Demo Faculty

204 articles

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Dec 2023 • Cancer Research

Mitochondrial DNA mutations as natural barcodes for lineage tracing of murine tumor models

Livius Penter, Elisa Ten Hacken, Jackson Southard, Caleb A Lareau, Leif S Ludwig, Shuqiang Li, Donna S Neuberg, Kenneth J Livak, Catherine J Wu

Murine models are indispensable tools for functional genomic studies and preclinical testing of novel therapeutic approaches. Mitochondrial single-cell assay for transposase-accessible chromatin using sequencing (mtscATAC-seq) enables the dissection of cellular heterogeneity and clonal dynamics by capturing chromatin accessibility, copy-number variations (CNV), and mitochondrial DNA (mtDNA) mutations, yet its applicability to murine studies remains unexplored. By leveraging mtscATAC-seq in novel chronic lymphocytic leukemia and Richter syndrome mouse models, we report the detection of mtDNA mutations, particularly in highly proliferative murine cells, alongside CNV and chromatin state changes indicative of clonal evolution upon secondary transplant. This study thus demonstrates the feasibility and utility of multi-modal single-cell and natural barcoding approaches to characterize …

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Dec 2023 • Blood Cancer Discovery

In Vivo Modeling of CLL Transformation to Richter Syndrome Reveals Convergent Evolutionary Paths and Therapeutic Vulnerabilities

Elisa ten Hacken, Tomasz Sewastianik, Shanye Yin, Gabriela Brunsting Hoffmann, Michaela Gruber, Kendell Clement, Livius Penter, Robert A Redd, Neil Ruthen, Sebastien Hergalant, Alanna Sholokhova, Geoffrey Fell, Erin M Parry, Julien Broseus, Romain Guieze, Fabienne Lucas, Maria Hernandez-Sanchez, Kaitlyn Baranowski, Jackson Southard, Heather Joyal, Leah Billington, Fara Faye D Regis, Elizabeth Witten, Mohamed Uduman, Binyamin A Knisbacher, Shuqiang Li, Haoxiang Lyu, Tiziana Vaisitti, Silvia Deaglio, Giorgio Inghirami, Pierre Feugier, Stephan Stilgenbauer, Eugen Tausch, Matthew S Davids, Gad Getz, Kenneth J Livak, Ivana Bozic, Donna S Neuberg, Ruben D Carrasco, Catherine J Wu

Transformation to aggressive disease histologies generates formidable clinical challenges across cancers, but biological insights remain few. We modeled the genetic heterogeneity of chronic lymphocytic leukemia (CLL) through multiplexed in vivo CRISPR-Cas9 B-cell editing of recurrent CLL loss-of-function drivers in mice, and recapitulated the process of transformation from indolent CLL into large cell lymphoma (i.e. Richter’s syndrome [RS]). Evolutionary trajectories of 64 mice carrying diverse combinatorial gene assortments revealed co-selection of mutations in Trp53, Mga, and Chd2 and the dual impact of clonal Mga/Chd2 mutations on E2F/MYC and interferon signaling dysregulation. Comparative human and murine RS analyses demonstrated tonic PI3K signaling as a key feature of transformed disease, with constitutive activation of the AKT and S6 kinases, down-modulation of the receptor …

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Feb 2023 • Transplantation and Cellular Therapy, Official Publication of the American Society for Transplantation and Cellular Therapy

Systematic Identification of Autosomal and Y-Encoded Minor Histocompatibility Antigens Reveals Predictors of Chronic GvHD and Candidate Gvl Targets

Nicoletta Cieri, Nidhi Hookeri, Kari Stromhaug, Jonathan Stevens, Kameron Kooshesh, Helen Ji, Susan Klaeger, Karl R Clauser, Siranush Sarkizova, David A Braun, Livius Penter, Giacomo Oliveira, Haesook T Kim, William J Lane, Shuqiang Li, Kenneth J Livak, Vincent T Ho, Jerome Ritz, Robert J Soiffer, Derin B Keskin, Chip Stewart, Alexander Gusev, Gad Getz, Catherine J Wu

