kim, H. Jeffrey, Brewer, Carmen, Katz, James D., Kuhns, Douglas B., Malech, Harry L., Follmann, Dean, Fay, Michael P., and Murphy, Philip M.

Subjects
Granulocyte colony-stimulating factor -- Testing -- Comparative analysis, Immunological deficiency syndromes -- Drug therapy, Health care industry
Abstract

BACKGROUND. Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a primary immunodeficiency disorder caused by heterozygous gain-of-function CXCR4 mutations. Myelokathexis is a kind of neutropenia caused by neutrophil retention in bone marrow and in WHIM syndrome is associated with lymphopenia and monocytopenia. The CXCR4 antagonist plerixafor mobilizes leukocytes to the blood; however, its safety and efficacy in WHIM syndrome are undefined. METHODS. In this investigator-initiated, single-center, quadruple-masked phase III crossover trial, we compared the total infection severity score (TISS) as the primary endpoint in an intent-to-treat manner in 19 patients with WHIM who each received 12 months treatment with plerixafor and 12 months treatment with granulocyte CSF (G-CSF, the standard of care for severe congenital neutropenia). The treatment order was randomized for each patient. RESULTS. Plerixafor was nonsuperior to G-CSF for TISS (P = 0.54). In exploratory endpoints, plerixafor was noninferior to G-CSF for maintaining neutrophil counts of more than 500 cells/[micro]L (P = 0.023) and was superior to G-CSF for maintaining lymphocyte counts above 1,000 cells/[micro]L (P < 0.0001). Complete regression of a subset of large wart areas occurred on plerixafor in 5 of 7 patients with major wart burdens at baseline. Transient rash occurred on plerixafor, and bone pain was more common on GCSF. There were no significant differences in drug preference or quality of life or the incidence of drug failure or serious adverse events. CONCLUSION. Plerixafor was not superior to G-CSF in patients with WHIM for TISS, the primary endpoint. Together with wart regression and hematologic improvement, the infection severity results support continued study of plerixafor as a potential treatment for WHIM syndrome. TRIAL REGISTRATION. Clinicaltrials.gov NCT02231879. FUNDING. This study was funded by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases., Introduction Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome presents in childhood, with severe congenital neutropenia (SCN), lymphopenia, hypogammaglobulinemia, recurrent otosinopulmonary and skin infections, and warts. Warts and hypogammaglobulinemia are incompletely [...]

Published
2023
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21. Pembrolizumab versus placebo as post-nephrectomy adjuvant therapy for clear cell renal cell carcinoma (KEYNOTE-564): 30-month follow-up analysis of a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial

