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1. Hope for motherhood: pregnancy after allogeneic hematopoietic cell transplantation (a national multicenter study)

Author

Sockel, Katja, Neu, Annika, Goeckenjan, Maren, Ditschkowski, Markus, Hilgendorf, Inken, Kröger, Nicolaus, Ayuk, Francis A., Stoelzel, Friedrich, Middeke, Jan Moritz, Eder, Matthias, Bethge, Wolfgang, Finke, Jürgen, Bertz, Hartmut, Kobbe, Guido, Kaufmann, Martin, Platzbecker, Uwe, Beverungen, David, Schmid, Christoph, von Bonin, Malte, Egger-Heidrich, Katharina, Heberling, Lisa, Trautmann-Grill, Karolin, Teipel, Raphael, Bug, Gesine, Tischer, Johanna, Fraccaroli, Alessia, Fante, Matthias, Wolff, Daniel, Luft, Thomas, Winkler, Julia, Schäfer-Eckart, Kerstin, Scheid, Christof, Holtick, Udo, Klein, Stefan, Blau, Igor Wolfgang, Burchert, Andreas, Wulf, Gerald, Hasenkamp, Justin, Schwerdtfeger, Rainer, Kaun, Stephan, Junghanss, Christian, Wortmann, Friederike, Winter, Susann, Neidlinger, Helga, Theuser, Catrin, Beyersmann, Jan, Bornhaeuser, Martin, Schmeller, Sandra, Schetelig, Johannes, Jost, Edgar, Schmid, Christoph, Baurmann, Herrad, Blau, Igor, Holderried, Tobias, Hertenstein, Bernd, Hänel, Mathias, Bornhäuser, Martin, Neidlinger, Helga, Kobbe, Guido, Winkler, Julia, Schroeder, Thomas, Bug, Gesine, Hopfer, Olaf, Finke, Jürgen, Hasenkamp, Justin, Krüger, William, Müller, Lutz, Kröger, Nikolaus, Eder, Matthias, Luft, Thomas, Hilgendorf, Inken, Ringhoffer, Mark, Stölzel, Friedrich, Scheid, Christoph, Platzbecker, Uwe, Wortmann, Friederike, Heinicke, Thomas, Wagner, Eva, Klein, Stefan, Burchert, Andreas, Tischer, Johanna, Stelljes, Matthias, Schäfer-Eckart, Kerstin, Wolff, Daniel, Junghanss, Christian, Ritter, Markus, Kaufmann, Martin, Bethge, Wolfgang, Mytilineos, Joannis, and Einsel, Hermann

Abstract

•Successful pregnancies are possible among female alloHCT recipients, although birth rate is >6 times lower than in the general population.•Key factors increasing the chance of pregnancy were younger age at HCT, nonmalignant disease, no TBI or dose <8 Gy and RIC/NMA conditioning

Published
2024
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2. Safety and efficacy of tafasitamab with or without lenalidomide added to first-line R-CHOP for DLBCL: the phase 1b First-MIND study

Author

Belada, David, Kopeckova, Katerina, Bergua Burgues, Juan Miguel, Stevens, Don, André, Marc, Persona, Ernesto Perez, Pichler, Petra, Staber, Philipp B., Trneny, Marek, Duell, Johannes, Waldron-Lynch, Maeve, Wagner, Steve, Mukhopadhyay, Amitava, Dirnberger-Hertweck, Maren, Burke, John M., and Nowakowski, Grzegorz S.

Abstract

•The novel combination of tafasitamab ± lenalidomide + R-CHOP showed signs of efficacy in patients with untreated DLBCL, with no new safety signals.•The results, including a post hoc analysis in patients with high-risk disease (IPI 3-5), support the ongoing phase 3 frontMIND trial.

Published
2023
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3. Analysis of the T-cell repertoire and transcriptome identifies mechanisms of regulatory T-cell suppression of GVHD

Author

Lohmeyer, Juliane K., Hirai, Toshihito, Turkoz, Mustafa, Buhler, Stephane, Lopes Ramos, Teresa, Köhler, Natalie, Baker, Jeanette, Melotti, Astrid, Wagner, Ingrid, Pradier, Amandine, Wang, Sisi, Ji, Xuhuai, Becattini, Simone, Villard, Jean, Merkler, Doron, Chalandon, Yves, Negrin, Robert S., and Simonetta, Federico

Abstract

CD4+FOXP3+ regulatory T cells (Tregs) have demonstrated efficacy in the prevention and treatment of graft-versus-host disease (GVHD). Preclinical and clinical studies indicate that Tregs are able to protect from GVHD without interfering with the graft-versus-tumor (GVT) effect of hematopoietic cell transplantation (HCT), although the underlying molecular mechanisms are largely unknown. To elucidate Treg suppressive function during in vivo suppression of acute GVHD, we performed paired T-cell receptor (TCRα and ΤCRβ genes) repertoire sequencing and RNA sequencing analysis on conventional T cells (Tcons) and Tregs before and after transplantation in a major histocompatibility complex –mismatched mouse model of HCT. We show that both Tregs and Tcons underwent clonal restriction, and Tregs did not interfere with the activation of alloreactive Tcon clones and the breadth of their TCR repertoire but markedly suppressed their expansion. Transcriptomic analysis revealed that Tregs predominantly affected the transcriptome of CD4 Tcons and, to a lesser extent, that of CD8 Tcons, thus modulating the transcription of genes encoding pro- and anti-inflammatory molecules as well as enzymes involved in metabolic processes, inducing a switch from glycolysis to oxidative phosphorylation. Finally, Tregs did not interfere with the induction of gene sets involved in the GVT effect. Our results shed light onto the mechanisms of acute GVHD suppression by Tregs and will support the clinical translation of this immunoregulatory approach.

Published
2023
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4. Analysis of the T-cell repertoire and transcriptome identifies mechanisms of regulatory T-cell suppression of GVHD

Author

Lohmeyer, Juliane K., Hirai, Toshihito, Turkoz, Mustafa, Buhler, Stephane, Lopes Ramos, Teresa, Köhler, Natalie, Baker, Jeanette, Melotti, Astrid, Wagner, Ingrid, Pradier, Amandine, Wang, Sisi, Ji, Xuhuai, Becattini, Simone, Villard, Jean, Merkler, Doron, Chalandon, Yves, Negrin, Robert S., and Simonetta, Federico

Abstract

•Regulatory T cells modulate Tcon transcriptome during GVHD suppression by affecting several nonredundant pathways.•Regulatory T cells undergo activation and clonal expansion during GVHD suppression.

Published
2023
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5. Prevention of acute GVHD using an orthogonal IL-2/IL-2Rβ system to selectively expand regulatory T cells in vivo

Author

Ramos, Teresa L., Bolivar-Wagers, Sara, Jin, Sujeong, Thangavelu, Govindarajan, Simonetta, Federico, Lin, Po-Yu, Hirai, Toshihito, Saha, Asim, Koehn, Brent, Su, Leon L., Picton, Lora K., Baker, Jeanette, Lohmeyer, Juliane K., Riddle, Megan, Eide, Cindy, Tolar, Jakub, Panoskaltsis-Mortari, Angela, Wagner, John E., Garcia, K. Christopher, Negrin, Robert S., and Blazar, Bruce R.

