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2. Investigating and reversing T-cell dysfunction in the Eμ-TCL1 mouse model of chronic lymphocytic leukaemia (CLL)

Author

McClanahan, Fabienne

Subjects
616.99, Cancer, chronic lymphocytic leukaemia, T-cell defects.
Abstract

Chronic lymphocytic leukaemia (CLL) is the most common adult leukaemia, and despite recent introduction of targeted therapies, remains incurable. An important hallmark of CLL is severe immune deficiency, including the failure to mount effective anti-tumour immune responses. This can partly be explained by insufficient antigen presentation, but also by the existence of complex CLL-induced T-cell defects. Based on the cancer immuno-editing hypothesis that the immune system not only protects a host against tumour formation but can also be compromised to actively provide a pro-tumour microenvironment, modulating cancer-induced T-cell defects could restore the full anti-tumour response and result in more durable clinical responses. The immune checkpoint molecules PD-1 (expressed on activated immune effector cells) and PD-L1 (expressed on antigen-presenting and microenvironmental cells including tumour cells) have emerged as important mediators of T-cell suppression. Several studies suggest that PD-L1/PD-1 inhibitory signalling in CLL might be overcome by the immune modulatory drug lenalidomide. Furthermore, directly targeting PDL-1/PD-1 interactions produces significant responses in solid cancers. However, similar studies are notably absent in CLL, and the effect of PDL-1/PD-1 blockade on restoring cancer-induced immune dysfunction is not understood. Transgenic Eμ-TCL1 mice have been extensively validated as an adequate preclinical model of aggressive human CLL, and our group showed their suitability to mirror T-cell defects observed in human CLL. Using the Eμ-TCL1 model, this dissertation project substantially extends our previous characterization of CLL-induced T-cell dysfunction and evaluates the functional impact of PD-L1/PD-1 inhibitory signalling both in parallel with disease development and in different microenvironments. The findings to be described here demonstrate that developing CLL is associated with specific T-cell subset alterations, phenotypic changes, and functional defects that are very similar in peripheral blood and secondary lymphoid organs. In addition to PD-L1, PD-L2 is identified as a potential mediator of inhibitory signalling in CLL. CD8+ T cells in leukaemic mice are characterised as a functionally heterogeneous population, in which subsets of cells are able to exert effector functions despite PD-1 expression. In vivo lenalidomide treatment repairs selected phenotypic alterations and immune synapse formation, and a PD-L1 IgG blocking antibody effectively controls disease and reverses global T-cell defects even in cells expressing PD-1. In sum, this work provides a strong rationale to explore PD-L1/PD-1 targeting in CLL clinical trials, potentially in combination with novel agents.

Published
2015

3. Supplementary Figure Legends from The Bruton Tyrosine Kinase (BTK) Inhibitor Acalabrutinib Demonstrates Potent On-Target Effects and Efficacy in Two Mouse Models of Chronic Lymphocytic Leukemia

Author

Herman, Sarah E.M., primary, Montraveta, Arnau, primary, Niemann, Carsten U., primary, Mora-Jensen, Helena, primary, Gulrajani, Michael, primary, Krantz, Fanny, primary, Mantel, Rose, primary, Smith, Lisa L., primary, McClanahan, Fabienne, primary, Harrington, Bonnie K., primary, Colomer, Dolors, primary, Covey, Todd, primary, Byrd, John C., primary, Izumi, Raquel, primary, Kaptein, Allard, primary, Ulrich, Roger, primary, Johnson, Amy J., primary, Lannutti, Brian J., primary, Wiestner, Adrian, primary, and Woyach, Jennifer A., primary

Published
2023
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4. Supplementary FiguresS1-5 from The Bruton Tyrosine Kinase (BTK) Inhibitor Acalabrutinib Demonstrates Potent On-Target Effects and Efficacy in Two Mouse Models of Chronic Lymphocytic Leukemia

Author

Herman, Sarah E.M., primary, Montraveta, Arnau, primary, Niemann, Carsten U., primary, Mora-Jensen, Helena, primary, Gulrajani, Michael, primary, Krantz, Fanny, primary, Mantel, Rose, primary, Smith, Lisa L., primary, McClanahan, Fabienne, primary, Harrington, Bonnie K., primary, Colomer, Dolors, primary, Covey, Todd, primary, Byrd, John C., primary, Izumi, Raquel, primary, Kaptein, Allard, primary, Ulrich, Roger, primary, Johnson, Amy J., primary, Lannutti, Brian J., primary, Wiestner, Adrian, primary, and Woyach, Jennifer A., primary

Published
2023
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9. Early autologous stem cell transplantation for chronic lymphocytic leukemia: long-term follow-up of the German CLL Study Group CLL3 trial

Author

Dreger, Peter, Döhner, Hartmut, McClanahan, Fabienne, Busch, Raymonde, Ritgen, Matthias, Greinix, Hildegard, Fink, Anna-Maria, Knauf, Wolfgang, Stadler, Michael, Pfreundschuh, Michael, Dührsen, Ulrich, Brittinger, Günter, Hensel, Manfred, Schetelig, Johannes, Winkler, Dirk, Bühler, Andreas, Kneba, Michael, Schmitz, Norbert, Hallek, Michael, and Stilgenbauer, Stephan

