255 results on '"Shipp, Margaret A."'
Search Results
2. MYD88L265Paugments proximal B-cell receptor signaling in large B-cell lymphomas via an interaction with DOCK8
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Mandato, Elisa, Yan, Qingsheng, Ouyang, Jing, Paczkowska, Julia, Qin, Yan, Hao, Yansheng, Bojarczuk, Kamil, Hansen, Julia, Chapuy, Björn, Rodig, Scott J., Khan, Sumbul Jawed, Redd, Robert A., and Shipp, Margaret A.
- Abstract
•In DLBCLs with MYD88L265Pand CD79BY196Falterations, MYD88L265Pselectively increased proximal BCR signaling and survival via DOCK8.•MYD88L265P/DOCK8–enhanced proximal BCR signaling is a basis for the increased sensitivity of MYD88L265P/CD79BY196FDLBCLs to BTK blockade.
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- 2023
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3. Diffuse large B-cell lymphomas have spatially defined, tumor immune microenvironments revealed by high-parameter imaging
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Wright, Kyle T., Weirather, Jason L., Jiang, Sizun, Kao, Katrina Z., Sigal, Yari, Giobbie-Hurder, Anita, Shipp, Margaret A., and Rodig, Scott J.
- Abstract
•DLBCLs are composed of local cell neighborhoods with distinct cellular, spatial, and functional features that define structured TIMEs.•DLBCL cell neighborhoods structurally define immune-deficient, DC-enriched, and macrophage-enriched immune microenvironments.
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- 2023
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4. The International Consensus Classification of Mature Lymphoid Neoplasms: a report from the Clinical Advisory Committee
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Campo, Elias, Jaffe, Elaine S., Cook, James R., Quintanilla-Martinez, Leticia, Swerdlow, Steven H., Anderson, Kenneth C., Brousset, Pierre, Cerroni, Lorenzo, de Leval, Laurence, Dirnhofer, Stefan, Dogan, Ahmet, Feldman, Andrew L., Fend, Falko, Friedberg, Jonathan W., Gaulard, Philippe, Ghia, Paolo, Horwitz, Steven M., King, Rebecca L., Salles, Gilles, San-Miguel, Jesus, Seymour, John F., Treon, Steven P., Vose, Julie M., Zucca, Emanuele, Advani, Ranjana, Ansell, Stephen, Au, Wing-Yan, Barrionuevo, Carlos, Bergsagel, Leif, Chan, Wing C., Cohen, Jeffrey I., d’Amore, Francesco, Davies, Andrew, Falini, Brunangelo, Ghobrial, Irene M., Goodlad, John R., Gribben, John G., Hsi, Eric D., Kahl, Brad S., Kim, Won-Seog, Kumar, Shaji, LaCasce, Ann S., Laurent, Camille, Lenz, Georg, Leonard, John P., Link, Michael P., Lopez-Guillermo, Armando, Mateos, Maria Victoria, Macintyre, Elizabeth, Melnick, Ari M., Morschhauser, Franck, Nakamura, Shigeo, Narbaitz, Marina, Pavlovsky, Astrid, Pileri, Stefano A., Piris, Miguel, Pro, Barbara, Rajkumar, Vincent, Rosen, Steven T., Sander, Birgitta, Sehn, Laurie, Shipp, Margaret A., Smith, Sonali M., Staudt, Louis M., Thieblemont, Catherine, Tousseyn, Thomas, Wilson, Wyndham H., Yoshino, Tadashi, Zinzani, Pier-Luigi, Dreyling, Martin, Scott, David W., Winter, Jane N., and Zelenetz, Andrew D.
- Abstract
Since the publication of the Revised European-American Classification of Lymphoid Neoplasms in 1994, subsequent updates of the classification of lymphoid neoplasms have been generated through iterative international efforts to achieve broad consensus among hematopathologists, geneticists, molecular scientists, and clinicians. Significant progress has recently been made in the characterization of malignancies of the immune system, with many new insights provided by genomic studies. They have led to this proposal. We have followed the same process that was successfully used for the third and fourth editions of the World Health Organization Classification of Hematologic Neoplasms. The definition, recommended studies, and criteria for the diagnosis of many entities have been extensively refined. Some categories considered provisional have now been upgraded to definite entities. Terminology for some diseases has been revised to adapt nomenclature to the current knowledge of their biology, but these modifications have been restricted to well-justified situations. Major findings from recent genomic studies have impacted the conceptual framework and diagnostic criteria for many disease entities. These changes will have an impact on optimal clinical management. The conclusions of this work are summarized in this report as the proposed International Consensus Classification of mature lymphoid, histiocytic, and dendritic cell tumors.
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- 2022
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5. Spatial signatures identify immune escape via PD-1 as a defining feature of T-cell/histiocyte-rich large B-cell lymphoma
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Griffin, Gabriel K., Weirather, Jason L., Roemer, Margaretha G. M., Lipschitz, Mikel, Kelley, Alyssa, Chen, Pei-Hsuan, Gusenleitner, Daniel, Jeter, Erin, Pak, Christine, Gjini, Evisa, Chapuy, Bjoern, Rosenthal, Michael H., Xu, Jie, Chen, Benjamin J., Sohani, Aliyah R., Lovitch, Scott B., Abramson, Jeremy S., Ishizuka, Jeffrey J., Kim, Austin I., Jacobson, Caron A., LaCasce, Ann S., Fletcher, Christopher D., Neuberg, Donna, Freeman, Gordon J., Hodi, F. Stephen, Wright, Kyle, Ligon, Azra H., Jacobsen, Eric D., Armand, Philippe, Shipp, Margaret A., and Rodig, Scott J.
- Abstract
T-cell/histiocyte-rich large B-cell lymphoma (TCRLBCL) is an aggressive variant of diffuse large B-cell lymphoma (DLBCL) characterized by rare malignant B cells within a robust but ineffective immune cell infiltrate. The mechanistic basis of immune escape in TCRLBCL is poorly defined and not targeted therapeutically. We performed a genetic and quantitative spatial analysis of the PD-1/PD-L1 pathway in a multi-institutional cohort of TCRLBCLs and found that malignant B cells harbored PD-L1/PD-L2 copy gain or amplification in 64% of cases, which was associated with increased PD-L1 expression (P = .0111). By directed and unsupervised spatial analyses of multiparametric cell phenotypic data within the tumor microenvironment, we found that TCRLBCL is characterized by tumor-immune “neighborhoods” in which malignant B cells are surrounded by exceptionally high numbers of PD-L1–expressing TAMs and PD-1+ T cells. Furthermore, unbiased clustering of spatially resolved immune signatures distinguished TCRLBCL from related subtypes of B-cell lymphoma, including classic Hodgkin lymphoma (cHL) and DLBCL-NOS. Finally, we observed clinical responses to PD-1 blockade in 3 of 5 patients with relapsed/refractory TCRLBCL who were enrolled in clinical trials for refractory hematologic malignancies (NCT03316573; NCT01953692), including 2 complete responses and 1 partial response. Taken together, these data implicate PD-1 signaling as an immune escape pathway in TCRLBCL and also support the potential utility of spatially resolved immune signatures to aid the diagnostic classification and immunotherapeutic prioritization of diverse tumor types.
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- 2021
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6. Spatial signatures identify immune escape via PD-1 as a defining feature of T-cell/histiocyte-rich large B-cell lymphoma
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Griffin, Gabriel K., Weirather, Jason L., Roemer, Margaretha G.M., Lipschitz, Mikel, Kelley, Alyssa, Chen, Pei-Hsuan, Gusenleitner, Daniel, Jeter, Erin, Pak, Christine, Gjini, Evisa, Chapuy, Bjoern, Rosenthal, Michael H., Xu, Jie, Chen, Benjamin J., Sohani, Aliyah R., Lovitch, Scott B., Abramson, Jeremy S., Ishizuka, Jeffrey J., Kim, Austin I., Jacobson, Caron A., LaCasce, Ann S., Fletcher, Christopher D., Neuberg, Donna, Freeman, Gordon J., Hodi, F. Stephen, Wright, Kyle, Ligon, Azra H., Jacobsen, Eric D., Armand, Philippe, Shipp, Margaret A., and Rodig, Scott J.
- Abstract
T-cell/histiocyte-rich large B-cell lymphoma (TCRLBCL) is an aggressive variant of diffuse large B-cell lymphoma (DLBCL) characterized by rare malignant B cells within a robust but ineffective immune cell infiltrate. The mechanistic basis of immune escape in TCRLBCL is poorly defined and not targeted therapeutically. We performed a genetic and quantitative spatial analysis of the PD-1/PD-L1 pathway in a multi-institutional cohort of TCRLBCLs and found that malignant B cells harbored PD-L1/PD-L2copy gain or amplification in 64% of cases, which was associated with increased PD-L1 expression (P= .0111). By directed and unsupervised spatial analyses of multiparametric cell phenotypic data within the tumor microenvironment, we found that TCRLBCL is characterized by tumor-immune “neighborhoods” in which malignant B cells are surrounded by exceptionally high numbers of PD-L1–expressing TAMs and PD-1+T cells. Furthermore, unbiased clustering of spatially resolved immune signatures distinguished TCRLBCL from related subtypes of B-cell lymphoma, including classic Hodgkin lymphoma (cHL) and DLBCL-NOS. Finally, we observed clinical responses to PD-1 blockade in 3 of 5 patients with relapsed/refractory TCRLBCL who were enrolled in clinical trials for refractory hematologic malignancies (NCT03316573; NCT01953692), including 2 complete responses and 1 partial response. Taken together, these data implicate PD-1 signaling as an immune escape pathway in TCRLBCL and also support the potential utility of spatially resolved immune signatures to aid the diagnostic classification and immunotherapeutic prioritization of diverse tumor types.
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- 2021
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7. A peripheral immune signature of responsiveness to PD-1 blockade in patients with classical Hodgkin lymphoma
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Cader, Fathima Zumla, Hu, Xihao, Goh, Walter L., Wienand, Kirsty, Ouyang, Jing, Mandato, Elisa, Redd, Robert, Lawton, Lee N., Chen, Pei-Hsuan, Weirather, Jason L., Schackmann, Ron C. J., Li, Bo, Ma, Wenjiang, Armand, Philippe, Rodig, Scott J., Neuberg, Donna, Liu, X. Shirley, and Shipp, Margaret A.