Abstract

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative option for patients with hematological disorders and bone marrow (BM) failure syndromes. Graft-versus-host disease (GVHD) remains a leading cause of morbidity posttransplant. Regulatory T cell (Treg) therapies are efficacious in ameliorating GVHD but limited by variable suppressive capacities and the need for a high therapeutic dose. Here, we sought to expand Treg in vivo by expressing an orthogonal interleukin 2 receptor β (oIL-2Rβ) that would selectively interact with oIL-2 cytokine and not wild-type (WT) IL-2. To test whether the orthogonal system would preferentially drive donor Treg expansion, we used a murine major histocompatibility complex–disparate GVHD model of lethally irradiated BALB/c mice given T cell–depleted BM from C57BL/6 (B6) mice alone or together with B6Foxp3+GFP+ Treg or oIL-2Rβ–transduced Treg at low cell numbers that typically do not control GVHD with WT Treg. On day 2, B6 activated T cells (Tcons) were injected to induce GVHD. Recipients were treated with phosphate-buffered saline (PBS) or oIL-2 daily for 14 days, then 3 times weekly for an additional 14 days. Mice treated with oIL-2Rβ Treg and oIL-2 compared with those treated with PBS had enhanced GVHD survival, in vivo selective expansion of Tregs, and greater suppression of Tcon expansion in secondary lymphoid organs and intestines. Importantly, oIL-2Rβ Treg maintained graft-versus-tumor (GVT) responses in 2 distinct tumor models (A20 and MLL-AF9). These data demonstrate a novel approach to enhance the efficacy of Treg therapy in allo-HSCT using an oIL-2/oIL-2Rβ system that allows for selective in vivo expansion of Treg leading to GVHD protection and GVT maintenance.

Published
2023
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6. Prevention of acute GVHD using an orthogonal IL-2/IL-2Rβ system to selectively expand regulatory T cells in vivo

Author

Ramos, Teresa L., Bolivar-Wagers, Sara, Jin, Sujeong, Thangavelu, Govindarajan, Simonetta, Federico, Lin, Po-Yu, Hirai, Toshihito, Saha, Asim, Koehn, Brent, Su, Leon L., Picton, Lora K., Baker, Jeanette, Lohmeyer, Juliane K., Riddle, Megan, Eide, Cindy, Tolar, Jakub, Panoskaltsis-Mortari, Angela, Wagner, John E., Garcia, K. Christopher, Negrin, Robert S., and Blazar, Bruce R.

Abstract

•oIL-2Rβ Tregs can be selectively expanded in vivo with oIL-2 administered after allo-HSCT.•Smaller numbers of oIL-2Rβ Tregs–oIL-2 are needed to reduce clinical scores, improve GVHD survival, and maintain GVT responses.

Published
2023
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7. Factors Associated with Refractoriness or Early Progression after Idecabtagene Vicleucel (Ide-cel) in Patients with Relapsed/Refractory Multiple Myeloma (RRMM): U.S. Myeloma CAR T Consortium Real World Experience

Author

Hashmi, Hamza, Hansen, Doris K., Peres, Lauren C., Castaneda Puglianini, Omar Alexis, Freeman, Ciara L., De Avila, Gabriel, Sidana, Surbhi, Shune, Leyla O., Sborov, Douglas W., Davis, James, Wagner, Charlotte B., Kocoglu, M. Hakan, Atrash, Shebli, Voorhees, Peter M., Simmons, Gary, Ferreri, Christopher J., Kalariya, Nilesh, Sannareddy, Aishwarya, Dima, Danai, Khouri, Jack, McGuirk, Joseph P., Locke, Frederick L., Baz, Rachid C., Patel, Krina, and Alsina, Melissa

Published
2022
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8. Factors Associated with Refractoriness or Early Progression after Idecabtagene Vicleucel (Ide-cel) in Patients with Relapsed/Refractory Multiple Myeloma (RRMM): U.S. Myeloma CAR T Consortium Real World Experience

Author

Hashmi, Hamza, Hansen, Doris K., Peres, Lauren C., Castaneda Puglianini, Omar Alexis, Freeman, Ciara L., De Avila, Gabriel, Sidana, Surbhi, Shune, Leyla O., Sborov, Douglas W., Davis, James, Wagner, Charlotte B., Kocoglu, M. Hakan, Atrash, Shebli, Voorhees, Peter M., Simmons, Gary, Ferreri, Christopher J., Kalariya, Nilesh, Sannareddy, Aishwarya, Dima, Danai, Khouri, Jack, McGuirk, Joseph P., Locke, Frederick L., Baz, Rachid C., Patel, Krina, and Alsina, Melissa

Published
2022
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9. GLA/DRST real-world outcome analysis of CAR T-cell therapies for large B-cell lymphoma in Germany

Author

Bethge, Wolfgang A., Martus, Peter, Schmitt, Michael, Holtick, Udo, Subklewe, Marion, von Tresckow, Bastian, Ayuk, Francis, Wagner-Drouet, Eva Marie, Wulf, Gerald G., Marks, Reinhard, Penack, Olaf, Schnetzke, Ulf, Koenecke, Christian, von Bonin, Malte, Stelljes, Matthias, Glass, Bertram, Baldus, Claudia D., Vucinic, Vladan, Mougiakakos, Dimitrios, Topp, Max, Fante, Matthias A., Schroers, Roland, Bayir, Lale, Borchmann, Peter, Buecklein, Veit, Hasenkamp, Justin, Hanoun, Christine, Thomas, Simone, Beelen, Dietrich W., Lengerke, Claudia, Kroeger, Nicolaus, and Dreger, Peter

Abstract

CD19-directed chimeric antigen receptor (CAR) T cells have evolved as a new standard-of-care (SOC) treatment in patients with relapsed/refractory (r/r) large B-cell lymphoma (LBCL). Here, we report the first German real-world data on SOC CAR T-cell therapies with the aim to explore risk factors associated with outcomes. Patients who received SOC axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel) for LBCL and were registered with the German Registry for Stem Cell Transplantation (DRST) were eligible. The main outcomes analyzed were toxicities, response, overall survival (OS), and progression-free survival (PFS). We report 356 patients who received axi-cel (n = 173) or tisa-cel (n = 183) between November 2018 and April 2021 at 21 German centers. Whereas the axi-cel and tisa-cel cohorts were comparable for age, sex, lactate dehydrogenase (LDH), international prognostic index (IPI), and pretreatment, the tisa-cel group comprised significantly more patients with poor performance status, ineligibility for ZUMA-1, and the need for bridging, respectively. With a median follow-up of 11 months, Kaplan-Meier estimates of OS, PFS, and nonrelapse mortality (NRM) 12 months after dosing were 52%, 30%, and 6%, respectively. While NRM was largely driven by infections subsequent to prolonged neutropenia and/or severe neurotoxicity and significantly higher with axi-cel, significant risk factors for PFS on the multivariate analysis included bridging failure, elevated LDH, age, and tisa-cel use. In conclusion, this study suggests that important outcome determinants of CD19-directed CAR T-cell treatment of LBCL in the real-world setting are bridging success, CAR-T product selection, LDH, and the absence of prolonged neutropenia and/or severe neurotoxicity. These findings may have implications for designing risk-adapted CAR T-cell therapy strategies.