Author

Tomczak, Piotr, Choueiri, Toni, Park, Se Hoon, Venugopal, Balaji, Ferguson, Thomas R., Hajek, Jaroslav, Lin, Tzu-Ping, Symeonides, Stefan N., Lee, Jae Lyun, Sawrycki, Piotr, Haas, Naomi B., Gurney, Howard P., Mahave, Mauricio, Sarwar, Naveed, Thiery-Vuillemin, Antoine, Gross-Goupil, Marine, Chevreau, Christine, Burke, John M., Doshi, Gurjyot, Melichar, Bohuslav, Topart, Delphine, Oudard, Stephane, Kopyltsov, Evgeniy, Hammers, Hans-Joerg, Quinn, David I., Alva, Ajjai, Menezes, Juliana de Janoski, Silva, Adriano Goncalves e, Winquist, Eric W., Hamzaj, Alketa, Procopio, Giuseppe, Karaszewska, Boguslawa, Nowakowska-Zajdel, Ewa M., Alekseev, Boris Y., Gafanov, Rustem A., Izmailov, Adel, Semenov, Andrey, Afanasyev, Sergey G., Lipatov, Oleg N., Powles, Thomas B., Srinivas, Sandy, McDermott, David, Kochuparambil, Samith T., Davis, Ian D., Peltola, Katriina, Sabbatini, Roberto, Chung, Jinsoo, Shkolnik, Michail I., Matveev, Vsevolod B., Gajate Borau, Pablo, McCune, Steven, Hutson, Thomas E., Dri, Alejandro, Sales, Silvio Correia, Yeung, Carrie, Alcala Castro, Carmen Marcela, Bostrom, Peter, Laguerre, Brigitte, Buttigliero, Consuelo, de Giorgi, Ugo, Fomin, Eugeniy A., Zakharia, Yousef, Hwang, Clara, Singer, Eric A., Yorio, Jeffrey T., Waterhouse, David, Kowalyszyn, Ruben Dario, Alfie, Margarita Sonia, Yanez Ruiz, Eduardo, Buchler, Tomas, Kankaanranta, Krista, Ferretti, Gianluigi, Kimura, Go, Nishimura, Kazuo, Masumori, Naoya, Tamada, Satoshi, Kato, Haruaki, Kitamura, Hiroshi, Danielewicz, Iwona, Wojcik-Tomaszewska, Joanna, Sala Gonzalez, Nuria, Chiu, Kun-Yuan, Atkins, Michael B., Heath, Elisabeth, Rojas-Uribe, Gustavo Adolfo, Gonzalez Fernandez, Manuel Enrique, Feyerabend, Susan, Pignata, Sandro, Numakura, Kazuyuki, Cybulska Stopa, Bozena, Zukov, Ruslan, Climent Duran, Miguel Angel, Maroto Rey, Pablo Jose, Montesa Pino, Alvaro, Chang, Chao-Hsiang, Vengalil, Salil, Waddell, Tom S., Cobb, Patrick W., Hauke, Ralph, Anderson, Daniel M., Sarantopoulos, John, Gourdin, Theodore, Zhang, Tian, Jayram, Gautam, Fein, Luis Enrique, Harris, Carole, Beato, Patricia Medeiros Milhomem, Flores, Francisco, Estay, Angela, Rubiano, Juan Andres, Bedke, Jens, Hauser, Stefan, Neisius, Andreas, Busch, Jonas, Anai, Satoshi, Tsunemori, Hiroyuki, Sawka, Dariusz, Sikora-Kupis, Bozena, Arranz, Jose Angel, Delgado, Ignacio, Chen, Chung-Hsin, Gunderson, Elizabeth, Tykodi, Scott, Koletsky, Alan, Chen, Kevin, Agrawal, Manish, Kaen, Diego Lucas, Sade, Juan Pablo, Tatangelo, Marcelo Daniel, Parnis, Francis, Barbosa, Fernando Maciel, Faucher, Genevieve, Iqbal, Nayyer, Marceau, Daniele, Paradis, Jean-Benoit, Hanna, Nawar, Acevedo, Alejandro, Ibanez, Carolina, Villanueva, Luis, Galaz, Pedro Pablo, Durango, Isabel Cristina, Manneh, Ray, Kral, Zdenek, Holeckova, Petra, Hakkarainen, Heikki, Ronkainen, Hanna, Abadie-Lacourtoisie, Sophie, Tartas, Sophie, Goebell, Peter J., Grimm, Marc-Oliver, Hoefner, Thomas, Wirth, Manfred, Panic, Andrej, Schultze-Seemann, Wolfgang, Yokomizo, Akira, Mizuno, Ryuichi, Uemura, Hirotsugu, Eto, Masatoshi, Tsujihata, Masao, Matsukawa, Yoshihisa, Murakami, Yoji, Kim, Miso, Hamberg, Paul, Marczewska-Skrodzka, Malgorzata, Szczylik, Cezary, Humphreys, Alison C., Jiang, Peter, Kumar, Birendra, Lu, Gary, Desai, Arpita, Karam, Jose Antonio, Keogh, George, Fleming, Mark, Zarba, Juan Jose, Leiva, Viviana E., Mendez, Guillermo Ariel, Harris, Samuel J., Brown, Stephen J., Antonio Junior, Joao Neif, Costamilan, Rita de Cassia, Rocha, Roberto Odebrecht, Muniz, David, Brust, Leandro, Lalani, Aly-Khan, Graham, Jeffrey, Levesque, Michael, Orlandi, Francisco, Kotasek, Rostislav, Deville, Jean L., Borchiellini, Delphine, Merseburger, Axel, Rink, Michael, Roos, Frederik, McDermott, Ray, Oyama, Masafumi, Yamamoto, Yoshiaki, Tomita, Yoshihiko, Miura, Yuji, Ioritani, Naomasa, Westgeest, Hans, Kubiatowski, Tomasz, Bal, Wieslaw, Girones Sarrio, Regina, Rowe, Julie, Prow, Debra M., Senecal, Francis, Hashemi-Sadraei, Neda, Cole, Scott W., Kendall, Stephan D., Richards, Donald A., Schnadig, Ian D., Gupta, Mukul, Powles, Thomas, Ferguson, Thomas, Symeonides, Stefan N, Gurney, Howard, Chang, Yen-Hwa, Haas, Naomi B, Burgents, Joseph E, Xu, Lei, Imai, Kentaro, Quinn, David I, and Choueiri, Toni K