- Abstract
PD-1 blockade is highly effective in classical Hodgkin lymphomas (cHLs), which exhibit frequent copy-number gains of CD274(PD-L1) and PDC1LG2(PD-L2) on chromosome 9p24.1. However, in this largely MHC-class-I-negative tumor, the mechanism of action of anti-PD-1 therapy remains undefined. We utilized the complementary approaches of T cell receptor (TCR) sequencing and cytometry by time-of-flight analysis to obtain a peripheral immune signature of responsiveness to PD-1 blockade in 56 patients treated in the CheckMate 205 phase II clinical trial (NCT02181738). Anti-PD-1 therapy was most effective in patients with a diverse baseline TCR repertoire and an associated expansion of singleton clones during treatment. CD4+, but not CD8+, TCR diversity significantly increased during therapy, most strikingly in patients who had achieved complete responses. Additionally, patients who responded to therapy had an increased abundance of activated natural killer cells and a newly identified CD3−CD68+CD4+GrB+subset. These studies highlight the roles of recently expanded, clonally diverse CD4+T cells and innate effectors in the efficacy of PD-1 blockade in cHL.
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- 2020
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8. PD-1 blockade for diffuse large B-cell lymphoma after autologous stem cell transplantation
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Frigault, Matthew J., Armand, Philippe, Redd, Robert A., Jeter, Erin, Merryman, Reid W., Coleman, Kimberly C., Herrera, Alex F., Dahi, Parastoo, Nieto, Yago, LaCasce, Ann S., Fisher, David C., Ng, Samuel Y., Odejide, Oreife O., Freedman, Arnold S., Kim, Austin I., Crombie, Jennifer L., Jacobson, Caron A., Jacobsen, Eric D., Wong, Jeffrey L., Bsat, Jad, Patel, Sanjay S., Ritz, Jerome, Rodig, Scott J., Shipp, Margaret A., Chen, Yi-Bin, and Joyce, Robin M.
- Abstract
Disease relapse remains the leading cause of failure after autologous stem cell transplantation (ASCT) for patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL). We conducted a phase 2, multicenter, single-arm study of the anti–PD-1 monoclonal antibody pembrolizumab given after ASCT in patients with chemosensitive DLBCL, hypothesizing that it would improve the progression-free survival (PFS) at 18 months after ASCT (primary endpoint) from 60% to 80%. Pembrolizumab was administered at 200 mg IV every 3 weeks for up to 8 cycles, starting within 21 days of post-ASCT discharge. Twenty-nine patients were treated on this study; 62% completed all 8 cycles. Seventy-nine percent of patients experienced at least one grade 3 or higher adverse event, and 34% experienced at least one grade 2 or higher immune-related adverse event. Overall, 59% of patients were alive and progression free at 18 months, which did not meet the primary endpoint. The 18-month overall survival was 93%. In conclusion, pembrolizumab was successfully administered as post-ASCT consolidation in patients with R/R DLBCL, but the PFS did not meet the protocol-specific primary objective and therefore does not support a larger confirmatory study. This trial was registered at www.clinicaltrials.gov as #NCT02362997.
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- 2020
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9. PD-1 blockade for diffuse large B-cell lymphoma after autologous stem cell transplantation
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Frigault, Matthew J., Armand, Philippe, Redd, Robert A., Jeter, Erin, Merryman, Reid W., Coleman, Kimberly C., Herrera, Alex F., Dahi, Parastoo, Nieto, Yago, LaCasce, Ann S., Fisher, David C., Ng, Samuel Y., Odejide, Oreife O., Freedman, Arnold S., Kim, Austin I., Crombie, Jennifer L., Jacobson, Caron A., Jacobsen, Eric D., Wong, Jeffrey L., Bsat, Jad, Patel, Sanjay S., Ritz, Jerome, Rodig, Scott J., Shipp, Margaret A., Chen, Yi-Bin, and Joyce, Robin M.
- Abstract
Disease relapse remains the leading cause of failure after autologous stem cell transplantation (ASCT) for patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL). We conducted a phase 2, multicenter, single-arm study of the anti–PD-1 monoclonal antibody pembrolizumab given after ASCT in patients with chemosensitive DLBCL, hypothesizing that it would improve the progression-free survival (PFS) at 18 months after ASCT (primary endpoint) from 60% to 80%. Pembrolizumab was administered at 200 mg IV every 3 weeks for up to 8 cycles, starting within 21 days of post-ASCT discharge. Twenty-nine patients were treated on this study; 62% completed all 8 cycles. Seventy-nine percent of patients experienced at least one grade 3 or higher adverse event, and 34% experienced at least one grade 2 or higher immune-related adverse event. Overall, 59% of patients were alive and progression free at 18 months, which did not meet the primary endpoint. The 18-month overall survival was 93%. In conclusion, pembrolizumab was successfully administered as post-ASCT consolidation in patients with R/R DLBCL, but the PFS did not meet the protocol-specific primary objective and therefore does not support a larger confirmatory study. This trial was registered at www.clinicaltrials.govas #NCT02362997.
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- 2020
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10. Genomic analyses of PMBL reveal new drivers and mechanisms of sensitivity to PD-1 blockade
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Chapuy, Bjoern, Stewart, Chip, Dunford, Andrew J., Kim, Jaegil, Wienand, Kirsty, Kamburov, Atanas, Griffin, Gabriel K., Chen, Pei-Hsuan, Lako, Ana, Redd, Robert A., Cote, Claire M., Ducar, Matthew D., Thorner, Aaron R., Rodig, Scott J., Getz, Gad, and Shipp, Margaret A.
- Abstract
Primary mediastinal large B-cell lymphomas (PMBLs) are aggressive tumors that typically present as large mediastinal masses in young women. PMBLs share clinical, transcriptional, and molecular features with classical Hodgkin lymphoma (cHL), including constitutive activation of nuclear factor ?B (NF-?B), JAK/STAT signaling, and programmed cell death protein 1 (PD-1)–mediated immune evasion. The demonstrated efficacy of PD-1 blockade in relapsed/refractory PMBLs led to recent approval by the US Food and Drug Administration and underscored the importance of characterizing targetable genetic vulnerabilities in this disease. Here, we report a comprehensive analysis of recurrent genetic alterations —somatic mutations, somatic copy number alterations, and structural variants—in a cohort of 37 newly diagnosed PMBLs. We identified a median of 9 genetic drivers per PMBL, including known and newly identified components of the JAK/STAT and NF-?B signaling pathways and frequent B2M alterations that limit major histocompatibility complex class I expression, as in cHL. PMBL also exhibited frequent, newly identified driver mutations in ZNF217 and an additional epigenetic modifier, EZH2. The majority of these alterations were clonal, which supports their role as early drivers. In PMBL, we identified several previously uncharacterized molecular features that may increase sensitivity to PD-1 blockade, including high tumor mutational burden, microsatellite instability, and an apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC) mutational signature. The shared genetic features between PMBL and cHL provide a framework for analyzing the mechanism of action of PD-1 blockade in these related lymphoid malignancies.
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- 2019
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11. Genomic analyses of PMBL reveal new drivers and mechanisms of sensitivity to PD-1 blockade
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Chapuy, Bjoern, Stewart, Chip, Dunford, Andrew J., Kim, Jaegil, Wienand, Kirsty, Kamburov, Atanas, Griffin, Gabriel K., Chen, Pei-Hsuan, Lako, Ana, Redd, Robert A., Cote, Claire M., Ducar, Matthew D., Thorner, Aaron R., Rodig, Scott J., Getz, Gad, and Shipp, Margaret A.
- Abstract
Primary mediastinal large B-cell lymphomas (PMBLs) are aggressive tumors that typically present as large mediastinal masses in young women. PMBLs share clinical, transcriptional, and molecular features with classical Hodgkin lymphoma (cHL), including constitutive activation of nuclear factor κB (NF-κB), JAK/STAT signaling, and programmed cell death protein 1 (PD-1)–mediated immune evasion. The demonstrated efficacy of PD-1 blockade in relapsed/refractory PMBLs led to recent approval by the US Food and Drug Administration and underscored the importance of characterizing targetable genetic vulnerabilities in this disease. Here, we report a comprehensive analysis of recurrent genetic alterations —somatic mutations, somatic copy number alterations, and structural variants—in a cohort of 37 newly diagnosed PMBLs. We identified a median of 9 genetic drivers per PMBL, including known and newly identified components of the JAK/STAT and NF-κB signaling pathways and frequent B2Malterations that limit major histocompatibility complex class I expression, as in cHL. PMBL also exhibited frequent, newly identified driver mutations in ZNF217and an additional epigenetic modifier, EZH2. The majority of these alterations were clonal, which supports their role as early drivers. In PMBL, we identified several previously uncharacterized molecular features that may increase sensitivity to PD-1 blockade, including high tumor mutational burden, microsatellite instability, and an apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC) mutational signature. The shared genetic features between PMBL and cHL provide a framework for analyzing the mechanism of action of PD-1 blockade in these related lymphoid malignancies.
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- 2019
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12. Genomic analyses of flow-sorted Hodgkin Reed-Sternberg cells reveal complementary mechanisms of immune evasion
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Wienand, Kirsty, Chapuy, Bjoern, Stewart, Chip, Dunford, Andrew J., Wu, David, Kim, Jaegil, Kamburov, Atanas, Wood, Timothy R., Cader, Fathima Zumla, Ducar, Matthew D., Thorner, Aaron R., Nag, Anwesha, Heubeck, Alexander T., Buonopane, Michael J., Redd, Robert A., Bojarczuk, Kamil, Lawton, Lee N., Armand, Philippe, Rodig, Scott J., Fromm, Jonathan R., Getz, Gad, and Shipp, Margaret A.
- Abstract
Classical Hodgkin lymphoma (cHL) is composed of rare malignant Hodgkin Reed-Sternberg (HRS) cells within an extensive, but ineffective, inflammatory/immune cell infiltrate. HRS cells exhibit near-universal somatic copy gains of chromosome 9p/9p24.1, which increase expression of the programmed cell death protein 1 (PD-1) ligands. To define genetic mechanisms of response and resistance to PD-1 blockade and identify complementary treatment targets, we performed whole-exome sequencing of flow cytometry–sorted HRS cells from 23 excisional biopsies of newly diagnosed cHLs, including 8 Epstein-Barr virus–positive (EBV+) tumors. We identified significantly mutated cancer candidate genes (CCGs) as well as somatic copy number alterations and structural variations and characterized their contribution to disease-defining immune evasion mechanisms and nuclear factor κB (NF-κB), JAK/STAT, and PI3K signaling pathways. EBV– cHLs had a higher prevalence of genetic alterations in the NF-κB and major histocompatibility complex class I antigen presentation pathways. In this young cHL cohort (median age, 26 years), we identified a predominant mutational signature of spontaneous deamination of cytosine- phosphate-guanines (“Aging”), in addition to apolipoprotein B mRNA editing catalytic polypeptide-like, activation-induced cytidine deaminase, and microsatellite instability (MSI)–associated hypermutation. In particular, the mutational burden in EBV– cHLs was among the highest reported, similar to that of carcinogen-induced tumors. Together, the overall high mutational burden, MSI-associated hypermutation, and newly identified genetic alterations represent additional potential bases for the efficacy of PD-1 blockade in cHL. Of note, recurrent cHL alterations, including B2M, TNFAIP3, STAT6, GNA13, and XPO1 mutations and 2p/2p15, 6p21.32, 6q23.3, and 9p/9p24.1 copy number alterations, were also identified in >20% of primary mediastinal B-cell lymphomas, highlighting shared pathogenetic mechanisms in these diseases.