At the core of the therapeutic effect of HLA-matched allo-HCT is T cell alloreactivity against minor histocompatibility antigens (mHAgs), polymorphic peptides resulting from donor-recipient disparity at sites of single nucleotide polymorphisms (SNPs). Despite their crucial role in GvL and GvHD, only few mHAgs have been characterized to date. To systematically identify autosomal and Y chromosome-encoded mHAgs, we devised a computational pipeline based on: i) comparison of whole exomes (WES) from donor-recipient pairs to define recipient-restricted exonic non-synonymous SNPs; ii) expression filters built by incorporating the analysis of single-cell RNA expression profiles from normal and malignant hematopoietic cells, and GvHD target organs (skin, liver, GI, lung, oral mucosa and lacrimal gland). Identified recipient-restricted SNPs, expressed in GvL or GvHD tissues, then underwent HLA-I binding prediction …

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Feb 2023 • Journal of Vision

The visual benefits of correcting longitudinal and transverse chromatic aberration

Austin Roorda, Steven A Cholewiak, Swati Bhargava, Nadav H Ivzan, Francesco LaRocca, Derek Nankivil, Martin S Banks

We describe a system—the Binocular Varichrome and Accommodation Measurement System—that can be used to measure and correct the eye’s longitudinal and transverse chromatic aberration (LCA and TCA) and to perform vision tests with custom corrections. We used the system to investigate how LCA and TCA affect visual performance. Specifically, we studied the effects of LCA and TCA on visual acuity, contrast sensitivity, and chromostereopsis. LCA exhibited inter subject variability but followed expected trends compared with previous reports. TCA at the fovea was variable between individuals but with a tendency for the shift at shorter wavelengths to be more temporalward in the visual field in each eye. We found that TCA was generally greater when LCA was corrected. For visual acuity, we found that a measurable benefit was realized only with both LCA and TCA correction unless the TCA was low. For contrast sensitivity, we found that the best sensitivity to a 10-cycle/degree polychromatic grating was attained when LCA and TCA were corrected. Finally, we found that the primary cause of chromostereopsis is the TCA of the eyes.

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Jan 2023 • Blood Journal

Mechanisms of response and resistance to combined decitabine and ipilimumab for advanced myeloid disease

Livius Penter, Yang Liu, Jacquelyn O Wolff, Lin Yang, Len Taing, Aashna Jhaveri, Jackson Southard, Manishkumar Patel, Nicole Cullen, Kathleen Lindahl Pfaff, Nicoletta Cieri, Giacomo Oliveira, Seunghee Kim-Schulze, Srinika Ranasinghe, Rebecca Leonard, Taylor Robertson, Elizabeth A Morgan, Helen Chen, Minkyung H Song, Magdalena Thurin, Shuqiang Li, Scott J Rodig, Carrie Cibulskis, Stacey Gabriel, Pavan Bachireddy, Jerome Ritz, Howard Streicher, Donna Neuberg, F Stephen Hodi, Sacha Gnjatic, Matthew S Davids, Kenneth J Livak, Jennifer Altreuter, Franziska Michor, Robert J Soiffer, Jacqueline S Garcia, Catherine J Wu

The challenge of eradicating leukemia for patients with acute myelogenous leukemia (AML) following initial cytoreduction has motivated modern efforts to combine synergistic active modalities including immunotherapy. Recently, the ETCTN/CTEP 10026 (NCT02890329) study tested the combination of the DNA methyltransferase inhibitor decitabine together with the immune checkpoint inhibitor ipilimumab for AML/myelodysplastic syndrome (MDS) either following allogeneic hematopoietic stem cell transplantation (HSCT) or in the HSCT-naïve setting. Integrative transcriptome-based analysis of 304,961 individual marrow-infiltrating cells for 18 of 48 subjects treated on study revealed the strong association of response with a high baseline ratio of T to AML cells. Clinical responses were predominantly driven by decitabine-induced cytoreduction. Evidence of immune activation was only apparent following ipilimumab …

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Dec 2022 • Cancer Research

Mitochondrial DNA mutations as natural barcodes for lineage tracing of murine tumor models

Livius Penter, Elisa ten Hacken, Jackson Southard, Caleb Lareau, Leif S Ludwig, Shuqiang Li, Donna S Neuberg, Kenneth J Livak, Catherine J Wu