Published
2022
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22. Æthelinghood, succession and kingship in late Anglo-Saxon England, with specific reference to Edmund II Ironside

Author

McDermott, David, Lavelle, Ryan, and Yorke, Barbara

Subjects
942.01
Abstract

This Thesis is an examination of the career and kingship of Edmund II Ironside. In making Edmund the focus, it is possible to re-examine æthelinghood, succession and kingship, from an alternative perspective. The primary sources consulted are chronicles, histories, diplomas and legislation. Central to the investigation of Edmund's life and career is the degree to which the pre- and post - conquest primary sources have been scrutinised in order to identify that which is most factual, from those which have been borrowed from other writers, instances of the author's personal opinion, and folkloric elements. It is argued that previous studies of Edmund have been advanced by investigating the households of late Anglo-Saxon æthelings and establishing their similarities to the entourages of kings. Previous examinations of the legal sources have also been extended to partially recreate Edmund's network of associates. It is also suggested that members of Edmund's retinue may have transferred their allegiance to Cnut. The re-investigation of Edmund's marriage and appropriation of property indicates that Edmund's actions were actually criminal. An appreciation of the mechanics of power in the early middle ages, and thereby an estimation of the limitations under which Edmund operated is demonstrated by similarities between his marriage, rebellion and alliance with Uhtred, to comparable actions committed by young aristocrats in pre- and post- conquest England, Carolingian France and Ottonian Germany. It is further argued that Edmund Ironside prevented a second Danish conquest in his lifetime, establishing himself as warrior-king. A biographical treatment of Edmund II Ironside provides new perspectives on the seminal issues and key personalities of late Anglo-Saxon England.

Published
2018

24. CXCR4 signaling determines the fate of hematopoietic multipotent progenitors by stimulating mTOR activity and mitochondrial metabolism.

Author

Rondeau, Vincent, Kalogeraki, Maria, Roland, Lilian, Nader, Zeina Abou, Gourhand, Vanessa, Bonaud, Amélie, Lemos, Julia, Khamyath, Mélanie, Moulin, Clémentine, Schell, Bérénice, Delord, Marc, Bidaut, Ghislain, Lecourt, Séverine, Freitas, Christelle, Anginot, Adrienne, Mazure, Nathalie, McDermott, David H., Parietti, Véronique, Setterblad, Niclas, and Dulphy, Nicolas

Subjects
BONE marrow cells, CXCR4 receptors, MYELOID cells, BONE marrow, PROGENITOR cells
Abstract