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- 2019
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13. Genomic analyses of flow-sorted Hodgkin Reed-Sternberg cells reveal complementary mechanisms of immune evasion
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Wienand, Kirsty, Chapuy, Bjoern, Stewart, Chip, Dunford, Andrew J., Wu, David, Kim, Jaegil, Kamburov, Atanas, Wood, Timothy R., Cader, Fathima Zumla, Ducar, Matthew D., Thorner, Aaron R., Nag, Anwesha, Heubeck, Alexander T., Buonopane, Michael J., Redd, Robert A., Bojarczuk, Kamil, Lawton, Lee N., Armand, Philippe, Rodig, Scott J., Fromm, Jonathan R., Getz, Gad, and Shipp, Margaret A.
- Abstract
Classical Hodgkin lymphoma (cHL) is composed of rare malignant Hodgkin Reed-Sternberg (HRS) cells within an extensive, but ineffective, inflammatory/immune cell infiltrate. HRS cells exhibit near-universal somatic copy gains of chromosome 9p/9p24.1, which increase expression of the programmed cell death protein 1 (PD-1) ligands. To define genetic mechanisms of response and resistance to PD-1 blockade and identify complementary treatment targets, we performed whole-exome sequencing of flow cytometry–sorted HRS cells from 23 excisional biopsies of newly diagnosed cHLs, including 8 Epstein-Barr virus–positive (EBV+) tumors. We identified significantly mutated cancer candidate genes (CCGs) as well as somatic copy number alterations and structural variations and characterized their contribution to disease-defining immune evasion mechanisms and nuclear factor κB (NF-κB), JAK/STAT, and PI3K signaling pathways. EBV–cHLs had a higher prevalence of genetic alterations in the NF-κB and major histocompatibility complex class I antigen presentation pathways. In this young cHL cohort (median age, 26 years), we identified a predominant mutational signature of spontaneous deamination of cytosine- phosphate-guanines (“Aging”), in addition to apolipoprotein B mRNA editing catalytic polypeptide-like, activation-induced cytidine deaminase, and microsatellite instability (MSI)–associated hypermutation. In particular, the mutational burden in EBV–cHLs was among the highest reported, similar to that of carcinogen-induced tumors. Together, the overall high mutational burden, MSI-associated hypermutation, and newly identified genetic alterations represent additional potential bases for the efficacy of PD-1 blockade in cHL. Of note, recurrent cHL alterations, including B2M, TNFAIP3, STAT6, GNA13, and XPO1mutations and 2p/2p15, 6p21.32, 6q23.3, and 9p/9p24.1 copy number alterations, were also identified in >20% of primary mediastinal B-cell lymphomas, highlighting shared pathogenetic mechanisms in these diseases.
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- 2019
- Full Text
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14. The microenvironmental niche in classic Hodgkin lymphoma is enriched for CTLA-4–positive T cells that are PD-1–negative
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Patel, Sanjay S., Weirather, Jason L., Lipschitz, Mikel, Lako, Ana, Chen, Pei-Hsuan, Griffin, Gabriel K., Armand, Philippe, Shipp, Margaret A., and Rodig, Scott J.
- Abstract
Classic Hodgkin lymphoma (cHL) is a tumor composed of rare, atypical, germinal center–derived B cells (Hodgkin Reed-Sternberg [HRS] cells) embedded within a robust but ineffective inflammatory milieu. The cHL tumor microenvironment (TME) is compartmentalized into “niches” rich in programmed cell death-1 ligand (PD-L1)–positive HRS cells and tumor-associated macrophages (TAMs), which associate with PD-1–positive T cells to suppress antitumor immunity via PD-L1/PD-1 signaling. Despite the exquisite sensitivity of cHL to PD-1 checkpoint blockade, most patients eventually relapse and need therapeutic alternatives. Using multiplex immunofluorescence microscopy with digital image analysis, we found that cHL is highly enriched for non–T-regulatory, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4)–positive T cells (compared with reactive lymphoid tissues) that outnumber PD-1–positive and lymphocyte-activating gene-3 (LAG-3)–positive T cells. In addition, T cells touching HRS cells are more frequently positive for CTLA-4 than for PD-1 or LAG-3. We further found that HRS cells, and a subset of TAMs, are positive for the CTLA-4 ligand CD86 and that the fractions of T cells and TAMs that are CTLA-4–positive and CD86-positive, respectively, are greater within a 75 µm HRS cell niche relative to areas outside this region (CTLA-4, 38% vs 18% [P = .0001]; CD86, 38% vs 24% [P = .0007]). Importantly, CTLA-4–positive cells are present, and focally contact HRS cells, in recurrent cHL tumors following a variety of therapies, including PD-1 blockade. These results implicate CTLA-4:CD86 interactions as a component of the immunologically privileged niche surrounding HRS cells and raise the possibility that patients with cHL refractory to PD-1 blockade may benefit from CTLA-4 blockade.
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- 2019
- Full Text
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15. The microenvironmental niche in classic Hodgkin lymphoma is enriched for CTLA-4–positive T cells that are PD-1–negative
- Author
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Patel, Sanjay S., Weirather, Jason L., Lipschitz, Mikel, Lako, Ana, Chen, Pei-Hsuan, Griffin, Gabriel K., Armand, Philippe, Shipp, Margaret A., and Rodig, Scott J.
- Abstract
Classic Hodgkin lymphoma (cHL) is a tumor composed of rare, atypical, germinal center–derived B cells (Hodgkin Reed-Sternberg [HRS] cells) embedded within a robust but ineffective inflammatory milieu. The cHL tumor microenvironment (TME) is compartmentalized into “niches” rich in programmed cell death-1 ligand (PD-L1)–positive HRS cells and tumor-associated macrophages (TAMs), which associate with PD-1–positive T cells to suppress antitumor immunity via PD-L1/PD-1 signaling. Despite the exquisite sensitivity of cHL to PD-1 checkpoint blockade, most patients eventually relapse and need therapeutic alternatives. Using multiplex immunofluorescence microscopy with digital image analysis, we found that cHL is highly enriched for non–T-regulatory, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4)–positive T cells (compared with reactive lymphoid tissues) that outnumber PD-1–positive and lymphocyte-activating gene-3 (LAG-3)–positive T cells. In addition, T cells touching HRS cells are more frequently positive for CTLA-4 than for PD-1 or LAG-3. We further found that HRS cells, and a subset of TAMs, are positive for the CTLA-4 ligand CD86 and that the fractions of T cells and TAMs that are CTLA-4–positive and CD86-positive, respectively, are greater within a 75 μm HRS cell niche relative to areas outside this region (CTLA-4, 38% vs 18% [P= .0001]; CD86, 38% vs 24% [P= .0007]). Importantly, CTLA-4–positive cells are present, and focally contact HRS cells, in recurrent cHL tumors following a variety of therapies, including PD-1 blockade. These results implicate CTLA-4:CD86 interactions as a component of the immunologically privileged niche surrounding HRS cells and raise the possibility that patients with cHL refractory to PD-1 blockade may benefit from CTLA-4 blockade.
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- 2019
- Full Text
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16. Nivolumab for Newly Diagnosed Advanced-Stage Classic Hodgkin Lymphoma: Safety and Efficacy in the Phase II CheckMate 205 Study.
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Ramchandren, Radhakrishnan, Domingo-Domènech, Eva, Rueda, Antonio, Trněný, Marek, Feldman, Tatyana A., Lee, Hun Ju, Provencio, Mariano, Sillaber, Christian, Cohen, Jonathon B., Savage, Kerry J., Willenbacher, Wolfgang, Ligon, Azra H., Ouyang, Jing, Redd, Robert, Rodig, Scott J., Shipp, Margaret A., Sacchi, Mariana, Sumbul, Anne, Armand, Philippe, and Ansell, Stephen M.
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- 2019
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17. Nivolumab for Relapsed/Refractory Diffuse Large B-Cell Lymphoma in Patients Ineligible for or Having Failed Autologous Transplantation: A Single-Arm, Phase II Study.
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Ansell, Stephen M., Minnema, Monique C., Johnson, Peter, Timmerman, John M., Armand, Philippe, Shipp, Margaret A., Rodig, Scott J., Ligon, Azra H., Roemer, Margaretha G.M., Reddy, Nishitha, Cohen, Jonathon B., Assouline, Sarit, Poon, Michelle, Sharma, Manish, Kato, Kazunobu, Samakoglu, Selda, Sumbul, Anne, and Grigg, Andrew
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- 2019
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18. Genome-Scale High-Resolution Spatial Mapping of the Pro-Tumorigenic Cellular Niche in Classic Hodgkin Lymphoma
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Shanmugam, Vignesh, Tokcan, Neriman, Chafamo, Daniel, Sullivan, Sean, Martin, Haley, Newton, Gail A, Borji, Mehdi, Nadaf, Naeem, Barrera, Irving, Cable, Dylan, Weir, Jackson, Ashenberg, Orr, Uhler, Caroline, Pinkus, Geraldine, Rodig, Scott, Shipp, Margaret A., Macosko, Evan, Louissaint, Abner, Chen, Fei, and Golub, Todd R.
- Abstract
Introduction:A fundamental hallmark of cancer is that tumor cells repurpose the tissue microenvironment to promote their own survival. An increased understanding of these mechanisms may lead to improved microenvironment-directed therapies, particularly in lymphoid malignancies. In classic Hodgkin lymphoma (cHL), the rare malignant Hodgkin Reed Sternberg (HRS) cells are surrounded by a CD4+ T-cell and macrophage-rich inflammatory infiltrate. Recent multiplexed immunofluorescence studies suggest that the micron-scale niche around HRS cells is composed of distinct populations of PD-L1+ macrophages and CD4+ T cells, including regulatory CTLA4+ and LAG3+ subsets (Carey et al. Blood 2017, Patel et al. Blood 2019 and Aoki et al. Cancer Discov 2020). However, the topography of the intact tumor microenvironment of cHL requires further definition. Recent single-cell RNA sequencing studies have led to important insights into the biology of cHL; however, they do not adequately capture myeloid cells, fibroblasts, and HRS cells, likely due to the relative fragility of these cells in conventional tissue dissociation protocols. In this study, we use tandem single nucleus and spatially resolved RNA sequencing to systematically dissect the pro-tumorigenic cellular niche of cHL to define potentially targetable microenvironmental dependencies.