Murine models are indispensable tools for functional genomic studies and preclinical testing of novel therapeutic approaches. Mitochondrial single-cell assay for transposase-accessible chromatin (mtscATAC-seq) enables the dissection of cellular heterogeneity and clonal dynamics by capturing chromatin accessibility, copy number variations (CNV), and mitochondrial DNA (mtDNA) mutations, yet its applicability to murine studies remains unexplored. By leveraging mtscATAC-seq in novel chronic lymphocytic leukemia and Richter syndrome mouse models, we report the detection of mtDNA mutations, particularly in highly proliferative murine cells, alongside CNV and chromatin state changes indicative of clonal evolution upon secondary transplant. This study thus demonstrates the feasibility and utility of multi-modal single-cell and natural barcoding approaches to characterize murine cancer models.

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Nov 2022 • Cancer Immunology Research

Immune phenotypes and target antigens of clonally expanded bone marrow T cells in treatment-naïve multiple myeloma

Carlotta Welters, María Fernanda Lammoglia Cobo, Christian Alexander Stein, Meng-Tung Hsu, Amin Ben Hamza, Livius Penter, Xiaojing Chen, Christopher Buccitelli, Oliver Popp, Philipp Mertins, Kerstin Dietze, Lars Bullinger, Andreas Moosmann, Eric Blanc, Dieter Beule, Armin Gerbitz, Julian Strobel, Holger Hackstein, Hans-Peter Rahn, Klaus Dornmair, Thomas Blankenstein, Leo Hansmann

Multiple myeloma is a hematologic malignancy of monoclonal plasma cells that accumulate in the bone marrow. Despite their clinical and pathophysiological relevance, the roles of bone marrow infiltrating T cells in treatment-naïve patients are incompletely understood. We investigated whether clonally expanded T cells i) were detectable in multiple myeloma bone marrow, ii) showed characteristic immune phenotypes, and iii) whether dominant clones recognized antigens selectively presented on multiple myeloma cells. Single-cell index sorting and T-cell receptor (TCR)αβ sequencing of bone marrow T cells from 13 treatment-naïve patients showed dominant clonal expansion within CD8+ cytolytic effector compartments, and only a minority of expanded T-cell clones expressed the classical immune checkpoint molecules PD 1, CTLA 4, or TIM 3. To identify their molecular targets, TCRs of 68 dominant bone marrow clones from five selected patients were re-expressed and incubated with multiple myeloma and non multiple myeloma cells from corresponding patients. Only one out of 68 TCRs recognized antigen presented on multiple myeloma cells. This TCR was HLA-C-restricted, self-peptide-specific, and could be activated by multiple myeloma cells of multiple patients. The remaining dominant T-cell clones did not recognize multiple myeloma cells and were, in part, specific for antigens associated with chronic viral infections. In conclusion, we showed that dominant bone marrow T-cell clones in treatment naïve patients rarely recognize antigens presented on multiple myeloma cells and exhibit low expression of classical immune checkpoint …

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Nov 2022 • Blood

Mechanisms of Response and Resistance to Combination Decitabine and Ipilimumab for Transplant Naïve and Post-Transplant AML/MDS

Livius Penter, Yang Liu, Lin Yang, Len Taing, Aashna Jhaveri, Jackson Southard, Manishkumar Patel, Jacquelyn Wolff, Nicole Cullen, Kathleen Pfaff, Nicoletta Cieri, Giacomo Oliveira, Seunghee Kim-Schulze, Srinika Ranasinghe, Rebecca Leonard, Taylor Robertson, Helen Chen, Magdalena Thurin, Shuqiang Li, Scott J Rodig, Carrie Cibulskis, Stacey Gabriel, Jerome Ritz, Howard Streicher, Donna S Neuberg, Stephen Hodi, Sacha Gnjatic, Kenneth J Livak, Jennifer Altreuter, Franziska Michor, Robert J Soiffer, Jacqueline S Garcia, Catherine J Wu