Both cell-intrinsic and niche-derived, cell-extrinsic cues drive the specification of hematopoietic multipotent progenitors (MPPs) in the bone marrow, which comprise multipotent MPP1 cells and lineage-restricted MPP2, MPP3, and MPP4 subsets. Patients with WHIM syndrome, a rare congenital immunodeficiency caused by mutations that prevent desensitization of the chemokine receptor CXCR4, have an excess of myeloid cells in the bone marrow. Here, we investigated the effects of increased CXCR4 signaling on the localization and fate of MPPs. Knock-in mice bearing a WHIM syndrome–associated CXCR4 mutation (CXCR41013) phenocopied the myeloid skewing of bone marrow in patients. Whereas MPP4 cells in wild-type mice differentiated into lymphoid cells, MPP4s in CXCR41013 knock-in mice differentiated into myeloid cells. This myeloid rewiring of MPP4s in CXCR41013 knock-in mice was associated with enhanced signaling mediated by the kinase mTOR and increased oxidative phosphorylation (OXPHOS). MPP4s also localized further from arterioles in the bone marrow of knock-in mice compared with wild-type mice, suggesting that the loss of extrinsic cues from the perivascular niche may also contribute to their myeloid skewing. Chronic treatment with the CXCR4 antagonist AMD3100 or the mTOR inhibitor rapamycin restored the lymphoid potential of MPP4s in knock-in mice. Thus, CXCR4 desensitization drives the lymphoid potential of MPP4 cells by dampening the mTOR-dependent metabolic changes that promote myeloid differentiation. Editor's summary: Truncations of the chemokine receptor CXCR4 prevent its internalization and cause WHIM syndrome, an inherited immunodeficiency characterized by increased numbers of myeloid cells in the bone marrow. In a mouse model of WHIM syndrome, Rondeau et al. found that a subset of multipotent progenitor cells that normally adopt a lymphoid fate were reprogrammed to instead adopt a myeloid fate. Impaired Cxcr4 desensitization in these cells caused their mislocalization within the bone marrow and an increase in mTOR signaling that metabolically rewired them toward a myeloid fate. These findings show that Cxcr4 promotes an mTOR-dependent metabolic program that confers myeloid identity. —Annalisa M. VanHook [ABSTRACT FROM AUTHOR]

Published
2024
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26. Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma

Author

McDermott, David F, Huseni, Mahrukh A, Atkins, Michael B, Motzer, Robert J, Rini, Brian I, Escudier, Bernard, Fong, Lawrence, Joseph, Richard W, Pal, Sumanta K, Reeves, James A, Sznol, Mario, Hainsworth, John, Rathmell, W Kimryn, Stadler, Walter M, Hutson, Thomas, Gore, Martin E, Ravaud, Alain, Bracarda, Sergio, Suárez, Cristina, Danielli, Riccardo, Gruenwald, Viktor, Choueiri, Toni K, Nickles, Dorothee, Jhunjhunwala, Suchit, Piault-Louis, Elisabeth, Thobhani, Alpa, Qiu, Jiaheng, Chen, Daniel S, Hegde, Priti S, Schiff, Christina, Fine, Gregg D, and Powles, Thomas

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Immunology, Kidney Disease, Cancer, Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, Antineoplastic Combined Chemotherapy Protocols, Bevacizumab, Carcinoma, Renal Cell, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Kaplan-Meier Estimate, Kidney Neoplasms, Male, Middle Aged, Mutation, Sunitinib, Treatment Outcome, Medical and Health Sciences, Biomedical and clinical sciences, Health sciences
Abstract

We describe results from IMmotion150, a randomized phase 2 study of atezolizumab (anti-PD-L1) alone or combined with bevacizumab (anti-VEGF) versus sunitinib in 305 patients with treatment-naive metastatic renal cell carcinoma. Co-primary endpoints were progression-free survival (PFS) in intent-to-treat and PD-L1+ populations. Intent-to-treat PFS hazard ratios for atezolizumab + bevacizumab or atezolizumab monotherapy versus sunitinib were 1.0 (95% confidence interval (CI), 0.69-1.45) and 1.19 (95% CI, 0.82-1.71), respectively; PD-L1+ PFS hazard ratios were 0.64 (95% CI, 0.38-1.08) and 1.03 (95% CI, 0.63-1.67), respectively. Exploratory biomarker analyses indicated that tumor mutation and neoantigen burden were not associated with PFS. Angiogenesis, T-effector/IFN-γ response, and myeloid inflammatory gene expression signatures were strongly and differentially associated with PFS within and across the treatments. These molecular profiles suggest that prediction of outcomes with anti-VEGF and immunotherapy may be possible and offer mechanistic insights into how blocking VEGF may overcome resistance to immune checkpoint blockade.

Published
2018

28. Association of machine learning (ML)–derived histological features with transcriptomic molecular subtypes in advanced renal cell carcinoma (RCC).