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- 2023
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19. Single-Cell RNA Sequencing Reveals the Interplay between Circulating CD4 +T Cells, B Cells and Cancer-Associated Monocytes in Classic Hodgkin Lymphoma Treated with PD-1 Blockade
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Paczkowska, Julia, Tang, Ming, Wright, Kyle T., Song, Li, Luu, Kelsey, Shanmugam, Vignesh, Welsh, Emma L., Weirather, Jason L., Pfaff, Kathleen, Redd, Robert A., Cader, Zumla, Mandato, Elisa, Ouyang, Jing, Bai, Gali, Lawton, Lee N., Armand, Philippe, Rodig, Scott, Liu, Xiaole Shirley, and Shipp, Margaret A.
- Abstract
Classic Hodgkin lymphoma (cHL) is a largely MHC class I-negative tumor with recurrent 9p24.1/ PD-L1/ PD-L2copy gains and the highest reported response rates to PD-1 blockade. In cHL, the efficacy of PD-1 blockade is closely associated with Hodgkin Reed-Sternberg (HRS) cell expression of MHC class II, highlighting the potential role of CD4 +T-cell effectors and additional non-MHC class I-mediated mechanisms of tumor cell killing. We utilized scRNA and scT-cell receptor (TCR) sequencing to characterize the peripheral immune response to PD-1 blockade and define non-CD8 +T-cell dependent mechanisms of immune evasion in cHL.
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- 2023
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20. A Phase I Study of Copanlisib and Venetoclax in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma
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Crombie, Jennifer L, Kim, Austin I, Bartlett, Nancy L., Redd, Robert A., Patterson, Victoria, Carey, Celeste, Balasubramanian, Sobana, Odejide, Oreofe O., Merryman, Reid W., LaCasce, Ann, Jacobson, Caron A, Jacobsen, Eric, Parry, Erin M, Fisher, David C, Herrera, Alex F., Davids, Matthew S, Shipp, Margaret A., Armand, Philippe, and Shouse, Geoffrey P.
- Abstract
Introduction:
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- 2023
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21. Cd70Deficiency Impairs CD4 +and CD8 +T-Cell Immune Surveillance in Bcl6-Driven Diffuse Large B-Cell Lymphomas
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Mandato, Elisa, Calabretta, Eleonora, Bai, Gali, Song, Li, Ma, Tianfang, Shanmugam, Vignesh, Paczkowska, Julia, Sun, Yanbo, Choi, Il-Kyu, Redd, Robert A., Neuberg, Donna S., Khan, Sumbul Jawed, Michor, Franziska, Rodig, Scott, Zhang, Baochun, and Shipp, Margaret A.
- Abstract
Anti-tumor immune responses to lymphoid malignancies are modulated by co-stimulatory and co-inhibitory pathways. Our group previously characterized the recurrent genetic alterations in primary diffuse large B-cell lymphomas (DLBCL) and identified frequent inactivating mutations or copy loss of the CD70co-stimulatory ligand in these tumors. CD70 co-stimulation of CD27 +T cells induces antigen-dependent T-cell expansion and immune surveillance of normal and malignant B cells. Given the frequent combination of CD70and BCL6alterations in our human DLBCL series, we investigated the consequences of CD70deficiency ( Cd70-/-) in a murine model of BCL6-driven lymphomagenesis ( Bcl6tg/+).
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- 2023
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22. Nivolumab for Relapsed/Refractory Classic Hodgkin Lymphoma After Failure of Autologous Hematopoietic Cell Transplantation: Extended Follow-Up of the Multicohort Single-Arm Phase II CheckMate 205 Trial.
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Armand, Philippe, Engert, Andreas, Younes, Anas, Fanale, Michelle, Santoro, Armando, Zinzani, Pier Luigi, Timmerman, John M., Collins, Graham P., Ramchandren, Radhakrishnan, Cohen, Jonathon B., De Boer, Jan Paul, Kuruvilla, John, Savage, Kerry J., Trneny, Marek, Shipp, Margaret A., Kato, Kazunobu, Sumbul, Anne, Farsaci, Benedetto, and Ansell, Stephen M.
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- 2018
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23. Pembrolizumab in relapsed or refractory Hodgkin lymphoma: 2-year follow-up of KEYNOTE-087
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Chen, Robert, Zinzani, Pier Luigi, Lee, Hun Ju, Armand, Philippe, Johnson, Nathalie A., Brice, Pauline, Radford, John, Ribrag, Vincent, Molin, Daniel, Vassilakopoulos, Theodoros P., Tomita, Akihiro, von Tresckow, Bastian, Shipp, Margaret A., Lin, Jianxin, Kim, Eunhee, Nahar, Akash, Balakumaran, Arun, and Moskowitz, Craig H.
- Abstract
Programmed death-1 inhibitors are approved for patients with relapsed or refractory classic Hodgkin lymphoma (RRcHL). We present the 2-year follow-up of the phase 2 KEYNOTE-087 study of pembrolizumab in 210 patients, based on HL progression after autologous stem cell transplantation (ASCT) and subsequent brentuximab vedotin (BV; cohort 1); salvage chemotherapy and BV, with ineligibility for SCT owing to chemorefractory disease (cohort 2); and progression after SCT without BV (cohort 3). With a median follow-up of 27.6 months, the objective response rate (ORR) by blinded independent central review was 71.9% (95% CI, 65.3-77.9), the complete response rate (CRR) was 27.6%, and the partial response (PR) rate was 44.3%. Median duration of response was 16.5 months (range, 0.0+ to 27.0+ [+, no progressive disease at last assessment]) in all patients, 22.1 months in cohort 1, 11.1 months in cohort 2, and 24.4 months in cohort 3. Median progression-free survival was not reached in all patients with CR: 13.8 months (95% CI, 12.0-22.1) for patients with PR and 10.9 months (95% CI, 5.6-11.1) for patients with stable disease. Median overall survival was not reached in all patients or in any cohort. Treatment-related adverse events (TRAEs) of any grade occurred in 153 (72.9%) patients; grades 3 and 4 occurred in 25 (12.0%) patients; none resulted in death. Results confirmed effective antitumor activity, durability of response, and manageable safety of pembrolizumab monotherapy in RRcHL, regardless of prior treatment and including chemoresistant cHL. This trial was registered at www.clinicaltrials.gov as #NCT02453594.
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- 2019
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24. Pembrolizumab in relapsed or refractory Hodgkin lymphoma: 2-year follow-up of KEYNOTE-087
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Chen, Robert, Zinzani, Pier Luigi, Lee, Hun Ju, Armand, Philippe, Johnson, Nathalie A., Brice, Pauline, Radford, John, Ribrag, Vincent, Molin, Daniel, Vassilakopoulos, Theodoros P., Tomita, Akihiro, von Tresckow, Bastian, Shipp, Margaret A., Lin, Jianxin, Kim, Eunhee, Nahar, Akash, Balakumaran, Arun, and Moskowitz, Craig H.
- Abstract
Programmed death-1 inhibitors are approved for patients with relapsed or refractory classic Hodgkin lymphoma (RRcHL). We present the 2-year follow-up of the phase 2 KEYNOTE-087 study of pembrolizumab in 210 patients, based on HL progression after autologous stem cell transplantation (ASCT) and subsequent brentuximab vedotin (BV; cohort 1); salvage chemotherapy and BV, with ineligibility for SCT owing to chemorefractory disease (cohort 2); and progression after SCT without BV (cohort 3). With a median follow-up of 27.6 months, the objective response rate (ORR) by blinded independent central review was 71.9% (95% CI, 65.3-77.9), the complete response rate (CRR) was 27.6%, and the partial response (PR) rate was 44.3%. Median duration of response was 16.5 months (range, 0.0+ to 27.0+ [+, no progressive disease at last assessment]) in all patients, 22.1 months in cohort 1, 11.1 months in cohort 2, and 24.4 months in cohort 3. Median progression-free survival was not reached in all patients with CR: 13.8 months (95% CI, 12.0-22.1) for patients with PR and 10.9 months (95% CI, 5.6-11.1) for patients with stable disease. Median overall survival was not reached in all patients or in any cohort. Treatment-related adverse events (TRAEs) of any grade occurred in 153 (72.9%) patients; grades 3 and 4 occurred in 25 (12.0%) patients; none resulted in death. Results confirmed effective antitumor activity, durability of response, and manageable safety of pembrolizumab monotherapy in RRcHL, regardless of prior treatment and including chemoresistant cHL. This trial was registered at www.clinicaltrials.govas #NCT02453594.
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- 2019
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25. PD-1 blockade with pembrolizumab for classical Hodgkin lymphoma after autologous stem cell transplantation
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Armand, Philippe, Chen, Yi-Bin, Redd, Robert A., Joyce, Robin M., Bsat, Jad, Jeter, Erin, Merryman, Reid W., Coleman, Kimberly C., Dahi, Parastoo B., Nieto, Yago, LaCasce, Ann S., Fisher, David C., Ng, Samuel Y., Odejide, Oreofe O., Freedman, Arnold S., Kim, Austin I., Crombie, Jennifer L., Jacobson, Caron A., Jacobsen, Eric D., Wong, Jeffrey L., Patel, Sanjay S., Ritz, Jerome, Rodig, Scott J., Shipp, Margaret A., and Herrera, Alex F.
- Abstract
Autologous stem cell transplantation (ASCT) remains the standard of care for patients with relapsed/refractory (RR) classical Hodgkin lymphoma (cHL) who respond to salvage chemotherapy. However, relapse after ASCT remains a frequent cause of treatment failure, with poor subsequent prognosis. Because cHL is uniquely vulnerable to programmed cell death-1 (PD-1) blockade, PD-1 blockade given as consolidation after ASCT could improve ASCT outcomes. We therefore conducted a multicohort phase 2 study of pembrolizumab in patients with RR cHL after ASCT, hypothesizing that it would improve the progression-free survival (PFS) at 18 months after ASCT (primary end point) from 60% to 80%. Pembrolizumab was administered at 200 mg IV every 3 weeks for up to 8 cycles, starting within 21 days of post-ASCT discharge. Thirty patients were treated on this study. The median age was 33 years, and 90% were high-risk by clinical criteria. Seventy-seven percent completed all 8 cycles. Toxicity was manageable, with 30% of patients experiencing at least 1 grade 3 or higher adverse event (AE), and 40% at least 1 grade 2 or higher immune-related AE. Two patients were lost to follow-up in complete remission at 12 months. The PFS at 18 months for the 28 evaluable patients was 82%, meeting the primary end point. The 18-month overall survival was 100%. In conclusion, pembrolizumab was successfully administered as post-ASCT consolidation in patients with RR cHL, and resulted in a promising PFS in a high-risk patient cohort, supporting the testing of this strategy in a randomized trial. This trial was registered at www.clinicaltrials.gov as #NCT02362997.