Treatment of patients with advanced myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) ineligible for intensive chemotherapy currently is mostly non-curative and therapeutic options for relapse after allogeneic hematopoietic stem cell transplantation (HSCT) rarely induce durable remissions. Novel strategies to address disease relapse are thus needed. Immune checkpoint blockade with CTLA-4 antibodies (ipilimumab) is an emerging concept that demonstrated potent clinical activity in relapsed leukemia cutis post-HSCT. Hypothesizing synergism with therapeutic hypomethylation, the ETCTN/CTEP study 10026 evaluated the safety and efficacy of combination decitabine and ipilimumab treatment in transplant-naïve AML/MDS and post-HSCT AML relapse (NCT02890329). Clinical activity has been encouraging with an overall response rate of 20%(post-HSCT) and 52%(transplant-naïve), however …

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Nov 2022 • Blood

Ipilimumab plus decitabine for patients with MDS or AML in post-transplant or transplant naïve settings

Jacqueline S Garcia, Yael Flamand, Livius Penter, Michael Keng, Benjamin K Tomlinson, Lourdes M Mendez, Paul Koller, Nicole Cullen, Yohei Arihara, Kathleen Pfaff, Jacquelyn O Wolff, Andrew M Brunner, Ilene Galinsky, Asad Bashey, Joseph H Antin, Corey Cutler, Vincent Ho, Brian A Jonas, Marlise R Luskin, Martha Wadleigh, Eric S Winer, Alexandra Savell, Rebecca Leonard, Taylor Robertson, Matthew S Davids, Howard Streicher, Scott J Rodig, Jerome Ritz, Catherine J Wu, Daniel J DeAngelo, Donna Neuberg, Richard M Stone, Robert J Soiffer


Nov 2022 • Blood

Ipilimumab plus decitabine for patients with MDS or AML in post-transplant or transplant naïve settings

Jacqueline S Garcia, Yael Flamand, Livius Penter, Michael Keng, Benjamin K Tomlinson, Lourdes M Mendez, Paul Koller, Nicole Cullen, Yohei Arihara, Kathleen Pfaff, Jacquelyn O Wolff, Andrew M Brunner, Ilene Galinsky, Asad Bashey, Joseph H Antin, Corey Cutler, Vincent Ho, Brian A Jonas, Marlise R Luskin, Martha Wadleigh, Eric S Winer, Alexandra Savell, Rebecca Leonard, Taylor Robertson, Matthew S Davids, Howard Streicher, Scott J Rodig, Jerome Ritz, Catherine J Wu, Daniel J DeAngelo, Donna Neuberg, Richard M Stone, Robert J Soiffer

Ipilimumab monotherapy has clinical activity in patients with acute myeloid leukemia (AML) who relapse after allogeneic hematopoietic stem cell transplant (HSCT) when disease burden is low. We hypothesized that ipilimumab-driven responses required alloreactivity and the addition of decitabine could augment responses without generating excessive toxicity. We conducted a multicenter phase 1 trial of ipilimumab and decitabine (IPI+ DEC) in relapsed, refractory or secondary untreated MDS/AML (CTEP10026; NCT02890329) with patients stratified by transplant status. Patients received a lead-in cycle of decitabine followed by combination therapy with IPI (3, 5, or 10 mg/kg) every 4 weeks for four cycles and then every 8 weeks for up to eight cycles. In total, 48 patients received IPI+ DEC (25 post-HSCT, 23 transplant naïve). In the post-HSCT cohort, 36%(9/25) experienced immune-related adverse events (irAEs …

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Nov 2022 • Blood

Systematic Identification of Autosomal and Y-Encoded Minor Histocompatibility Antigens Reveals Predictors of Chronic Gvhd and Candidate GVL Targets

Nicoletta Cieri, Nidhi Hookeri, Kari Stromhaug, Jonathan Stevens, Kameron Kooshesh, Susan Klaeger, Karl R Clauser, Siranush Sarkizova, David A Braun, Livius Penter, Giacomo Oliveira, Haesook T Kim, William J Lane, Shuqiang Li, Kenneth J Livak, Vincent T Ho, Jerome Ritz, Robert J Soiffer, Derin B Keskin, Chip Stewart, Alexander Gusev, Gad Getz, Catherine J Wu

At the core of the therapeutic effect of HLA-matched allogeneic hematopoietic cell transplantation (allo-HCT) is T cell alloreactivity against minor histocompatibility antigens (mHAgs), polymorphic peptides resulting from donor-recipient disparity at sites of single nucleotide gene polymorphisms (SNPs). Despite their crucial role in graft-versus-leukemia (GvL) and graft-versus-host disease (GvHD), only few mHAgs have been characterized to date.