Published
2022
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10. The interaction between anti-PF4 antibodies and anticoagulants in vaccine-induced thrombotic thrombocytopenia

Author

Singh, Anurag, Toma, Filip, Uzun, Günalp, Wagner, Teresa R., Pelzl, Lisann, Zlamal, Jan, Freytag, Verena, Weich, Karoline, Nowak-Harnau, Stefanie, Rothbauer, Ulrich, Althaus, Karina, and Bakchoul, Tamam

Abstract

Life-threatening thrombotic events at unusual sites have been reported after vector-based vaccinations against severe acute respiratory syndrome coronavirus 2. This phenomenon is now termed vaccine-induced immune thrombotic thrombocytopenia (VITT). The pathophysiology of VITT is similar to that of heparin-induced thrombocytopenia (HIT) and is associated with platelet-activating antibodies (Abs) against platelet factor 4 (PF4). Therefore, current guidelines suggest nonheparin anticoagulants to treat VITT patients. In this study, we investigated the interactions of heparin, danaparoid, fondaparinux, and argatroban with VITT–Ab/PF4 complexes using an ex vivo model for thrombus formation as well as in vitro assays to analyze Ab binding and platelet activation. We found that immunoglobulin Gs (IgGs) from VITT patients induce increased adherent platelets/thrombus formation in comparison with IgGs from healthy controls. In this ex vivo flow-based model, the procoagulant activity of VITT IgGs was effectively inhibited with danaparoid and argatroban but also by heparin. Interestingly, heparin and danaparoid not only inhibited IgG binding to PF4 but were also able to effectively dissociate the preformed PF4/IgG complexes. Fondaparinux reduced the in vitro generation of procoagulant platelets and thrombus formation; however, it did not affect platelet aggregation. In contrast, argatroban showed no effect on procoagulant platelets and aggregation but significantly inhibited VITT-mediated thrombus formation. Taken together, our data indicate that negatively charged anticoagulants can disrupt VITT–Ab/PF4 interactions, which might serve as an approach to reduce Ab-mediated complications in VITT. Our results should be confirmed, however, in a clinical setting before a recommendation regarding the selection of anticoagulants in VITT patients could be made.

Published
2022
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11. The interaction between anti-PF4 antibodies and anticoagulants in vaccine-induced thrombotic thrombocytopenia

Author

Singh, Anurag, Toma, Filip, Uzun, Günalp, Wagner, Teresa R., Pelzl, Lisann, Zlamal, Jan, Freytag, Verena, Weich, Karoline, Nowak-Harnau, Stefanie, Rothbauer, Ulrich, Althaus, Karina, and Bakchoul, Tamam

Abstract

Life-threatening thrombotic events at unusual sites have been reported after vector-based vaccinations against severe acute respiratory syndrome coronavirus 2. This phenomenon is now termed vaccine-induced immune thrombotic thrombocytopenia (VITT). The pathophysiology of VITT is similar to that of heparin-induced thrombocytopenia (HIT) and is associated with platelet-activating antibodies (Abs) against platelet factor 4 (PF4). Therefore, current guidelines suggest nonheparin anticoagulants to treat VITT patients. In this study, we investigated the interactions of heparin, danaparoid, fondaparinux, and argatroban with VITT–Ab/PF4 complexes using an ex vivo model for thrombus formation as well as in vitro assays to analyze Ab binding and platelet activation. We found that immunoglobulin Gs (IgGs) from VITT patients induce increased adherent platelets/thrombus formation in comparison with IgGs from healthy controls. In this ex vivo flow-based model, the procoagulant activity of VITT IgGs was effectively inhibited with danaparoid and argatroban but also by heparin. Interestingly, heparin and danaparoid not only inhibited IgG binding to PF4 but were also able to effectively dissociate the preformed PF4/IgG complexes. Fondaparinux reduced the in vitro generation of procoagulant platelets and thrombus formation; however, it did not affect platelet aggregation. In contrast, argatroban showed no effect on procoagulant platelets and aggregation but significantly inhibited VITT-mediated thrombus formation. Taken together, our data indicate that negatively charged anticoagulants can disrupt VITT–Ab/PF4 interactions, which might serve as an approach to reduce Ab-mediated complications in VITT. Our results should be confirmed, however, in a clinical setting before a recommendation regarding the selection of anticoagulants in VITT patients could be made.

Published
2022
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12. Phase 1/dose expansion trial of brentuximab vedotin and lenalidomide in relapsed or refractory diffuse large B-cell lymphoma

Author

Ward, Jeffrey P., Berrien-Elliott, Melissa M., Gomez, Felicia, Luo, Jingqin, Becker-Hapak, Michelle, Cashen, Amanda F., Wagner-Johnston, Nina D., Maddocks, Kami, Mosior, Matthew, Foster, Mark, Krysiak, Kilannin, Schmidt, Alina, Skidmore, Zachary L., Desai, Sweta, Watkins, Marcus P., Fischer, Anne, Griffith, Malachi, Griffith, Obi L., Fehniger, Todd A., and Bartlett, Nancy L.

Abstract

New therapies are needed for patients with relapsed/refractory (rel/ref) diffuse large B-cell lymphoma (DLBCL) who do not benefit from or are ineligible for stem cell transplant and chimeric antigen receptor therapy. The CD30-targeted, antibody-drug conjugate brentuximab vedotin (BV) and the immunomodulator lenalidomide (Len) have demonstrated promising activity as single agents in this population. We report the results of a phase 1/dose expansion trial evaluating the combination of BV/Len in rel/ref DLBCL. Thirty-seven patients received BV every 21 days, with Len administered continuously for a maximum of 16 cycles. The maximum tolerated dose of the combination was 1.2 mg/kg BV with 20 mg/d Len. BV/Len was well tolerated with a toxicity profile consistent with their use as single agents. Most patients required granulocyte colony-stimulating factor support because of neutropenia. The overall response rate was 57% (95% CI, 39.6-72.5), complete response rate, 35% (95% CI, 20.7-52.6); median duration of response, 13.1 months; median progression-free survival, 10.2 months (95% CI, 5.5-13.7); and median overall survival, 14.3 months (95% CI, 10.2-35.6). Response rates were highest in patients with CD30+ DLBCL (73%), but they did not differ according to cell of origin (P = .96). NK cell expansion and phenotypic changes in CD8+ T-cell subsets in nonresponders were identified by mass cytometry. BV/Len represents a potential treatment option for patients with rel/ref DLBCL. This combination is being further explored in a phase 3 study (registered on https://clinicaltrials.org as NCT04404283). This trial was registered on https://clinicaltrials.gov as NCT02086604.