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- 2019
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26. PD-1 blockade with pembrolizumab for classical Hodgkin lymphoma after autologous stem cell transplantation
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Armand, Philippe, Chen, Yi-Bin, Redd, Robert A., Joyce, Robin M., Bsat, Jad, Jeter, Erin, Merryman, Reid W., Coleman, Kimberly C., Dahi, Parastoo B., Nieto, Yago, LaCasce, Ann S., Fisher, David C., Ng, Samuel Y., Odejide, Oreofe O., Freedman, Arnold S., Kim, Austin I., Crombie, Jennifer L., Jacobson, Caron A., Jacobsen, Eric D., Wong, Jeffrey L., Patel, Sanjay S., Ritz, Jerome, Rodig, Scott J., Shipp, Margaret A., and Herrera, Alex F.
- Abstract
Autologous stem cell transplantation (ASCT) remains the standard of care for patients with relapsed/refractory (RR) classical Hodgkin lymphoma (cHL) who respond to salvage chemotherapy. However, relapse after ASCT remains a frequent cause of treatment failure, with poor subsequent prognosis. Because cHL is uniquely vulnerable to programmed cell death-1 (PD-1) blockade, PD-1 blockade given as consolidation after ASCT could improve ASCT outcomes. We therefore conducted a multicohort phase 2 study of pembrolizumab in patients with RR cHL after ASCT, hypothesizing that it would improve the progression-free survival (PFS) at 18 months after ASCT (primary end point) from 60% to 80%. Pembrolizumab was administered at 200 mg IV every 3 weeks for up to 8 cycles, starting within 21 days of post-ASCT discharge. Thirty patients were treated on this study. The median age was 33 years, and 90% were high-risk by clinical criteria. Seventy-seven percent completed all 8 cycles. Toxicity was manageable, with 30% of patients experiencing at least 1 grade 3 or higher adverse event (AE), and 40% at least 1 grade 2 or higher immune-related AE. Two patients were lost to follow-up in complete remission at 12 months. The PFS at 18 months for the 28 evaluable patients was 82%, meeting the primary end point. The 18-month overall survival was 100%. In conclusion, pembrolizumab was successfully administered as post-ASCT consolidation in patients with RR cHL, and resulted in a promising PFS in a high-risk patient cohort, supporting the testing of this strategy in a randomized trial. This trial was registered at www.clinicaltrials.govas #NCT02362997.
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- 2019
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27. Targeted inhibition of PI3Kα/δ is synergistic with BCL-2 blockade in genetically defined subtypes of DLBCL
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Bojarczuk, Kamil, Wienand, Kirsty, Ryan, Jeremy A., Chen, Linfeng, Villalobos-Ortiz, Mariana, Mandato, Elisa, Stachura, Joanna, Letai, Anthony, Lawton, Lee N., Chapuy, Bjoern, and Shipp, Margaret A.
- Abstract
Inhibition of the B-cell receptor (BCR) signaling pathway is a promising treatment strategy in multiple B-cell malignancies. However, the role of BCR blockade in diffuse large B-cell lymphoma (DLBCL) remains undefined. We recently characterized primary DLBCL subsets with distinct genetic bases for perturbed BCR/phosphoinositide 3-kinase (PI3K) signaling and dysregulated B-cell lymphoma 2 (BCL-2) expression. Herein, we explore the activity of PI3K inhibitors and BCL-2 blockade in a panel of functionally and genetically characterized DLBCL cell line models. A PI3K inhibitor with predominant α/δ activity, copanlisib, exhibited the highest cytotoxicity in all BCR-dependent DLBCLs. The proapoptotic effect of copanlisib was associated with DLBCL subtype-specific dysregulated expression of BCL-2 family members including harakiri (HRK) and its antiapoptotic partner BCL extra large (BCL-xL), BCL2 related protein A1, myeloid cell leukemia 1 (MCL-1), and BCL2 interacting mediator of cell death. Using functional BH3 profiling, we found that the cytotoxic activity of copanlisib was primarily mediated through BCL-xL and MCL-1–dependent mechanisms that might complement BCL-2 blockade. For these reasons, we evaluated single-agent activity of venetoclax in the DLBCLs and identified a subset with limited sensitivity to BCL-2 blockade despite having genetic bases of BCL-2 dysregulation. As these were largely BCR-dependent DLBCLs, we hypothesized that combined inhibition of PI3Kα/δ and BCL-2 would perturb BCR-dependent and BCL-2–mediated survival pathways. Indeed, we observed synergistic activity of copanlisib/venetoclax in BCR-dependent DLBCLs with genetic bases for BCL-2 dysregulation in vitro and confirmed these findings in a xenograft model. These results provide preclinical evidence for the rational combination of PI3Kα/δ and BCL-2 blockade in genetically defined DLBCLs.
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- 2019
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28. Targeted inhibition of PI3Kα/δ is synergistic with BCL-2 blockade in genetically defined subtypes of DLBCL
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Bojarczuk, Kamil, Wienand, Kirsty, Ryan, Jeremy A., Chen, Linfeng, Villalobos-Ortiz, Mariana, Mandato, Elisa, Stachura, Joanna, Letai, Anthony, Lawton, Lee N., Chapuy, Bjoern, and Shipp, Margaret A.
- Abstract
Inhibition of the B-cell receptor (BCR) signaling pathway is a promising treatment strategy in multiple B-cell malignancies. However, the role of BCR blockade in diffuse large B-cell lymphoma (DLBCL) remains undefined. We recently characterized primary DLBCL subsets with distinct genetic bases for perturbed BCR/phosphoinositide 3-kinase (PI3K) signaling and dysregulated B-cell lymphoma 2 (BCL-2) expression. Herein, we explore the activity of PI3K inhibitors and BCL-2 blockade in a panel of functionally and genetically characterized DLBCL cell line models. A PI3K inhibitor with predominant α/δ activity, copanlisib, exhibited the highest cytotoxicity in all BCR-dependent DLBCLs. The proapoptotic effect of copanlisib was associated with DLBCL subtype-specific dysregulated expression of BCL-2 family members including harakiri (HRK) and its antiapoptotic partner BCL extra large (BCL-xL), BCL2 related protein A1, myeloid cell leukemia 1 (MCL-1), and BCL2 interacting mediator of cell death. Using functional BH3 profiling, we found that the cytotoxic activity of copanlisib was primarily mediated through BCL-xL and MCL-1–dependent mechanisms that might complement BCL-2 blockade. For these reasons, we evaluated single-agent activity of venetoclax in the DLBCLs and identified a subset with limited sensitivity to BCL-2 blockade despite having genetic bases of BCL-2 dysregulation. As these were largely BCR-dependent DLBCLs, we hypothesized that combined inhibition of PI3Kα/δ and BCL-2 would perturb BCR-dependent and BCL-2–mediated survival pathways. Indeed, we observed synergistic activity of copanlisib/venetoclax in BCR-dependent DLBCLs with genetic bases for BCL-2 dysregulation in vitro and confirmed these findings in a xenograft model. These results provide preclinical evidence for the rational combination of PI3Kα/δ and BCL-2 blockade in genetically defined DLBCLs.
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- 2019
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29. Phase II Study of the Efficacy and Safety of Pembrolizumab for Relapsed/Refractory Classic Hodgkin Lymphoma.
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Chen, Robert, Zinzani, Pier Luigi, Fanale, Michelle A, Armand, Philippe, Johnson, Nathalie A, Brice, Pauline, Radford, John, Ribrag, Vincent, Molin, Daniel, Vassilakopoulos, Theodoros P, Tomita, Akihiro, von Tresckow, Bastian, Shipp, Margaret A, Zhang, Yinghua, Ricart, Alejandro D, Balakumaran, Arun, Moskowitz, Craig H, and KEYNOTE-087
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- 2017
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30. Programmed Death-1 Blockade With Pembrolizumab in Patients With Classical Hodgkin Lymphoma After Brentuximab Vedotin Failure.
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Armand, Philippe, Shipp, Margaret A., Ribrag, Vincent, Michot, Jean-Marie, Zinzani, Pier Luigi, Kuruvilla, John, Snyder, Ellen S., Ricart, Alejandro D., Balakumaran, Arun, Rose, Shelonitda, and Moskowitz, Craig H.
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- 2016
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31. Mass cytometry of Hodgkin lymphoma reveals a CD4+ regulatory T-cell–rich and exhausted T-effector microenvironment
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Cader, Fathima Zumla, Schackmann, Ron C. J., Hu, Xihao, Wienand, Kirsty, Redd, Robert, Chapuy, Bjoern, Ouyang, Jing, Paul, Nicole, Gjini, Evisa, Lipschitz, Mikel, Armand, Philippe, Wu, David, Fromm, Jonathan R., Neuberg, Donna, Liu, X. Shirley, Rodig, Scott J., and Shipp, Margaret A.
- Abstract
In classical Hodgkin lymphoma (cHL), the host antitumor immune response is ineffective. Hodgkin Reed-Sternberg (HRS) cells have multifaceted mechanisms to evade the immune system, including 9p24.1/CD274(PD-L1)/PDCD1LG2(PD-L2) genetic alterations, overexpression of PD-1 ligands, and associated T-cell exhaustion and additional structural bases of aberrant antigen presentation. The clinical success of PD-1 blockade in cHL suggests that the tumor microenvironment (TME) contains reversibly exhausted T effector cells (Teffs). However, durable responses are observed in patients with β2-microglobulin/major histocompatibility complex (MHC) class I loss on HRS cells, raising the possibility of non-CD8+ T cell–mediated mechanisms of efficacy of PD-1 blockade. These observations highlight the need for a detailed analysis of the cHL TME. Using a customized time-of-flight mass cytometry panel, we simultaneously assessed cell suspensions from diagnostic cHL biopsies and control reactive lymph node/tonsil (RLNT) samples. Precise phenotyping of immune cell subsets revealed salient differences between cHLs and RLNTs. The TME in cHL is CD4+ T-cell rich, with frequent loss of MHC class I expression on HRS cells. In cHLs, we found concomitant expansion of T helper 1 (Th1)-polarized Teffs and regulatory T cells (Tregs). The cHL Th1 Tregs expressed little or no PD-1, whereas the Th1 Teffs were PD-1+. The differential PD-1 expression and likely functional Th1-polarized CD4+ Tregs and exhausted Teffs may represent complementary mechanisms of immunosuppression in cHL.