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Sep 2022 • Cancer Immunology Research

Immune phenotypes and target antigens of clonally expanded bone marrow T cells in treatment-naïve multiple myeloma

Carlotta Welters, Lammoglia Cobo MF, Christian Alexander Stein, Meng Tung Hsu, L Penter, X Chen, C Buccitelli, O Popp, P Mertins, K Dietze, L Bullinger, A Moosmann, E Blanc, D Beule, A Gerbitz, J Strobel, H Hackstein, HP Rahn, K Dornmair, T Blankenstein, L Hansmann


Sep 2022 • Blood, The Journal of the American Society of Hematology

AML relapse after a TIGIT race

Livius Penter, Catherine J Wu

In this issue of Blood, Gournay et al 1 dissect donor immune reconstitution after allogeneic hematopoietic stem cell transplantation (HSCT) with mass cytometry and identify T-cell immunoreceptor with Ig and ITIM domains (TIGIT) and CD161-expressing CD4+ T cells as early immune correlates of subsequent acute myelogenous leukemia (AML) relapse after HSCT.The high relapse rate of AML after stem cell transplant has remained one of the most tenacious problems in malignant hematology. With the graft-versusleukemia (GVL) effect at the core of successful long-term disease control, the early posttransplant course can be thought of as a delicate race between nascent donor immune reconstitution and recovering malignant cell populations that seek to escape GVL. AML relapse after HSCT thus often associates with donor immune cell dysfunction through upregulated immune checkpoint molecules or reduced …

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Sep 2022 • Nucleic Acids Research

TISMO: syngeneic mouse tumor database to model tumor immunity and immunotherapy response

Zexian Zeng, Cheryl J Wong, Lin Yang, Nofal Ouardaoui, Dian Li, Wubing Zhang, Shengqing Gu, Yi Zhang, Yang Liu, Xiaoqing Wang, Jingxin Fu, Liye Zhou, Boning Zhang, Sarah Kim, Kathleen B Yates, Myles Brown, Gordon J Freeman, Ravindra Uppaluri, Robert Manguso, X Shirley Liu

Syngeneic mouse models are tumors derived from murine cancer cells engrafted on genetically identical mouse strains. They are widely used tools for studying tumor immunity and immunotherapy response in the context of a fully functional murine immune system. Large volumes of syngeneic mouse tumor expression profiles under different immunotherapy treatments have been generated, although a lack of systematic collection and analysis makes data reuse challenging. We present Tumor Immune Syngeneic MOuse (TISMO), a database with an extensive collection of syngeneic mouse model profiles with interactive visualization features. TISMO contains 605 in vitro RNA-seq samples from 49 syngeneic cancer cell lines across 23 cancer types, of which 195 underwent cytokine treatment. TISMO also includes 1518 in vivo RNA-seq samples from 68 syngeneic mouse tumor models across 19 cancer types, of …

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Jun 2022 • Cancer Research

Immune population changes in mammary adipose tissue during the development of obesity and their influence on triple negative breast cancer progression

Shimeng Liu, Yi Zhang, Myles Brown

Obesity is associated with increased risk for many cancer types, including triple-negative breast cancer (TNBC). In addition to obesity’s role in TNBC pathogenesis, it is also recognized as a marker of poor prognosis for survival in pre- and post-menopausal women. However, the mechanism underlying how obesity leads to worsened TNBC progression remains unclear. In this study, we aim to characterize the immune population changes in mammary adipose during the development of obesity and their impact on TNBC progression. First, we utilized a diet-induced obesity mouse model to evaluate tumor growth under obese condition. Four weeks after E0771 (TNBC cell line) mammary fat pad injection, TNBC tumors volume were 1.6-fold larger in obese C57BL/6 mice compared to their lean counterparts. To profile the transcriptome changes induced by obesity, we performed single-cell RNA-Seq on mammary …