Published
2022
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13. A CD45-targeted antibody-drug conjugate successfully conditions for allogeneic hematopoietic stem cell transplantation in mice

Author

Saha, Asim, Hyzy, Sharon, Lamothe, Tahirih, Hammond, Katelyn, Clark, Nicholas, Lanieri, Leanne, Bhattarai, Prashant, Palchaudhuri, Rahul, Gillard, Geoffrey O., Proctor, Jennifer, Riddle, Megan J., Panoskaltsis-Mortari, Angela, MacMillan, Margaret L., Wagner, John E., Kiem, Hans-Peter, Olson, Lisa M., and Blazar, Bruce R.

Abstract

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment of patients with nonmalignant or malignant blood disorders. Its success has been limited by graft-versus-host disease (GVHD). Current systemic nontargeted conditioning regimens mediate tissue injury and potentially incite and amplify GVHD, limiting the use of this potentially curative treatment beyond malignant disorders. Minimizing systemic nontargeted conditioning while achieving alloengraftment without global immune suppression is highly desirable. Antibody-drug-conjugates (ADCs) targeting hematopoietic cells can specifically deplete host stem and immune cells and enable alloengraftment. We report an anti-mouse CD45-targeted-ADC (CD45-ADC) that facilitates stable murine multilineage donor cell engraftment. Conditioning with CD45-ADC (3 mg/kg) was effective as a single agent in both congenic and minor-mismatch transplant models resulting in full donor chimerism comparable to lethal total body irradiation (TBI). In an MHC-disparate allo-HSCT model, pretransplant CD45-ADC (3 mg/kg) combined with low-dose TBI (150 cGy) and a short course of costimulatory blockade with anti-CD40 ligand antibody enabled 89% of recipients to achieve stable alloengraftment (mean value: 72%). When CD45-ADC was combined with pretransplant TBI (50 cGy) and posttransplant rapamycin, cyclophosphamide (Cytoxan), or a JAK inhibitor, 90% to 100% of recipients achieved stable chimerism (mean: 77%, 59%, 78%, respectively). At a higher dose (5 mg/kg), CD45-ADC as a single agent was sufficient for rapid, high-level multilineage chimerism sustained through the 22 weeks observation period. Therefore, CD45-ADC has the potential utility to confer the benefit of fully myeloablative conditioning but with substantially reduced toxicity when given as a single agent or at lower doses in conjunction with reduced-intensity conditioning.

Published
2022
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14. A CD45-targeted antibody-drug conjugate successfully conditions for allogeneic hematopoietic stem cell transplantation in mice

Author

Saha, Asim, Hyzy, Sharon, Lamothe, Tahirih, Hammond, Katelyn, Clark, Nicholas, Lanieri, Leanne, Bhattarai, Prashant, Palchaudhuri, Rahul, Gillard, Geoffrey O., Proctor, Jennifer, Riddle, Megan J., Panoskaltsis-Mortari, Angela, MacMillan, Margaret L., Wagner, John E., Kiem, Hans-Peter, Olson, Lisa M., and Blazar, Bruce R.

Abstract

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment of patients with nonmalignant or malignant blood disorders. Its success has been limited by graft-versus-host disease (GVHD). Current systemic nontargeted conditioning regimens mediate tissue injury and potentially incite and amplify GVHD, limiting the use of this potentially curative treatment beyond malignant disorders. Minimizing systemic nontargeted conditioning while achieving alloengraftment without global immune suppression is highly desirable. Antibody-drug-conjugates (ADCs) targeting hematopoietic cells can specifically deplete host stem and immune cells and enable alloengraftment. We report an anti-mouse CD45-targeted-ADC (CD45-ADC) that facilitates stable murine multilineage donor cell engraftment. Conditioning with CD45-ADC (3 mg/kg) was effective as a single agent in both congenic and minor-mismatch transplant models resulting in full donor chimerism comparable to lethal total body irradiation (TBI). In an MHC-disparate allo-HSCT model, pretransplant CD45-ADC (3 mg/kg) combined with low-dose TBI (150 cGy) and a short course of costimulatory blockade with anti-CD40 ligand antibody enabled 89% of recipients to achieve stable alloengraftment (mean value: 72%). When CD45-ADC was combined with pretransplant TBI (50 cGy) and posttransplant rapamycin, cyclophosphamide (Cytoxan), or a JAK inhibitor, 90% to 100% of recipients achieved stable chimerism (mean: 77%, 59%, 78%, respectively). At a higher dose (5 mg/kg), CD45-ADC as a single agent was sufficient for rapid, high-level multilineage chimerism sustained through the 22 weeks observation period. Therefore, CD45-ADC has the potential utility to confer the benefit of fully myeloablative conditioning but with substantially reduced toxicity when given as a single agent or at lower doses in conjunction with reduced-intensity conditioning.

Published
2022
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15. Absolute Lymphocyte Count and Outcomes of Multiple Myeloma Patients Treated with Idecabtagene Vicleucel: The U.S. Myeloma CAR T Consortium Real World Experience

Author

Khouri, Jack, Li, Hong, Hansen, Doris K., Sidana, Surbhi, Shune, Leyla O., DeJarnette, Shaun, Anwer, Faiz, Sborov, Douglas W, Wagner, Charlotte B, Kocoglu, M. Hakan, Atrash, Shebli, Voorhees, Peter M., Valent, Jason, Peres, Lauren C., Hovanky, Vanna, Simmons, Gary, Dima, Danai, Kalariya, Nilesh, Afrough, Aimaz, Kaur, Gurbakhash, Sannareddy, Aishwarya, Ferreri, Christopher J., Davis, James, McGuirk, Joseph P., Locke, Frederick L., Baz, Rachid C., Hamilton, Betty K., Alsina, Melissa, Sauter, Craig S., Hashmi, Hamza, and Patel, Krina

Published
2022
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17. Racial and Ethnic Differences in Clinical Outcomes Among Multiple Myeloma Patients Treated with CAR T Therapy

Author

Peres, Lauren C., Oswald, Laura B., Dillard, Christen, De Avila, Gabriel, Nishihori, Taiga, Blue, Brandon J., Freeman, Ciara L., Locke, Frederick L., Alsina, Melissa, Castaneda Puglianini, Omar Alexis, Shune, Leyla O., Sborov, Douglas W., Wagner, Charlotte B, Dima, Danai, Hashmi, Hamza, Davis, James, Kocoglu, M. Hakan, Atrash, Shebli, Simmons, Gary, Kalariya, Nilesh, Ferreri, Christopher J., Sannareddy, Aishwarya, Afrough, Aimaz, Voorhees, Peter M., Khouri, Jack, McGuirk, Joseph P., Sidana, Surbhi, Hansen, Doris K., and Patel, Krina