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- 2018
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32. Mass cytometry of Hodgkin lymphoma reveals a CD4+regulatory T-cell–rich and exhausted T-effector microenvironment
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Cader, Fathima Zumla, Schackmann, Ron C.J., Hu, Xihao, Wienand, Kirsty, Redd, Robert, Chapuy, Bjoern, Ouyang, Jing, Paul, Nicole, Gjini, Evisa, Lipschitz, Mikel, Armand, Philippe, Wu, David, Fromm, Jonathan R., Neuberg, Donna, Liu, X. Shirley, Rodig, Scott J., and Shipp, Margaret A.
- Abstract
In classical Hodgkin lymphoma (cHL), the host antitumor immune response is ineffective. Hodgkin Reed-Sternberg (HRS) cells have multifaceted mechanisms to evade the immune system, including 9p24.1/CD274(PD-L1)/PDCD1LG2(PD-L2)genetic alterations, overexpression of PD-1 ligands, and associated T-cell exhaustion and additional structural bases of aberrant antigen presentation. The clinical success of PD-1 blockade in cHL suggests that the tumor microenvironment (TME) contains reversibly exhausted T effector cells (Teffs). However, durable responses are observed in patients with β2-microglobulin/major histocompatibility complex (MHC) class I loss on HRS cells, raising the possibility of non-CD8+T cell–mediated mechanisms of efficacy of PD-1 blockade. These observations highlight the need for a detailed analysis of the cHL TME. Using a customized time-of-flight mass cytometry panel, we simultaneously assessed cell suspensions from diagnostic cHL biopsies and control reactive lymph node/tonsil (RLNT) samples. Precise phenotyping of immune cell subsets revealed salient differences between cHLs and RLNTs. The TME in cHL is CD4+T-cell rich, with frequent loss of MHC class I expression on HRS cells. In cHLs, we found concomitant expansion of T helper 1 (Th1)-polarized Teffs and regulatory T cells (Tregs). The cHL Th1 Tregs expressed little or no PD-1, whereas the Th1 Teffs were PD-1+. The differential PD-1 expression and likely functional Th1-polarized CD4+Tregs and exhausted Teffs may represent complementary mechanisms of immunosuppression in cHL.
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- 2018
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33. Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes
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Chapuy, Bjoern, Stewart, Chip, Dunford, Andrew J., Kim, Jaegil, Kamburov, Atanas, Redd, Robert A., Lawrence, Mike S., Roemer, Margaretha G. M., Li, Amy J., Ziepert, Marita, Staiger, Annette M., Wala, Jeremiah A., Ducar, Matthew D., Leshchiner, Ignaty, Rheinbay, Ester, Taylor-Weiner, Amaro, Coughlin, Caroline A., Hess, Julian M., Pedamallu, Chandra S., Livitz, Dimitri, Rosebrock, Daniel, Rosenberg, Mara, Tracy, Adam A., Horn, Heike, van Hummelen, Paul, Feldman, Andrew L., Link, Brian K., Novak, Anne J., Cerhan, James R., Habermann, Thomas M., Siebert, Reiner, Rosenwald, Andreas, Thorner, Aaron R., Meyerson, Matthew L., Golub, Todd R., Beroukhim, Rameen, Wulf, Gerald G., Ott, German, Rodig, Scott J., Monti, Stefano, Neuberg, Donna S., Loeffler, Markus, Pfreundschuh, Michael, Trümper, Lorenz, Getz, Gad, and Shipp, Margaret A.
- Abstract
Diffuse large B cell lymphoma (DLBCL), the most common lymphoid malignancy in adults, is a clinically and genetically heterogeneous disease that is further classified into transcriptionally defined activated B cell (ABC) and germinal center B cell (GCB) subtypes. We carried out a comprehensive genetic analysis of 304 primary DLBCLs and identified low-frequency alterations, captured recurrent mutations, somatic copy number alterations, and structural variants, and defined coordinate signatures in patients with available outcome data. We integrated these genetic drivers using consensus clustering and identified five robust DLBCL subsets, including a previously unrecognized group of low-risk ABC-DLBCLs of extrafollicular/marginal zone origin; two distinct subsets of GCB-DLBCLs with different outcomes and targetable alterations; and an ABC/GCB-independent group with biallelic inactivation of TP53, CDKN2Aloss, and associated genomic instability. The genetic features of the newly characterized subsets, their mutational signatures, and the temporal ordering of identified alterations provide new insights into DLBCL pathogenesis. The coordinate genetic signatures also predict outcome independent of the clinical International Prognostic Index and suggest new combination treatment strategies. More broadly, our results provide a roadmap for an actionable DLBCL classification.
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- 2018
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34. Signaling pathways and immune evasion mechanisms in classical Hodgkin lymphoma
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Liu, W. Robert and Shipp, Margaret A.
- Abstract
Classical Hodgkin lymphoma (cHL) is an unusual B-cell–derived malignancy in which rare malignant Hodgkin and Reed-Sternberg (HRS) cells are surrounded by an extensive but ineffective inflammatory/immune cell infiltrate. This striking feature suggests that malignant HRS cells escape immunosurveillance and interact with immune cells in the cancer microenvironment for survival and growth. We previously found that cHLs have a genetic basis for immune evasion: near-uniform copy number alterations of chromosome 9p24.1 and the associated PD-1 ligand loci, CD274/PD-L1 and PDCD1LG2/PD-L2, and copy number–dependent increased expression of these ligands. HRS cells expressing PD-1 ligands are thought to engage PD-1 receptor–positive immune effectors in the tumor microenvironment and induce PD-1 signaling and associated immune evasion. The genetic bases of enhanced PD-1 signaling in cHL make these tumors uniquely sensitive to PD-1 blockade.
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- 2017
- Full Text
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35. Topological analysis reveals a PD-L1-associated microenvironmental niche for Reed-Sternberg cells in Hodgkin lymphoma
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Carey, Christopher D., Gusenleitner, Daniel, Lipschitz, Mikel, Roemer, Margaretha G.M., Stack, Edward C., Gjini, Evisa, Hu, Xihao, Redd, Robert, Freeman, Gordon J., Neuberg, Donna, Hodi, F. Stephen, Liu, Xiaole Shirley, Shipp, Margaret A., and Rodig, Scott J.
- Abstract
Signaling between programmed cell death protein 1 (PD-1) and the PD-1 ligands (PD-L1, PD-L2) is essential for malignant Hodgkin Reed-Sternberg (HRS) cells to evade antitumor immunity in classical Hodgkin lymphoma (cHL). Copy number alterations of 9p24.1/CD274(PD-L1)/PDCD1LG2(PD-L2) contribute to robust PD-L1 and PD-L2 expression by HRS cells. PD-L1 is also expressed by nonmalignant tumor-associated macrophages (TAMs), but the relationships among PD-L1+HRS cells, PD-L1+TAMs, and PD-1+T cells remain undefined. We used multiplex immunofluorescence and digital image analysis to examine the topography of PD-L1+and PD-1+cells in the tumor microenvironment (TME) of cHL. We find that the majority of PD-L1 in the TME is expressed by the abundant PD-L1+TAMs, which physically colocalize with PD-L1+HRS cells in a microenvironmental niche. PD-L1+TAMs are enriched for contacts with T cells, and PD-L1+HRS cells are enriched for contacts with CD4+T cells, a subset of which are PD-1+. Our data define a unique topology of cHL in which PD-L1+TAMs surround HRS cells and implicate CD4+T cells as a target of PD-1 blockade.
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- 2017
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36. Topological analysis reveals a PD-L1-associated microenvironmental niche for Reed-Sternberg cells in Hodgkin lymphoma
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Carey, Christopher D., Gusenleitner, Daniel, Lipschitz, Mikel, Roemer, Margaretha G. M., Stack, Edward C., Gjini, Evisa, Hu, Xihao, Redd, Robert, Freeman, Gordon J., Neuberg, Donna, Hodi, F. Stephen, Liu, Xiaole Shirley, Shipp, Margaret A., and Rodig, Scott J.
- Abstract
Signaling between programmed cell death protein 1 (PD-1) and the PD-1 ligands (PD-L1, PD-L2) is essential for malignant Hodgkin Reed-Sternberg (HRS) cells to evade antitumor immunity in classical Hodgkin lymphoma (cHL). Copy number alterations of 9p24.1/CD274(PD-L1)/PDCD1LG2(PD-L2) contribute to robust PD-L1 and PD-L2 expression by HRS cells. PD-L1 is also expressed by nonmalignant tumor-associated macrophages (TAMs), but the relationships among PD-L1+ HRS cells, PD-L1+ TAMs, and PD-1+ T cells remain undefined. We used multiplex immunofluorescence and digital image analysis to examine the topography of PD-L1+ and PD-1+ cells in the tumor microenvironment (TME) of cHL. We find that the majority of PD-L1 in the TME is expressed by the abundant PD-L1+ TAMs, which physically colocalize with PD-L1+ HRS cells in a microenvironmental niche. PD-L1+ TAMs are enriched for contacts with T cells, and PD-L1+ HRS cells are enriched for contacts with CD4+ T cells, a subset of which are PD-1+. Our data define a unique topology of cHL in which PD-L1+ TAMs surround HRS cells and implicate CD4+ T cells as a target of PD-1 blockade.
- Published
- 2017
- Full Text
- View/download PDF
37. Signaling pathways and immune evasion mechanisms in classical Hodgkin lymphoma
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Liu, W. Robert and Shipp, Margaret A.
- Abstract
Classical Hodgkin lymphoma (cHL) is an unusual B-cell–derived malignancy in which rare malignant Hodgkin and Reed-Sternberg (HRS) cells are surrounded by an extensive but ineffective inflammatory/immune cell infiltrate. This striking feature suggests that malignant HRS cells escape immunosurveillance and interact with immune cells in the cancer microenvironment for survival and growth. We previously found that cHLs have a genetic basis for immune evasion: near-uniform copy number alterations of chromosome 9p24.1 and the associated PD-1 ligand loci, CD274/PD-L1 and PDCD1LG2/PD-L2, and copy number–dependent increased expression of these ligands. HRS cells expressing PD-1 ligands are thought to engage PD-1 receptor–positive immune effectors in the tumor microenvironment and induce PD-1 signaling and associated immune evasion. The genetic bases of enhanced PD-1 signaling in cHL make these tumors uniquely sensitive to PD-1 blockade.
- Published
- 2017
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38. Signaling pathways and immune evasion mechanisms in classical Hodgkin lymphoma
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Liu, W. Robert and Shipp, Margaret A.