Author

Beig, Niha, primary, Nofallah, Shima, additional, McDermott, David F., additional, Motzer, Robert J., additional, Powles, Thomas, additional, Rini, Brian I., additional, Koeppen, Hartmut, additional, Banchereau, Romain, additional, Markey, Miles, additional, Finberg, Isaac, additional, Singh, Geetika, additional, Yu, Limin, additional, Egger, Robert, additional, Parmar, Chintan, additional, Conway, Jake, additional, Hennek, Stephanie, additional, Ruderman, Daniel, additional, Vilchez, Samuel, additional, Huseni, Mahrukh A, additional, and Giltnane, Jennifer Margaret, additional

Published
2024
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29. Overall Survival with Adjuvant Pembrolizumab in Renal-Cell Carcinoma

Author

Choueiri, Toni K., primary, Tomczak, Piotr, additional, Park, Se Hoon, additional, Venugopal, Balaji, additional, Ferguson, Tom, additional, Symeonides, Stefan N., additional, Hajek, Jaroslav, additional, Chang, Yen-Hwa, additional, Lee, Jae-Lyun, additional, Sarwar, Naveed, additional, Haas, Naomi B., additional, Gurney, Howard, additional, Sawrycki, Piotr, additional, Mahave, Mauricio, additional, Gross-Goupil, Marine, additional, Zhang, Tian, additional, Burke, John M., additional, Doshi, Gurjyot, additional, Melichar, Bohuslav, additional, Kopyltsov, Evgeniy, additional, Alva, Ajjai, additional, Oudard, Stephane, additional, Topart, Delphine, additional, Hammers, Hans, additional, Kitamura, Hiroshi, additional, McDermott, David F., additional, Silva, Adriano, additional, Winquist, Eric, additional, Cornell, Jerry, additional, Elfiky, Aymen, additional, Burgents, Joseph E., additional, Perini, Rodolfo F., additional, and Powles, Thomas, additional

Published
2024
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30. Treatment-free survival outcomes from the phase II study of nivolumab and salvage nivolumab/ipilimumab in advanced clear cell renal cell carcinoma (HCRN GU16-260-Cohort A)

Author

Atkins, Michael B, primary, Jegede, Opeyemi A, additional, Haas, Naomi B, additional, Mcdermott, David F, additional, Bilen, Mehmet A, additional, Stein, Mark, additional, Sosman, Jeffrey, additional, Alter, Robert, additional, Plimack, Elizabeth R, additional, Ornstein, Moshe C, additional, Hurwitz, Michael, additional, Peace, David J, additional, Einstein, David, additional, Catalano, Paul J, additional, Hammers, Hans, additional, and Regan, Meredith M, additional

Published
2024
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31. Antibody responses to the SARS-CoV-2 vaccine in individuals with various inborn errors of immunity

Author

Delmonte, Ottavia M., Bergerson, Jenna R.E., Burbelo, Peter D., Durkee-Shock, Jessica R., Dobbs, Kerry, Bosticardo, Marita, Keller, Michael D., McDermott, David H., Rao, V. Koneti, Dimitrova, Dimana, Quiros-Roldan, Eugenia, Imberti, Luisa, Ferrè, Elise M.N., Schmitt, Monica, Lafeer, Christine, Pfister, Justina, Shaw, Dawn, Draper, Deborah, Truong, Meng, Ulrick, Jean, DiMaggio, Tom, Urban, Amanda, Holland, Steven M., Lionakis, Michail S., Cohen, Jeffrey I., Ricotta, Emily E., Notarangelo, Luigi D., and Freeman, Alexandra F.

Published
2021
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36. Inhibition of hypoxia-inducible factor-2[alpha] in renal cell carcinoma with belzutifan: a phase 1 trial and biomarker analysis

Author

Choueiri, Toni K., Bauer, Todd M., Papadopoulos, Kyriakos P., Plimack, Elizabeth R., Merchan, Jaime R., McDermott, David F., Michaelson, M. Dror, Appleman, Leonard J., Thamake, Sanjay, Perini, Rodolfo F., Zojwalla, Naseem J., and Jonasch, Eric

Subjects
Antineoplastic agents -- Testing, Biological response modifiers -- Testing, Carcinoma, Renal cell -- Drug therapy, Transcription factors -- Health aspects, Antimitotic agents -- Testing, Biological sciences, Health
Abstract