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May 2022 • Cell

Topical therapy for regression and melanoma prevention of congenital giant nevi

Yeon Sook Choi, Tal H Erlich, Max von Franque, Inbal Rachmin, Jessica L Flesher, Erik B Schiferle, Yi Zhang, Marcello Pereira da Silva, Alva Jiang, Allison S Dobry, Mack Su, Sharon Germana, Sebastian Lacher, Orly Freund, Ezra Feder, Jose L Cortez, Suyeon Ryu, Tamar Babila Propp, Yedidyah Leo Samuels, Labib R Zakka, Marjan Azin, Christin E Burd, Norman E Sharpless, X Shirley Liu, Clifford Meyer, William Gerald Austen Jr, Branko Bojovic, Curtis L Cetrulo Jr, Martin C Mihm, Dave S Hoon, Shadmehr Demehri, Elena B Hawryluk, David E Fisher

Giant congenital melanocytic nevi are NRAS-driven proliferations that may cover up to 80% of the body surface. Their most dangerous consequence is progression to melanoma. This risk often triggers preemptive extensive surgical excisions in childhood, producing severe lifelong challenges. We have presented preclinical models, including multiple genetically engineered mice and xenografted human lesions, which enabled testing locally applied pharmacologic agents to avoid surgery. The murine models permitted the identification of proliferative versus senescent nevus phases and treatments targeting both. These nevi recapitulated the histologic and molecular features of human giant congenital nevi, including the risk of melanoma transformation. Cutaneously delivered MEK, PI3K, and c-KIT inhibitors or proinflammatory squaric acid dibutylester (SADBE) achieved major regressions. SADBE triggered innate …

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May 2022 • Cytotherapy

Rapid single-cell identification of Epstein–Barr virus-specific T-cell receptors for cellular therapy

María Fernanda Lammoglia Cobo, Carlotta Welters, Leonie Rosenberger, Matthias Leisegang, Kerstin Dietze, Christian Pircher, Livius Penter, Regina Gary, Lars Bullinger, Anna Takvorian, Andreas Moosmann, Klaus Dornmair, Thomas Blankenstein, Thomas Kammertöns, Armin Gerbitz, Leo Hansmann

Background and aimsEpstein–Barr virus (EBV) is associated with solid and hematopoietic malignancies. After allogeneic stem cell transplantation, EBV infection or reactivation represents a potentially life-threatening condition with no specific treatment available in clinical routine. In vitro expansion of naturally occurring EBV-specific T cells for adoptive transfer is time-consuming and influenced by the donor's T-cell receptor (TCR) repertoire and requires a specific memory compartment that is non-existent in seronegative individuals.The authors present highly efficient identification of EBV-specific TCRs that can be expressed on human T cells and recognize EBV-infected cells.Methods and ResultsMononuclear cells from six stem cell grafts were expanded in vitro with three HLA-B*35:01- or four HLA-A*02:01-presented peptides derived from six EBV proteins expressed during latent and lytic infection. Epitope-specific …

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May 2022 • Cytotherapy

Rapid single-cell identification of Epstein–Barr virus-specific T-cell receptors for cellular therapy

María Fernanda Lammoglia Cobo, Carlotta Welters, Leonie Rosenberger, Matthias Leisegang, Kerstin Dietze, Christian Pircher, Livius Penter, Regina Gary, Lars Bullinger, Anna Takvorian, Andreas Moosmann, Klaus Dornmair, Thomas Blankenstein, Thomas Kammertöns, Armin Gerbitz, Leo Hansmann

Background and aimsEpstein–Barr virus (EBV) is associated with solid and hematopoietic malignancies. After allogeneic stem cell transplantation, EBV infection or reactivation represents a potentially life-threatening condition with no specific treatment available in clinical routine. In vitro expansion of naturally occurring EBV-specific T cells for adoptive transfer is time-consuming and influenced by the donor's T-cell receptor (TCR) repertoire and requires a specific memory compartment that is non-existent in seronegative individuals.The authors present highly efficient identification of EBV-specific TCRs that can be expressed on human T cells and recognize EBV-infected cells.Methods and ResultsMononuclear cells from six stem cell grafts were expanded in vitro with three HLA-B*35:01- or four HLA-A*02:01-presented peptides derived from six EBV proteins expressed during latent and lytic infection. Epitope-specific …