Published
2022
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18. Comparison of Fludarabine/Melphalan (FluMel) with Fludarabine/Melphalan/BCNU or Thiotepa (FBM/FTM) in Patients with AML in First Complete Remission Undergoing Allogeneic Hematopoietic Stem Cell Transplantation - a Registry Study on Behalf of the EBMT Acute Leukemia Working Party

Author

Duque Afonso, Jesus, Finke, Jürgen, Ngoya, Maud, Galimard, Jacques-Emmanuel, Craddock, Charles, Raj, Kavita, Bloor, Adrian, Nicholson, Emma, Eder, Matthias, Orchard, Kim H., Valerius, Thomas, Snowden, John A., Tholouli, Eleni, Crawley, Charles, Collin, Matthew P., Wilson, Keith, Gadisseur, Alain, Protheroe, Rachel Elizabeth, Wagner, Eva Maria, Savani, Bipin, Spyridonidis, Alexandros, Ciceri, Fabio, Nagler, Arnon, and Mohty, Mohamad

Published
2022
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20. In Patients with Relapsed/Refractory AML Sequential Conditioning and Immediate Allogeneic Stem Cell Transplantation (allo-HCT) Results in Similar Overall and Leukemia-Free Survival Compared to Intensive Remission Induction Chemotherapy Followed By Allo-HCT: Results from the Randomized Phase III ASAP Trial

Author

Stelljes, Matthias, Middeke, Jan Moritz, Bug, Gesine, Wagner, Eva-Maria, Mueller, Lutz Peter, Christoph, Schmid, Krause, Stefan W., Bethge, Wolfgang, Jost, Edgar, Platzbecker, Uwe, Klein, Stefan, Schubert, Jörg, Niederland, Judith, Kaufmann, Martin, Schäfer-Eckart, Kerstin, Schaich, Markus, Baldauf, Henning, Stölzel, Friedrich, Petzold, Cathleen, Röllig, Christoph, Alakel, Nael, Steffen, Björn, Hauptrock, Beate, Reicherts, Christian, Schliemann, Christoph, Serve, Hubert, Schmidt, Alexander H., Bornhäuser, Martin, Mikesch, Jan-Henrik, and Schetelig, Johannes

Published
2022
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22. Absolute Lymphocyte Count and Outcomes of Multiple Myeloma Patients Treated with Idecabtagene Vicleucel: The U.S. Myeloma CAR T Consortium Real World Experience

Author

Khouri, Jack, Li, Hong, Hansen, Doris K., Sidana, Surbhi, Shune, Leyla O., DeJarnette, Shaun, Anwer, Faiz, Sborov, Douglas W, Wagner, Charlotte B, Kocoglu, M. Hakan, Atrash, Shebli, Voorhees, Peter M., Valent, Jason, Peres, Lauren C., Hovanky, Vanna, Simmons, Gary, Dima, Danai, Kalariya, Nilesh, Afrough, Aimaz, Kaur, Gurbakhash, Sannareddy, Aishwarya, Ferreri, Christopher J., Davis, James, McGuirk, Joseph P., Locke, Frederick L., Baz, Rachid C., Hamilton, Betty K., Alsina, Melissa, Sauter, Craig S., Hashmi, Hamza, and Patel, Krina

Published
2022
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23. Idecabtagene Vicleucel (Ide-cel) Chimeric Antigen Receptor (CAR) T-Cell Therapy in Patients with Relapsed/Refractory Multiple Myeloma (RRMM) Who Have Received a Prior BCMA-Targeted Therapy: Real World, Multi-Institutional Experience

Author

Ferreri, Christopher J., Hildebrandt, Michelle A.T., Hashmi, Hamza, Shune, Leyla O., McGuirk, Joseph P., Sborov, Douglas W., Wagner, Charlotte B, Kocoglu, M. Hakan, Atrash, Shebli, Voorhees, Peter M., Khouri, Jack, Dima, Danai, Afrough, Aimaz, Sannareddy, Aishwarya, Simmons, Gary, Davis, James, Kalariya, Nilesh, Peres, Lauren C., Alsina, Melissa, Locke, Frederick L., Sidana, Surbhi, Hansen, Doris K., Patel, Krina, and Castaneda Puglianini, Omar Alexis

Published
2022
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24. Allogeneic Blood or Marrow Transplantation (AlloBMT) with High-Dose Post-Transplantation Cyclophosphamide (PTCy) for Acute Lymphoblastic Leukemia (ALL) in Patients Aged ≥ 55: Best Results in B ALL in First Remission (CR1) with Reduced-Intensity Conditioning (RIC)

Author

Webster, Jonathan Allen, Reed, Madison C., Tsai, Hua-Ling, Ambinder, Alexander J., Jain, Tania, DeZern, Amy E., Levis, Mark J., Showel, Margaret M., Prince, Gabrielle T., Hourigan, Christopher S., Bolaños-Meade, Javier, Gondek, Lukasz P., Ghiaur, Gabriel, Dalton, William Brian, Paul, Suman, Fuchs, Ephraim J., Gocke, Christian B., Ali, Abbas Abbas, Gladstone, Douglas E., Huff, Carol Ann, Borrello, Ivan M., Swinnen, Lode J., Wagner-Johnston, Nina D., Ambinder, Richard F., Luznik, Leo, Gojo, Ivana, Smith, B. Douglas Douglas, Varadhan, Ravi, Jones, Richard J., and Imus, Philip H.

Published
2022
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25. In Patients with Relapsed/Refractory AML Sequential Conditioning and Immediate Allogeneic Stem Cell Transplantation (allo-HCT) Results in Similar Overall and Leukemia-Free Survival Compared to Intensive Remission Induction Chemotherapy Followed By Allo-HCT: Results from the Randomized Phase III ASAP Trial

Author

Stelljes, Matthias, Middeke, Jan Moritz, Bug, Gesine, Wagner, Eva-Maria, Mueller, Lutz Peter, Christoph, Schmid, Krause, Stefan W., Bethge, Wolfgang, Jost, Edgar, Platzbecker, Uwe, Klein, Stefan, Schubert, Jörg, Niederland, Judith, Kaufmann, Martin, Schäfer-Eckart, Kerstin, Schaich, Markus, Baldauf, Henning, Stölzel, Friedrich, Petzold, Cathleen, Röllig, Christoph, Alakel, Nael, Steffen, Björn, Hauptrock, Beate, Reicherts, Christian, Schliemann, Christoph, Serve, Hubert, Schmidt, Alexander H., Bornhäuser, Martin, Mikesch, Jan-Henrik, and Schetelig, Johannes

Published
2022
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26. Randomized Phase 2 Trial of First-Line Bendamustine-Rituximab (BR)-Based Induction Followed By Rituximab (R) ± Lenalidomide (L) Consolidation for Mantle Cell Lymphoma ECOG-ACRIN E1411

Author

Smith, Mitchell R, Jegede, Opeyemi, Martin, Peter, Till, Brian G., Parekh, Samir, Yang, David T., Kostakoglu, Lale, Casulo, Carla, Bartlett, Nancy, Caimi, Paolo F, Al Baghdadi, Tareq, Maddocks, Kami J., Romer, Mark D., Inwards, David J., Lerner, Rachel E., Wagner, Lynne I., Little, Richard, Friedberg, Jonathan W., Leonard, John P., and Kahl, Brad S.