Hypoxia-inducible factor-2[alpha] (HIF-2[alpha]) is a transcription factor that frequently accumulates in clear cell renal cell carcinoma (ccRCC), resulting in constitutive activation of genes involved in carcinogenesis. Belzutifan (MK-6482, previously known as PT2977) is a potent, selective small molecule inhibitor of HIF-2[alpha]. Maximum tolerated dose, safety, pharmacokinetics, pharmacodynamics and anti-tumor activity of belzutifan were evaluated in this first-in-human phase 1 study (NCT02974738). Patients had advanced solid tumors (dose-escalation cohort) or previously treated advanced ccRCC (dose-expansion cohort). Belzutifan was administered orally using a 3 + 3 dose-escalation design, followed by expansion at the recommended phase 2 dose (RP2D) in patients with ccRCC. In the dose-escalation cohort (n = 43), no dose-limiting toxicities occurred at doses up to 160 mg once daily, and the maximum tolerated dose was not reached; the RP2D was 120 mg once daily. Plasma erythropoietin reductions were observed at all doses; erythropoietin concentrations correlated with plasma concentrations of belzutifan. In patients with ccRCC who received 120 mg once daily (n = 55), the confirmed objective response rate was 25% (all partial responses), and the median progression-free survival was 14.5 months. The most common grade [greater than or equal to]3 adverse events were anemia (27%) and hypoxia (16%). Belzutifan was well tolerated and demonstrated preliminary anti-tumor activity in heavily pre-treated patients, suggesting that HIF-2[alpha] inhibition might offer an effective treatment for ccRCC. A first-in-human trial of hypoxia-inducible factor (HIF)-2[alpha] inhibitor belzutifan (MK-6482) has a favorable safety profile and shows promising clinical activity for the treatment of patients with renal cell carcinoma who have been heavily pre-treated., Author(s): Toni K. Choueiri [sup.1] , Todd M. Bauer [sup.2] , Kyriakos P. Papadopoulos [sup.3] , Elizabeth R. Plimack [sup.4] , Jaime R. Merchan [sup.5] , David F. McDermott [sup.6] [...]

Published
2021
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37. TREC Screening for WHIM Syndrome

Author

Evans, II, Martin Oman, Petersen, Maureen M., Khojah, Amer, Jyonouchi, Soma C., Edwardson, George S., Khan, Yasmin West, Connelly, James Albert, Morris, David, Majumdar, Shamik, McDermott, David H., Walter, Jolan E., and Murphy, Philip M.

Published
2021
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39. Plasma Kidney Injury Molecule-1 for Preoperative Prediction of Renal Cell Carcinoma Versus Benign Renal Masses, and Association With Clinical Outcomes.

Author

Xu, Wenxin, Gaborieau, Valerie, Niman, Samuel M., Mukeria, Anush, Liu, Xiaowen, Maremanda, Krishna P., Takakura, Ayumi, Zaridze, David, Freedman, Matthew L., Xie, Wanling, McDermott, David F., Choueiri, Toni K., Catalano, Paul J., Sabbisetti, Venkata, Bonventre, Joseph V., Pierorazio, Phillip M., Singla, Nirmish, Brennan, Paul, and Bhatt, Rupal S.

Published
2024
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43. Nivolumab plus ipilimumab versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended 4-year follow-up of the phase III CheckMate 214 trial

Author

Albiges, Laurence, Tannir, Nizar M., Burotto, Mauricio, McDermott, David, Plimack, Elizabeth R., Barthélémy, Philippe, Porta, Camillo, Powles, Thomas, Donskov, Frede, George, Saby, Kollmannsberger, Christian K., Gurney, Howard, Grimm, Marc-Oliver, Tomita, Yoshihiko, Castellano, Daniel, Rini, Brian I., Choueiri, Toni K., Saggi, Shruti Shally, McHenry, M. Brent, and Motzer, Robert J.