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May 2022 • Cell

Topical therapy for regression and melanoma prevention of congenital giant nevi

Yeon Sook Choi, Tal H Erlich, Max von Franque, Inbal Rachmin, Jessica L Flesher, Erik B Schiferle, Yi Zhang, Marcello Pereira da Silva, Alva Jiang, Allison S Dobry, Mack Su, Sharon Germana, Sebastian Lacher, Orly Freund, Ezra Feder, Jose L Cortez, Suyeon Ryu, Tamar Babila Propp, Yedidyah Leo Samuels, Labib R Zakka, Marjan Azin, Christin E Burd, Norman E Sharpless, X Shirley Liu, Clifford Meyer, William Gerald Austen Jr, Branko Bojovic, Curtis L Cetrulo Jr, Martin C Mihm, Dave S Hoon, Shadmehr Demehri, Elena B Hawryluk, David E Fisher

Giant congenital melanocytic nevi are NRAS-driven proliferations that may cover up to 80% of the body surface. Their most dangerous consequence is progression to melanoma. This risk often triggers preemptive extensive surgical excisions in childhood, producing severe lifelong challenges. We have presented preclinical models, including multiple genetically engineered mice and xenografted human lesions, which enabled testing locally applied pharmacologic agents to avoid surgery. The murine models permitted the identification of proliferative versus senescent nevus phases and treatments targeting both. These nevi recapitulated the histologic and molecular features of human giant congenital nevi, including the risk of melanoma transformation. Cutaneously delivered MEK, PI3K, and c-KIT inhibitors or proinflammatory squaric acid dibutylester (SADBE) achieved major regressions. SADBE triggered innate …

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Apr 2022 • Clinical Cancer Research: an Official Journal of the American Association for Cancer Research

Improved T cell immunity following neoadjuvant chemotherapy in ovarian cancer.

Min Liu, Nabihah Tayob, Livius Penter, M Sellars, Anna Tarren, Vipheaviny Chea, Isabel Carulli, Teddy Huang, Shuqiang Li, Su-Chun Cheng, Phuong Le, Laura Frackiewicz, Julia Fasse, Courtney Qi, Joyce F Liu, Elizabeth H Stover, Jennifer Curtis, Kenneth J Livak, Donna Neuberg, Guang Lan Zhang, Ursula A Matulonis, Catherine J Wu, Derin B Keskin, Panagiotis A Konstantinopoulos

PurposeAlthough local tissue-based immune responses are critical for elucidating direct tumor-immune cell interactions, peripheral immune responses are increasingly recognized as occupying an important role in anti-cancer immunity. We evaluated serial blood samples from patients with epithelial ovarian cancer (EOC) undergoing standard-of-care neoadjuvant carboplatin and paclitaxel chemotherapy (including dexamethasone for prophylaxis of paclitaxel-associated hypersensitivity reactions) to characterize the evolution of the peripheral immune cell function and composition during therapy.

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Apr 2022 • Clinical Cancer Research: an Official Journal of the American Association for Cancer Research

Improved T cell immunity following neoadjuvant chemotherapy in ovarian cancer.

Min Liu, Nabihah Tayob, Livius Penter, M Sellars, Anna Tarren, Vipheaviny Chea, Isabel Carulli, Teddy Huang, Shuqiang Li, Su-Chun Cheng, Phuong Le, Laura Frackiewicz, Julia Fasse, Courtney Qi, Joyce F Liu, Elizabeth H Stover, Jennifer Curtis, Kenneth J Livak, Donna Neuberg, Guang Lan Zhang, Ursula A Matulonis, Catherine J Wu, Derin B Keskin, Panagiotis A Konstantinopoulos

PurposeAlthough local tissue-based immune responses are critical for elucidating direct tumor-immune cell interactions, peripheral immune responses are increasingly recognized as occupying an important role in anti-cancer immunity. We evaluated serial blood samples from patients with epithelial ovarian cancer (EOC) undergoing standard-of-care neoadjuvant carboplatin and paclitaxel chemotherapy (including dexamethasone for prophylaxis of paclitaxel-associated hypersensitivity reactions) to characterize the evolution of the peripheral immune cell function and composition during therapy.

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