- Abstract
Classical Hodgkin lymphoma (cHL) is an unusual B-cell–derived malignancy in which rare malignant Hodgkin and Reed-Sternberg (HRS) cells are surrounded by an extensive but ineffective inflammatory/immune cell infiltrate. This striking feature suggests that malignant HRS cells escape immunosurveillance and interact with immune cells in the cancer microenvironment for survival and growth. We previously found that cHLs have a genetic basis for immune evasion: near-uniform copy number alterations of chromosome 9p24.1 and the associated PD-1 ligand loci, CD274/PD-L1 and PDCD1LG2/PD-L2, and copy number–dependent increased expression of these ligands. HRS cells expressing PD-1 ligands are thought to engage PD-1 receptor–positive immune effectors in the tumor microenvironment and induce PD-1 signaling and associated immune evasion. The genetic bases of enhanced PD-1 signaling in cHL make these tumors uniquely sensitive to PD-1 blockade.
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- 2017
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39. Nivolumab in Patients With Relapsed or Refractory Hematologic Malignancy: Preliminary Results of a Phase Ib Study.
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Lesokhin, Alexander M., Ansell, Stephen M., Armand, Philippe, Scott, Emma C., Halwani, Ahmad, Gutierrez, Martin, Millenson, Michael M., Cohen, Adam D., Schuster, Stephen J., Lebovic, Daniel, Dhodapkar, Madhav, Avigan, David, Chapuy, Bjoern, Ligon, Azra H., Freeman, Gordon J., Rodig, Scott J., Cattry, Deepika, Grosso, Joseph F., Garelik, M. Brigid Bradley, and Shipp, Margaret A.
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- 2016
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40. PD-L1 and PD-L2 Genetic Alterations Define Classical Hodgkin Lymphoma and Predict Outcome.
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Roemer, Margaretha G. M., Advani, Ranjana H., Ligon, Azra H., Natkunam, Yasodha, Redd, Robert A., Homer, Heather, Connelly, Courtney F., Sun, Heather H., Daadi, Sarah E., Freeman, Gordon J., Armand, Philippe, Chapuy, Bjoern, de Jong, Daphne, Hoppe, Richard T., Neuberg, Donna S., Rodig, Scott J., and Shipp, Margaret A.
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- 2016
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41. Safety and tolerability of pembrolizumab in patients with relapsed/refractory primary mediastinal large B-cell lymphoma
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Zinzani, Pier Luigi, Ribrag, Vincent, Moskowitz, Craig H., Michot, Jean-Marie, Kuruvilla, John, Balakumaran, Arun, Zhang, Yayan, Chlosta, Sabine, Shipp, Margaret A., and Armand, Philippe
- Abstract
Treatment options for relapsed/refractory primary mediastinal large B-cell lymphoma (rrPMBCL) are limited, and prognosis is generally poor (overall response rate [ORR] 0% to 25%; 2-year overall survival 15%). PMBCL frequently involves PD-1 ligand overexpression, potentially making PMBCL particularly susceptible to PD-1 blockade. We evaluated safety and antitumor activity of pembrolizumab, an anti–PD-1 antibody, in rrPMBCL as part of the KEYNOTE-013 multicohort phase 1b trial. At time of data cutoff, 18 patients (median age 30 years; median 3 prior lines of therapy) had been enrolled and treated, of whom 17 were included in the efficacy analyses. Eleven patients (61%) experienced drug-related adverse events (mostly grade 1-2); none discontinued treatment due to adverse events. ORR was 41% (7/17); 6 additional patients (35%) had stable disease. Of patients evaluable by imaging, 13 out of 16 (81%) had decreases in target lesions. With a median follow-up of 11.3 months, median duration of response was not reached. Two patients reached the maximum 2-year treatment duration and remain in remission. Median overall survival was not reached for treated patients overall; all responders were still alive at data cutoff. These results in heavily pretreated rrPMBCL patients demonstrate that PD-1 blockade with pembrolizumab has a manageable safety profile and promising antitumor activity. This trial was registered at www.clinicaltrials.govas #NCT01953692.
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- 2017
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42. Safety and tolerability of pembrolizumab in patients with relapsed/refractory primary mediastinal large B-cell lymphoma
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Zinzani, Pier Luigi, Ribrag, Vincent, Moskowitz, Craig H., Michot, Jean-Marie, Kuruvilla, John, Balakumaran, Arun, Zhang, Yayan, Chlosta, Sabine, Shipp, Margaret A., and Armand, Philippe
- Abstract
Treatment options for relapsed/refractory primary mediastinal large B-cell lymphoma (rrPMBCL) are limited, and prognosis is generally poor (overall response rate [ORR] 0% to 25%; 2-year overall survival 15%). PMBCL frequently involves PD-1 ligand overexpression, potentially making PMBCL particularly susceptible to PD-1 blockade. We evaluated safety and antitumor activity of pembrolizumab, an anti–PD-1 antibody, in rrPMBCL as part of the KEYNOTE-013 multicohort phase 1b trial. At time of data cutoff, 18 patients (median age 30 years; median 3 prior lines of therapy) had been enrolled and treated, of whom 17 were included in the efficacy analyses. Eleven patients (61%) experienced drug-related adverse events (mostly grade 1-2); none discontinued treatment due to adverse events. ORR was 41% (7/17); 6 additional patients (35%) had stable disease. Of patients evaluable by imaging, 13 out of 16 (81%) had decreases in target lesions. With a median follow-up of 11.3 months, median duration of response was not reached. Two patients reached the maximum 2-year treatment duration and remain in remission. Median overall survival was not reached for treated patients overall; all responders were still alive at data cutoff. These results in heavily pretreated rrPMBCL patients demonstrate that PD-1 blockade with pembrolizumab has a manageable safety profile and promising antitumor activity. This trial was registered at www.clinicaltrials.gov as #NCT01953692.
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- 2017
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43. Differential contribution of the mitochondrial translation pathway to the survival of diffuse large B-cell lymphoma subsets
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Norberg, Erik, Lako, Ana, Chen, Pei-Hsuan, Stanley, Illana A, Zhou, Feng, Ficarro, Scott B, Chapuy, Bjoern, Chen, Linfeng, Rodig, Scott, Shin, Donghyuk, Choi, Dong Wook, Lee, Sangho, Shipp, Margaret A, Marto, Jarrod A, and Danial, Nika N
- Abstract
Diffuse large B-cell lymphomas (DLBCLs) are a highly heterogeneous group of tumors in which subsets share molecular features revealed by gene expression profiles and metabolic fingerprints. While B-cell receptor (BCR)-dependent DLBCLs are glycolytic, OxPhos-DLBCLs rely on mitochondrial energy transduction and nutrient utilization pathways that provide pro-survival benefits independent of BCR signaling. Integral to these metabolic distinctions is elevated mitochondrial electron transport chain (ETC) activity in OxPhos-DLBCLs compared with BCR-DLBCLs, which is linked to greater protein abundance of ETC components. To gain insights into molecular determinants of the selective increase in ETC activity and dependence on mitochondrial energy metabolism in OxPhos-DLBCLs, we examined the mitochondrial translation pathway in charge of the synthesis of mitochondrial DNA encoded ETC subunits. Quantitative mass spectrometry identified increased expression of mitochondrial translation factors in OxPhos-DLBCL as compared with the BCR subtype. Biochemical and functional assays indicate that the mitochondrial translation pathway is required for increased ETC activity and mitochondrial energy reserves in OxPhos-DLBCL. Importantly, molecular depletion of several mitochondrial translation proteins using RNA interference or pharmacological perturbation of the mitochondrial translation pathway with the FDA-approved inhibitor tigecycline (Tigecyl) is selectively toxic to OxPhos-DLBCL cell lines and primary tumors. These findings provide additional molecular insights into the metabolic characteristics of OxPhos-DLBCLs, and mark the mitochondrial translation pathway as a potential therapeutic target in these tumors.
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- 2017
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44. Pembrolizumab in relapsed or refractory primary mediastinal large B-cell lymphoma: final analysis of KEYNOTE-170
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Zinzani, Pier Luigi, Thieblemont, Catherine, Melnichenko, Vladimir, Bouabdallah, Krimo, Walewski, Jan, Majlis, Alejandro, Fogliatto, Laura, Garcia-Sancho, A. Martin, Christian, Beth, Gulbas, Zafer, Özcan, Muhit, Perini, Guilherme Fleury, Ghesquieres, Herve, Shipp, Margaret A., Thompson, Seth, Chakraborty, Samhita, Marinello, Patricia, and Armand, Philippe
- Abstract
•Pembrolizumab monotherapy provides sustained antitumor activity in heavily pretreated R/R PMBCL.•Complete responses were maintained after ∼4 years of follow-up.
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- 2023
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45. Five-year follow-up of KEYNOTE-087: pembrolizumab monotherapy in relapsed/refractory classical Hodgkin lymphoma
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Armand, Philippe, Zinzani, Pier Luigi, Lee, Hun Ju, Johnson, Nathalie A., Brice, Pauline, Radford, John, Ribrag, Vincent, Molin, Daniel, Vassilakopoulos, Theodoros P., Tomita, Akihiro, von Tresckow, Bastian, Shipp, Margaret A., Herrera, Alex F., Lin, Jianxin, Kim, Eunhee, Chakraborty, Samhita, Marinello, Patricia, and Moskowitz, Craig H.
- Abstract
•Pembrolizumab monotherapy can produce very durable responses in a subset of patients with R/R cHL•Second-course pembrolizumab frequently reinduced sustained response in patients relapsing from CR
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- 2023
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46. Diffuse large B-cell lymphoma patient-derived xenograft models capture the molecular and biological heterogeneity of the disease
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Chapuy, Bjoern, Cheng, Hongwei, Watahiki, Akira, Ducar, Matthew D., Tan, Yuxiang, Chen, Linfeng, Roemer, Margaretha G. M., Ouyang, Jing, Christie, Amanda L., Zhang, Liye, Gusenleitner, Daniel, Abo, Ryan P., Farinha, Pedro, von Bonin, Frederike, Thorner, Aaron R., Sun, Heather H., Gascoyne, Randy D., Pinkus, Geraldine S., van Hummelen, Paul, Wulf, Gerald G., Aster, Jon C., Weinstock, David M., Monti, Stefano, Rodig, Scott J., Wang, Yuzhuo, and Shipp, Margaret A.