Published
2022
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27. Idecabtagene Vicleucel Chimeric Antigen Receptor T-Cell Therapy for Relapsed/Refractory Multiple Myeloma with Renal Insufficiency: Real World Experience

Author

Sidana, Surbhi, Peres, Lauren C., Hashmi, Hamza, Hosoya, Hitomi, Ferreri, Christopher J., Atrash, Shebli, Khouri, Jack, Voorhees, Peter M., Dima, Danai, Simmons, Gary, Kalariya, Nilesh, Hovanky, Vanna, Bharadwaj, Sushma, Arai, Sally, Miklos, David B., Wagner, Charlotte B, Davis, James, Sborov, Douglas W., Nishihori, Taiga, Alsina, Melissa, Locke, Frederick L., Gonzalez, Rebecca, Kocoglu, M. Hakan, Sannareddy, Aishwarya, Afrough, Aimaz, McGuirk, Joseph P., Shune, Leyla O., Patel, Krina, and Hansen, Doris K.

Published
2022
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29. A Simplified Patient Care Strategy to Decrease Early Deaths in Acute Promyelocytic Leukemia (APL): Results of the ECOG-ACRIN EA9131 Trial

Author

Jillella, Anand P., Lee, Sandra J., Altman, Jessica K., Luger, Selina M., Tallman, Martin S., Foran, James M., Law, Lisa Y., Bryan, Locke J., Abou Zahr, Abdallah, Begna, Kebede, Perl, Alexander, Vadakara, Joseph, Sanchez, Federico, Bergan, Raymond C., Fisch, Michael J., Carlos, Ruth C., Wagner, Lynne I., Litzow, Mark R., and Kota, Vamsi K.

Published
2022
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30. Real World Outcomes of Brentuximab Vedotin Maintenance after Autologous Stem Cell Transplant in Relapsed/Refractory Classical Hodgkin Lymphoma: An Time-Variable Analysis of the Effect of Dose on Progression Free Survival

Author

Wagner, Charlotte B, Ermann, Daniel A., Boucher, Ken, Nedved, Adrienne N., Micallef, Ivana N., Desai, Sanjal H, Hatic, Haris, Goyal, Gaurav, Zacholski, Erin, Fegley, Amanda, Sigmund, Audrey M., Bond, David A., Samuels, Courtney, Kamdar, Manali K., Ba Aqeel, Sheeba, Torka, Pallawi, MacDougall, Kira, Borogovac, Azra, Rajeeve, Sridevi, Sundaram, Suchitra, Fedak, Kalub, Modi, Dipenkumar, Travers, Elizabeth, Ayyappan, Sabarish, Chilakamarri, Nitin, Brem, Elizabeth A, Stephens, Deborah M., Hu, Boyu, Fitzgerald, Lindsey A., and Shah, Harsh

Published
2022
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32. Randomized Phase 2 Trial of First-Line Bendamustine-Rituximab (BR)-Based Induction Followed By Rituximab (R) ± Lenalidomide (L) Consolidation for Mantle Cell Lymphoma ECOG-ACRIN E1411

Author

Smith, Mitchell R, Jegede, Opeyemi, Martin, Peter, Till, Brian G., Parekh, Samir, Yang, David T., Kostakoglu, Lale, Casulo, Carla, Bartlett, Nancy, Caimi, Paolo F, Al Baghdadi, Tareq, Maddocks, Kami J., Romer, Mark D., Inwards, David J., Lerner, Rachel E., Wagner, Lynne I., Little, Richard, Friedberg, Jonathan W., Leonard, John P., and Kahl, Brad S.

Published
2022
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33. Real World Outcomes of Brentuximab Vedotin Maintenance after Autologous Stem Cell Transplant in Relapsed/Refractory Classical Hodgkin Lymphoma: An Time-Variable Analysis of the Effect of Dose on Progression Free Survival

Author

Wagner, Charlotte B, Ermann, Daniel A., Boucher, Ken, Nedved, Adrienne N., Micallef, Ivana N., Desai, Sanjal H, Hatic, Haris, Goyal, Gaurav, Zacholski, Erin, Fegley, Amanda, Sigmund, Audrey M., Bond, David A., Samuels, Courtney, Kamdar, Manali K., Ba Aqeel, Sheeba, Torka, Pallawi, MacDougall, Kira, Borogovac, Azra, Rajeeve, Sridevi, Sundaram, Suchitra, Fedak, Kalub, Modi, Dipenkumar, Travers, Elizabeth, Ayyappan, Sabarish, Chilakamarri, Nitin, Brem, Elizabeth A, Stephens, Deborah M., Hu, Boyu, Fitzgerald, Lindsey A., and Shah, Harsh

Published
2022
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34. Outcomes of Second-Line (2L) Triplet+ Regimens in Patients with Relapsed/Refractory Multiple Myeloma (MM) Following Progression after First-Line (1L) Lenalidomide in the Connect® MM Disease Registry

Author

Lee, Hans C., Abonour, Rafat, Ailawadhi, Sikander, Durie, Brian G.M., Gasparetto, Cristina J., Hardin, James W., Narang, Mohit, Omel, James, Rifkin, Robert M., Terebelo, Howard, Toomey, Kathleen, Wagner, Lynne I., Slaff, Samantha, Danforth, Dailan, Chung, Weiyuan, Anand, Jasmeet, Yu, Edward, Tang, Derek, and Jagannath, Sundar

Published
2022
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35. Outcomes of Second-Line (2L) Triplet+ Regimens in Patients with Relapsed/Refractory Multiple Myeloma (MM) Following Progression after First-Line (1L) Lenalidomide in the Connect® MM Disease Registry

Author

Lee, Hans C., Abonour, Rafat, Ailawadhi, Sikander, Durie, Brian G.M., Gasparetto, Cristina J., Hardin, James W., Narang, Mohit, Omel, James, Rifkin, Robert M., Terebelo, Howard, Toomey, Kathleen, Wagner, Lynne I., Slaff, Samantha, Danforth, Dailan, Chung, Weiyuan, Anand, Jasmeet, Yu, Edward, Tang, Derek, and Jagannath, Sundar

Published
2022
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37. Validation of the Transplant Conditioning Intensity (TCI) Score for Allogeneic Hematopoietic Cell Transplantation

Author

Spyridonidis, Alexandros, Labopin, Myriam, Gedde-Dahl, Tobias, Ganser, Arnold, Stelljes, Matthias, Craddock, Charles, Wagner, Eva Maria, Versluis, Jurjen, Schroeder, Thomas, Blau, Igor Wolfgang, Wulf, Gerald, Dreger, Peter, Olesen, Gitte, Sengeloev, Henrik, Kröger, Nicolaus, Potter, Victoria, Forcade, Edouard, Passweg, Jakob, Peffault de Latour, Régis, Maertens, Johan, Wilson, Keith, Bourhis, Jean-Henri, Savani, Bipin, Ciceri, Fabio, Nagler, Arnon, and Mohty, Mohamad