Published
2020
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46. A Pooled Analysis of Treatment-Free Survival in Advanced Renal Cell Carcinoma

Author

Chang, Elaine, primary, Zhou, Jiaxi, additional, Song, Chi, additional, Gittleman, Haley, additional, Fernandes, Laura, additional, Weinstock, Chana, additional, Atkins, Michael B., additional, Agrawal, Sundeep, additional, Sridhara, Rajeshwari, additional, Gormley, Nicole, additional, Tang, Shenghui, additional, Suzman, Daniel L., additional, Amiri-Kordestani, Laleh, additional, Kluetz, Paul G., additional, Pazdur, Richard, additional, Rini, Brian I., additional, McDermott, David F., additional, and Regan, Meredith M., additional

Published
2024
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47. Figure S6 from PD-1 Expression on Intratumoral Regulatory T Cells Is Associated with Lack of Benefit from Anti–PD-1 Therapy in Metastatic Clear-Cell Renal Cell Carcinoma Patients

Author

Denize, Thomas, primary, Jegede, Opeyemi A., primary, Matar, Sayed, primary, El Ahmar, Nourhan, primary, West, Destiny J., primary, Walton, Emily, primary, Bagheri, Aseman Sheshdeh, primary, Savla, Varunika, primary, Nabil Laimon, Yasmin, primary, Gupta, Saurabh, primary, Vemula, Sai Vikram, primary, Braun, David A., primary, Burke, Kelly P., primary, Catalano, Paul J., primary, Freeman, Gordon J., primary, Motzer, Robert J., primary, Atkins, Michael B., primary, McDermott, David F., primary, Sharpe, Arlene H., primary, Choueiri, Toni K., primary, and Signoretti, Sabina, primary

Published
2024
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48. Data from PD-1 Expression on Intratumoral Regulatory T Cells Is Associated with Lack of Benefit from Anti–PD-1 Therapy in Metastatic Clear-Cell Renal Cell Carcinoma Patients

Author

Denize, Thomas, primary, Jegede, Opeyemi A., primary, Matar, Sayed, primary, El Ahmar, Nourhan, primary, West, Destiny J., primary, Walton, Emily, primary, Bagheri, Aseman Sheshdeh, primary, Savla, Varunika, primary, Nabil Laimon, Yasmin, primary, Gupta, Saurabh, primary, Vemula, Sai Vikram, primary, Braun, David A., primary, Burke, Kelly P., primary, Catalano, Paul J., primary, Freeman, Gordon J., primary, Motzer, Robert J., primary, Atkins, Michael B., primary, McDermott, David F., primary, Sharpe, Arlene H., primary, Choueiri, Toni K., primary, and Signoretti, Sabina, primary

Published
2024
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49. Supplementary Methods 1 from PD-1 Expression on Intratumoral Regulatory T Cells Is Associated with Lack of Benefit from Anti–PD-1 Therapy in Metastatic Clear-Cell Renal Cell Carcinoma Patients

Author

Denize, Thomas, primary, Jegede, Opeyemi A., primary, Matar, Sayed, primary, El Ahmar, Nourhan, primary, West, Destiny J., primary, Walton, Emily, primary, Bagheri, Aseman Sheshdeh, primary, Savla, Varunika, primary, Nabil Laimon, Yasmin, primary, Gupta, Saurabh, primary, Vemula, Sai Vikram, primary, Braun, David A., primary, Burke, Kelly P., primary, Catalano, Paul J., primary, Freeman, Gordon J., primary, Motzer, Robert J., primary, Atkins, Michael B., primary, McDermott, David F., primary, Sharpe, Arlene H., primary, Choueiri, Toni K., primary, and Signoretti, Sabina, primary

Published
2024
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50. Supplementary Tables 1-6 from PD-1 Expression on Intratumoral Regulatory T Cells Is Associated with Lack of Benefit from Anti–PD-1 Therapy in Metastatic Clear-Cell Renal Cell Carcinoma Patients

Author

Denize, Thomas, primary, Jegede, Opeyemi A., primary, Matar, Sayed, primary, El Ahmar, Nourhan, primary, West, Destiny J., primary, Walton, Emily, primary, Bagheri, Aseman Sheshdeh, primary, Savla, Varunika, primary, Nabil Laimon, Yasmin, primary, Gupta, Saurabh, primary, Vemula, Sai Vikram, primary, Braun, David A., primary, Burke, Kelly P., primary, Catalano, Paul J., primary, Freeman, Gordon J., primary, Motzer, Robert J., primary, Atkins, Michael B., primary, McDermott, David F., primary, Sharpe, Arlene H., primary, Choueiri, Toni K., primary, and Signoretti, Sabina, primary

Published
2024
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