- Abstract
Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease defined by transcriptional classifications, specific signaling and survival pathways, and multiple low-frequency genetic alterations. Preclinical model systems that capture the genetic and functional heterogeneity of DLBCL are urgently needed. Here, we generated and characterized a panel of large B-cell lymphoma (LBCL) patient-derived xenograft (PDX) models, including 8 that reflect the immunophenotypic, transcriptional, genetic, and functional heterogeneity of primary DLBCL and 1 that is a plasmablastic lymphoma. All LBCL PDX models were subjected to whole-transcriptome sequencing to classify cell of origin and consensus clustering classification (CCC) subtypes. Mutations and chromosomal rearrangements were evaluated by whole-exome sequencing with an extended bait set. Six of the 8 DLBCL models were activated B-cell (ABC)-type tumors that exhibited ABC-associated mutations such as MYD88, CD79B, CARD11, and PIM1. The remaining 2 DLBCL models were germinal B-cell type, with characteristic alterations of GNA13, CREBBP, and EZH2, and chromosomal translocations involving IgH and either BCL2 or MYC. Only 25% of the DLBCL PDX models harbored inactivating TP53 mutations, whereas 75% exhibited copy number alterations of TP53 or its upstream modifier, CDKN2A, consistent with the reported incidence and type of p53 pathway alterations in primary DLBCL. By CCC criteria, 6 of 8 DLBCL PDX models were B-cell receptor (BCR)-type tumors that exhibited selective surface immunoglobulin expression and sensitivity to entospletinib, a recently developed spleen tyrosine kinase inhibitor. In summary, we have established and characterized faithful PDX models of DLBCL and demonstrated their usefulness in functional analyses of proximal BCR pathway inhibition.
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- 2016
- Full Text
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47. Diffuse large B-cell lymphoma patient-derived xenograft models capture the molecular and biological heterogeneity of the disease
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Chapuy, Bjoern, Cheng, Hongwei, Watahiki, Akira, Ducar, Matthew D., Tan, Yuxiang, Chen, Linfeng, Roemer, Margaretha G.M., Ouyang, Jing, Christie, Amanda L., Zhang, Liye, Gusenleitner, Daniel, Abo, Ryan P., Farinha, Pedro, von Bonin, Frederike, Thorner, Aaron R., Sun, Heather H., Gascoyne, Randy D., Pinkus, Geraldine S., van Hummelen, Paul, Wulf, Gerald G., Aster, Jon C., Weinstock, David M., Monti, Stefano, Rodig, Scott J., Wang, Yuzhuo, and Shipp, Margaret A.
- Abstract
Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease defined by transcriptional classifications, specific signaling and survival pathways, and multiple low-frequency genetic alterations. Preclinical model systems that capture the genetic and functional heterogeneity of DLBCL are urgently needed. Here, we generated and characterized a panel of large B-cell lymphoma (LBCL) patient-derived xenograft (PDX) models, including 8 that reflect the immunophenotypic, transcriptional, genetic, and functional heterogeneity of primary DLBCL and 1 that is a plasmablastic lymphoma. All LBCL PDX models were subjected to whole-transcriptome sequencing to classify cell of origin and consensus clustering classification (CCC) subtypes. Mutations and chromosomal rearrangements were evaluated by whole-exome sequencing with an extended bait set. Six of the 8 DLBCL models were activated B-cell (ABC)-type tumors that exhibited ABC-associated mutations such as MYD88, CD79B, CARD11, and PIM1.The remaining 2 DLBCL models were germinal B-cell type, with characteristic alterations of GNA13, CREBBP, and EZH2, and chromosomal translocations involving IgHand either BCL2or MYC. Only 25% of the DLBCL PDX models harbored inactivating TP53mutations, whereas 75% exhibited copy number alterations of TP53or its upstream modifier, CDKN2A, consistent with the reported incidence and type of p53pathway alterations in primary DLBCL. By CCC criteria, 6 of 8 DLBCL PDX models were B-cell receptor (BCR)-type tumors that exhibited selective surface immunoglobulin expression and sensitivity to entospletinib, a recently developed spleen tyrosine kinase inhibitor. In summary, we have established and characterized faithful PDX models of DLBCL and demonstrated their usefulness in functional analyses of proximal BCR pathway inhibition.
- Published
- 2016
- Full Text
- View/download PDF
48. Genetic Basis for PD-L1 Expression in Squamous Cell Carcinomas of the Cervix and Vulva
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Howitt, Brooke E., Sun, Heather H., Roemer, Margaretha G. M., Kelley, Alyssa, Chapuy, Bjoern, Aviki, Emeline, Pak, Christine, Connelly, Courtney, Gjini, Evisa, Shi, Yunling, Lee, Larissa, Viswanathan, Akila, Horowitz, Neil, Neuberg, Donna, Crum, Christopher P., Lindeman, Neal L., Kuo, Frank, Ligon, Azra H., Freeman, Gordon J., Hodi, F. Stephen, Shipp, Margaret A., and Rodig, Scott J.
- Abstract
IMPORTANCE: Patients with squamous cell carcinoma (SCC) of the cervix or vulva have limited therapeutic options, and the potential for immunotherapy for this population has not been evaluated. Recent trials suggest that tumors with a genetic basis for PD-1 (programmed cell death protein 1) ligand expression are highly sensitive to therapeutic antibodies targeting PD-1. OBJECTIVE: To determine the genetic status of CD274 (encoding PD-L1 [programmed cell death 1 ligand 1]) and PDCD1LG2 (encoding PD-L2 [programmed cell death 1 ligand 2]) in SCCs of the cervix and vulva and to correlate the findings with PD-L1 protein expression. DESIGN, SETTING, AND PARTICIPANTS: We performed fluorescence in situ hybridization (FISH) using probes targeting CD274, PDCD1LG2, and the centromeric portion of chromosome 9, and immunohistochemistry (IHC) using an antibody recognizing PD-L1 on formalin-fixed, paraffin-embedded (FFPE) biopsy specimens from 48 cervical SCCs and 23 vulvar SCCs. MAIN OUTCOMES AND MEASURES: Tumors were categorized according to the genetic abnormality in CD274 and PDCD1LG2 (coamplification > cogain > polysomy > disomy) as detected by FISH, and evaluated on a semiquantitative scale (modified H score, the product of the percentage of tumor cells with positive staining and the maximum intensity of positive staining) for PD-L1 protein expression as detected by IHC. RESULTS: Overall, 71 samples of FFPE tissue from cases of cervical SCCs (n = 48) and vulvar SCCs (n = 23) were retrieved from the archives of Brigham and Women’s Hospital and included in this study. We observed cogain or coamplification of CD274 and PDCD1LG2 in 32 of 48 cervical SCCs (67%) and 10 of 23 vulvar SCCs (43%). Median PD-L1 protein expression was highest among tumors with CD274 and PDCD1LG2 coamplification and lowest among tumors with disomy. CONCLUSIONS AND RELEVANCE: Recurrent copy number gain of the genes encoding the PD-1 ligands provides a genetic basis for PD-L1 expression in a subset of cervical and vulvar SCCs and identifies a class of patients that are rational candidates for therapies targeting PD-1.
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- 2016
- Full Text
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49. Targetable genetic features of primary testicular and primary central nervous system lymphomas
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Chapuy, Bjoern, Roemer, Margaretha G. M., Stewart, Chip, Tan, Yuxiang, Abo, Ryan P., Zhang, Liye, Dunford, Andrew J., Meredith, David M., Thorner, Aaron R., Jordanova, Ekaterina S., Liu, Gang, Feuerhake, Friedrich, Ducar, Matthew D., Illerhaus, Gerald, Gusenleitner, Daniel, Linden, Erica A., Sun, Heather H., Homer, Heather, Aono, Miyuki, Pinkus, Geraldine S., Ligon, Azra H., Ligon, Keith L., Ferry, Judith A., Freeman, Gordon J., van Hummelen, Paul, Golub, Todd R., Getz, Gad, Rodig, Scott J., de Jong, Daphne, Monti, Stefano, and Shipp, Margaret A.
- Abstract
Primary central nervous system lymphomas (PCNSLs) and primary testicular lymphomas (PTLs) are extranodal large B-cell lymphomas (LBCLs) with inferior responses to current empiric treatment regimens. To identify targetable genetic features of PCNSL and PTL, we characterized their recurrent somatic mutations, chromosomal rearrangements, copy number alterations (CNAs), and associated driver genes, and compared these comprehensive genetic signatures to those of diffuse LBCL and primary mediastinal large B-cell lymphoma (PMBL). These studies identify unique combinations of genetic alterations in discrete LBCL subtypes and subtype-selective bases for targeted therapy. PCNSLs and PTLs frequently exhibit genomic instability, and near-uniform, often biallelic, CDKN2A loss with rare TP53 mutations. PCNSLs and PTLs also use multiple genetic mechanisms to target key genes and pathways and exhibit near-uniform oncogenic Toll-like receptor signaling as a result of MYD88 mutation and/or NFKBIZ amplification, frequent concurrent B-cell receptor pathway activation, and deregulation of BCL6. Of great interest, PCNSLs and PTLs also have frequent 9p24.1/PD-L1/PD-L2 CNAs and additional translocations of these loci, structural bases of immune evasion that are shared with PMBL.
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- 2016
- Full Text
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50. Targetable genetic features of primary testicular and primary central nervous system lymphomas
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Chapuy, Bjoern, Roemer, Margaretha G.M., Stewart, Chip, Tan, Yuxiang, Abo, Ryan P., Zhang, Liye, Dunford, Andrew J., Meredith, David M., Thorner, Aaron R., Jordanova, Ekaterina S., Liu, Gang, Feuerhake, Friedrich, Ducar, Matthew D., Illerhaus, Gerald, Gusenleitner, Daniel, Linden, Erica A., Sun, Heather H., Homer, Heather, Aono, Miyuki, Pinkus, Geraldine S., Ligon, Azra H., Ligon, Keith L., Ferry, Judith A., Freeman, Gordon J., van Hummelen, Paul, Golub, Todd R., Getz, Gad, Rodig, Scott J., de Jong, Daphne, Monti, Stefano, and Shipp, Margaret A.
- Abstract
Primary central nervous system lymphomas (PCNSLs) and primary testicular lymphomas (PTLs) are extranodal large B-cell lymphomas (LBCLs) with inferior responses to current empiric treatment regimens. To identify targetable genetic features of PCNSL and PTL, we characterized their recurrent somatic mutations, chromosomal rearrangements, copy number alterations (CNAs), and associated driver genes, and compared these comprehensive genetic signatures to those of diffuse LBCL and primary mediastinal large B-cell lymphoma (PMBL). These studies identify unique combinations of genetic alterations in discrete LBCL subtypes and subtype-selective bases for targeted therapy. PCNSLs and PTLs frequently exhibit genomic instability, and near-uniform, often biallelic, CDKN2Aloss with rare TP53mutations. PCNSLs and PTLs also use multiple genetic mechanisms to target key genes and pathways and exhibit near-uniform oncogenic Toll-like receptor signaling as a result of MYD88mutation and/or NFKBIZamplification, frequent concurrent B-cell receptor pathway activation, and deregulation of BCL6. Of great interest, PCNSLs and PTLs also have frequent 9p24.1/PD-L1/PD-L2CNAs and additional translocations of these loci, structural bases of immune evasion that are shared with PMBL.
- Published
- 2016
- Full Text
- View/download PDF
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