Published
2022
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38. Idecabtagene Vicleucel (Ide-cel) Chimeric Antigen Receptor (CAR) T-Cell Therapy in Patients with Relapsed/Refractory Multiple Myeloma (RRMM) Who Have Received a Prior BCMA-Targeted Therapy: Real World, Multi-Institutional Experience

Author

Ferreri, Christopher J., Hildebrandt, Michelle A.T., Hashmi, Hamza, Shune, Leyla O., McGuirk, Joseph P., Sborov, Douglas W., Wagner, Charlotte B, Kocoglu, M. Hakan, Atrash, Shebli, Voorhees, Peter M., Khouri, Jack, Dima, Danai, Afrough, Aimaz, Sannareddy, Aishwarya, Simmons, Gary, Davis, James, Kalariya, Nilesh, Peres, Lauren C., Alsina, Melissa, Locke, Frederick L., Sidana, Surbhi, Hansen, Doris K., Patel, Krina, and Castaneda Puglianini, Omar Alexis

Published
2022
Full Text
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39. A Simplified Patient Care Strategy to Decrease Early Deaths in Acute Promyelocytic Leukemia (APL): Results of the ECOG-ACRIN EA9131 Trial

Author

Jillella, Anand P., Lee, Sandra J., Altman, Jessica K., Luger, Selina M., Tallman, Martin S., Foran, James M., Law, Lisa Y., Bryan, Locke J., Abou Zahr, Abdallah, Begna, Kebede, Perl, Alexander, Vadakara, Joseph, Sanchez, Federico, Bergan, Raymond C., Fisch, Michael J., Carlos, Ruth C., Wagner, Lynne I., Litzow, Mark R., and Kota, Vamsi K.

Published
2022
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40. Validation of the Transplant Conditioning Intensity (TCI) Score for Allogeneic Hematopoietic Cell Transplantation

Author

Spyridonidis, Alexandros, Labopin, Myriam, Gedde-Dahl, Tobias, Ganser, Arnold, Stelljes, Matthias, Craddock, Charles, Wagner, Eva Maria, Versluis, Jurjen, Schroeder, Thomas, Blau, Igor Wolfgang, Wulf, Gerald, Dreger, Peter, Olesen, Gitte, Sengeloev, Henrik, Kröger, Nicolaus, Potter, Victoria, Forcade, Edouard, Passweg, Jakob, Peffault de Latour, Régis, Maertens, Johan, Wilson, Keith, Bourhis, Jean-Henri, Savani, Bipin, Ciceri, Fabio, Nagler, Arnon, and Mohty, Mohamad

Published
2022
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42. Allogeneic Blood or Marrow Transplantation (AlloBMT) with High-Dose Post-Transplantation Cyclophosphamide (PTCy) for Acute Lymphoblastic Leukemia (ALL) in Patients Aged ≥ 55: Best Results in B ALL in First Remission (CR1) with Reduced-Intensity Conditioning (RIC)

Author

Webster, Jonathan Allen, Reed, Madison C., Tsai, Hua-Ling, Ambinder, Alexander J., Jain, Tania, DeZern, Amy E., Levis, Mark J., Showel, Margaret M., Prince, Gabrielle T., Hourigan, Christopher S., Bolaños-Meade, Javier, Gondek, Lukasz P., Ghiaur, Gabriel, Dalton, William Brian, Paul, Suman, Fuchs, Ephraim J., Gocke, Christian B., Ali, Abbas Abbas, Gladstone, Douglas E., Huff, Carol Ann, Borrello, Ivan M., Swinnen, Lode J., Wagner-Johnston, Nina D., Ambinder, Richard F., Luznik, Leo, Gojo, Ivana, Smith, B. Douglas Douglas, Varadhan, Ravi, Jones, Richard J., and Imus, Philip H.

Published
2022
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43. Comparison of Fludarabine/Melphalan (FluMel) with Fludarabine/Melphalan/BCNU or Thiotepa (FBM/FTM) in Patients with AML in First Complete Remission Undergoing Allogeneic Hematopoietic Stem Cell Transplantation - a Registry Study on Behalf of the EBMT Acute Leukemia Working Party

Author

Duque Afonso, Jesus, Finke, Jürgen, Ngoya, Maud, Galimard, Jacques-Emmanuel, Craddock, Charles, Raj, Kavita, Bloor, Adrian, Nicholson, Emma, Eder, Matthias, Orchard, Kim H., Valerius, Thomas, Snowden, John A., Tholouli, Eleni, Crawley, Charles, Collin, Matthew P., Wilson, Keith, Gadisseur, Alain, Protheroe, Rachel Elizabeth, Wagner, Eva Maria, Savani, Bipin, Spyridonidis, Alexandros, Ciceri, Fabio, Nagler, Arnon, and Mohty, Mohamad

Published
2022
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44. Racial and Ethnic Differences in Clinical Outcomes Among Multiple Myeloma Patients Treated with CAR T Therapy

Author

Peres, Lauren C., Oswald, Laura B., Dillard, Christen, De Avila, Gabriel, Nishihori, Taiga, Blue, Brandon J., Freeman, Ciara L., Locke, Frederick L., Alsina, Melissa, Castaneda Puglianini, Omar Alexis, Shune, Leyla O., Sborov, Douglas W., Wagner, Charlotte B, Dima, Danai, Hashmi, Hamza, Davis, James, Kocoglu, M. Hakan, Atrash, Shebli, Simmons, Gary, Kalariya, Nilesh, Ferreri, Christopher J., Sannareddy, Aishwarya, Afrough, Aimaz, Voorhees, Peter M., Khouri, Jack, McGuirk, Joseph P., Sidana, Surbhi, Hansen, Doris K., and Patel, Krina

Published
2022
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46. Idecabtagene Vicleucel Chimeric Antigen Receptor T-Cell Therapy for Relapsed/Refractory Multiple Myeloma with Renal Insufficiency: Real World Experience

Author

Sidana, Surbhi, Peres, Lauren C., Hashmi, Hamza, Hosoya, Hitomi, Ferreri, Christopher J., Atrash, Shebli, Khouri, Jack, Voorhees, Peter M., Dima, Danai, Simmons, Gary, Kalariya, Nilesh, Hovanky, Vanna, Bharadwaj, Sushma, Arai, Sally, Miklos, David B., Wagner, Charlotte B, Davis, James, Sborov, Douglas W., Nishihori, Taiga, Alsina, Melissa, Locke, Frederick L., Gonzalez, Rebecca, Kocoglu, M. Hakan, Sannareddy, Aishwarya, Afrough, Aimaz, McGuirk, Joseph P., Shune, Leyla O., Patel, Krina, and Hansen, Doris K.

Published
2022
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47. Gasdermin D inhibition prevents multiple organ dysfunction during sepsis by blocking NET formation

Author

Silva, Camila Meirelles S., Wanderley, Carlos Wagner S., Veras, Flavio P., Sonego, Fabiane, Nascimento, Daniele C., Gonçalves, Augusto V., Martins, Timna V., Cólon, David F., Borges, Vanessa F., Brauer, Verônica S., Damasceno, Luis Eduardo A., Silva, Katiussia P., Toller-Kawahisa, Juliana E., Batah, Sabrina S., Souza, Ana Letícia J., Monteiro, Valter S., Oliveira, Antônio Edson R., Donate, Paula B., Zoppi, Daniel, Borges, Marcos C., Almeida, Fausto, Nakaya, Helder I., Fabro, Alexandre T., Cunha, Thiago M., Alves-Filho, José Carlos, Zamboni, Dario S., and Cunha, Fernando Q.

Abstract

Multiple organ dysfunction is the most severe outcome of sepsis progression and is highly correlated with a worse prognosis. Excessive neutrophil extracellular traps (NETs) are critical players in the development of organ failure during sepsis. Therefore, interventions targeting NET release would likely effectively prevent NET-based organ injury associated with this disease. Herein, we demonstrate that the pore-forming protein gasdermin D (GSDMD) is active in neutrophils from septic humans and mice and plays a crucial role in NET release. Inhibition of GSDMD with disulfiram or genic deletion abrogated NET formation, reducing multiple organ dysfunction and sepsis lethality. Mechanistically, we demonstrate that during sepsis, activation of the caspase-11/GSDMD pathway controls NET release by neutrophils during sepsis. In summary, our findings uncover a novel therapeutic use for disulfiram and suggest that GSDMD is a therapeutic target to improve sepsis treatment.

Published
2021
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48. Gasdermin D inhibition prevents multiple organ dysfunction during sepsis by blocking NET formation

Author

Silva, Camila Meirelles S., Wanderley, Carlos Wagner S., Veras, Flavio P., Sonego, Fabiane, Nascimento, Daniele C., Gonçalves, Augusto V., Martins, Timna V., Cólon, David F., Borges, Vanessa F., Brauer, Verônica S., Damasceno, Luis Eduardo A., Silva, Katiussia P., Toller-Kawahisa, Juliana E., Batah, Sabrina S., Souza, Ana Letícia J., Monteiro, Valter S., Oliveira, Antônio Edson R., Donate, Paula B., Zoppi, Daniel, Borges, Marcos C., Almeida, Fausto, Nakaya, Helder I., Fabro, Alexandre T., Cunha, Thiago M., Alves-Filho, José Carlos, Zamboni, Dario S., and Cunha, Fernando Q.

Abstract

Multiple organ dysfunction is the most severe outcome of sepsis progression and is highly correlated with a worse prognosis. Excessive neutrophil extracellular traps (NETs) are critical players in the development of organ failure during sepsis. Therefore, interventions targeting NET release would likely effectively prevent NET-based organ injury associated with this disease. Herein, we demonstrate that the pore-forming protein gasdermin D (GSDMD) is active in neutrophils from septic humans and mice and plays a crucial role in NET release. Inhibition of GSDMD with disulfiram or genic deletion abrogated NET formation, reducing multiple organ dysfunction and sepsis lethality. Mechanistically, we demonstrate that during sepsis, activation of the caspase-11/GSDMD pathway controls NET release by neutrophils during sepsis. In summary, our findings uncover a novel therapeutic use for disulfiram and suggest that GSDMD is a therapeutic target to improve sepsis treatment.

Published
2021
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49. Prevention of CMV/EBV Reactivation By Double-Specific T Cells in Patients after Allogeneic Stem Cell Transplantation: Results from the Randomized Phase I/IIa Multivir-01 Study

Author

Gerbitz, Armin, Gary, Regina, Aigner, Michael, Moosmann, Andreas, Kremer, Anita, Schmidt, Christoph, Hirschbuehl, Klaus, Wagner Drouet, Eva, Hauptrock, Beate, Teschner, Daniel, Roesler, Wolf, Spriewald, Bernd, Tischer, Johanna, Moi, Stephanie, Balzer, Heidi, Schaffer, Stefanie, Bausenwein, Judith, Wagner, Anja, Schmidt, Franziska, Brestrich, Jens, Ullrich, Barbara, Maas, Stefanie, Herold, Susanne, Strobel, Julian, Zimmermann, Robert, Weisbach, Volker, Hansmann, Leo, Lammoglia Cobo, María Fernanda, Remberger, Mats, Stelljes, Matthias, Ayuk, Francis A., Zeiser, Robert, and Mackensen, Andreas

Abstract

Allogeneic stem cell transplantation (aSCT) is used to cure hematologic malignancies or deficiencies of the hematopoietic system. It is associated with severe immunodeficiency of the host early after transplant and therefore early reactivation of latent herpesviruses such as CMV and EBV within the first 100 days are frequent. Small studies and case series indicated that application of herpes virus specific T cells can control and prevent disease in this patient population.

Published
2023
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50. Cytomegalovirus-specific T-cell reconstitution following letermovir prophylaxis after hematopoietic cell transplantation

Author

Zamora, Danniel, Duke, Elizabeth R., Xie, Hu, Edmison, Bradley C., Akoto, Brenda, Kiener, Richard, Stevens-Ayers, Terry, Wagner, Ralf, Mielcarek, Marco, Leisenring, Wendy M., Jerome, Keith R., Schiffer, Joshua T., Finak, Greg, De Rosa, Stephen C., and Boeckh, Michael

Abstract

Decreased cytomegalovirus (CMV)-specific immunity after hematopoietic cell transplantation (HCT) is associated with late CMV reactivation and increased mortality. Whether letermovir prophylaxis-associated reduction in viral exposure influences CMV-specific immune reconstitution is unknown. In a prospective cohort of allogeneic HCT recipients who received letermovir, we compared polyfunctional CMV-specific T-cell responses to those of controls who received PCR-guided preemptive therapy before the introduction of letermovir. Thirteen-color flow cytometry was used to assess T-cell responses at 3 months after HCT following stimulation with CMV immediate early-1 (IE-1) antigen and phosphoprotein 65 (pp65) antigens. Polyfunctionality was characterized by combinatorial polyfunctionality analysis of antigen-specific T-cell subsets. Use of letermovir and reduction of viral exposure were assessed for their association with CMV-specific T-cell immunity. Polyfunctional T-cell responses to IE-1 and pp65 were decreased in letermovir recipients and remained diminished after adjustment for donor CMV serostatus, absolute lymphocyte count, and steroid use. Among letermovir recipients, greater peak CMV DNAemia and increased viral shedding were associated with stronger CD8+ responses to pp65, whereas the CMV shedding rate was associated with greater CD4+ responses to IE-1. In summary, our study provided initial evidence that letermovir may delay CMV-specific cellular reconstitution, possibly related to decreased CMV antigen exposure. Evaluating T-cell polyfunctionality may identify patients at risk for late CMV infection after HCT.

Published
2021
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