Published
2012
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12. Diffusion-weighted imaging for non-invasive and quantitative monitoring of bone marrow infiltration in patients with monoclonal plasma cell disease: a comparative study with histology

Author

Hillengass, Jens, Bäuerle, Tobias, Bartl, Reiner, Andrulis, Mindaugas, McClanahan, Fabienne, Laun, Frederik B., Zechmann, Christian Martin, Shah, Rajiv, Wagner-Gund, Barbara, Simon, Dirk, Heiss, Christiane, Neben, Kai, Ho, Anthony D., Schlemmer, Heinz-Peter, Goldschmidt, Hartmut, Delorme, Stefan, and Stieltjes, Bram

Published
2011
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15. Allogeneic transplantation for chronic lymphocytic leukemia in the age of novel treatment strategies

Author

Schwarzbich, Mark-Alexander, McClanahan, Fabienne, and Gribben, John

Subjects
Hematopoietic stem cells -- Transplantation, Chronic lymphocytic leukemia -- Health aspects -- Care and treatment, Health
Abstract

Hematopoietic stem cell transplantation (HSCT) is the only established potentially curative treatment option for chronic lymphocytic leukemia (CLL) to date. However, this approach is associated with high toxicity and significant treatment-related morbidity and mortality; thus, it is suitable for only a minority of high-risk patients, given that most persons with CLL have comorbidities and are of advanced age. Until very recently, international guidelines recommended HSCT for physically fit patients who displayed poor-risk features or had only a short response to immunochemotherapy. In the wake of novel treatment approaches that offer high efficacy and highly durable responses with little toxicity, our approach to HSCT in CLL needs to be re-evaluated. While we wait for data on the long-term efficacy of novel therapies to inform the choice of HSCT or alternative treatment, strategies must be assessed individually for every patient, and treatment must be conducted in the setting of randomized clinical trials whenever possible., Introduction Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the Western world. Its hallmark is the accumulation of mature B lymphocytes within the bone marrow, blood, and [...]

Published
2016

16. The Bruton Tyrosine Kinase (BTK) Inhibitor Acalabrutinib Demonstrates Potent On-Target Effects and Efficacy in Two Mouse Models of Chronic Lymphocytic Leukemia

Author

Herman, Sarah E.M., primary, Montraveta, Arnau, additional, Niemann, Carsten U., additional, Mora-Jensen, Helena, additional, Gulrajani, Michael, additional, Krantz, Fanny, additional, Mantel, Rose, additional, Smith, Lisa L., additional, McClanahan, Fabienne, additional, Harrington, Bonnie K., additional, Colomer, Dolors, additional, Covey, Todd, additional, Byrd, John C., additional, Izumi, Raquel, additional, Kaptein, Allard, additional, Ulrich, Roger, additional, Johnson, Amy J., additional, Lannutti, Brian J., additional, Wiestner, Adrian, additional, and Woyach, Jennifer A., additional

Published
2017
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17. Exploring the Functional Relevance of BTK Beyond Chronic Lymphocytic Leukemia (CLL) Cells: BTK Expression in Non-Malignant Immune Cells of the Microenvironment Mediates CLL Development and Progression In Vivo

Author

McClanahan, Fabienne, primary, Reiff, Sean D., additional, Guinn, Daphne, additional, Tran, Minh, additional, Beaver, Larry, additional, McWorther, Samantha, additional, Mantel, Rose, additional, Smith, Lisa L., additional, Johnson, Amy J., additional, Byrd, John C., additional, and Woyach, Jennifer A., additional

Published
2016
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18. REDX08608, a Novel, Potent and Selective, Reversible BTK Inhibitor with Efficacy and Equivalent Potency Against Wild-Type and Mutant C481S BTK

Author

Guisot, Nicolas E. S., primary, Best, Stuart A., additional, Wright, Victoria, additional, Thomason, Andrew, additional, Woyach, Jennifer A., additional, Mantel, Rose, additional, McClanahan, Fabienne, additional, Abet, Valentina, additional, Castagna, Diana, additional, Cousin, Peggy, additional, Emmerich, Juliette, additional, Ho, Kelvin, additional, Kelly, James Russell, additional, King-Tours, James, additional, Lyons, Kristina, additional, Muller, Melanie, additional, Refuerzo, Julienne, additional, Sargent, Louise, additional, Talab, Fatima, additional, Bingham, Matilda, additional, Phillips, Caroline, additional, and Armer, Richard, additional

Published
2016
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19. BRAFV600E Accelerates Disease Progression and Increases Immune Suppression in a Mouse Model of B-Cell Leukemia

Author

Tsai, Yo-Ting, primary, Lakshmanan, Aparna, additional, Lehman, Amy M., additional, Sass, Ellen J., additional, Tran, Minh, additional, McClanahan, Fabienne, additional, Long, Meixiao, additional, Harrington, Bonnie K., additional, La Perle, Krista, additional, Coppola, Vincenzo, additional, Lozanski, Gerard, additional, Muthusamy, Natarajan, additional, Byrd, John C., additional, Grever, Michael R., additional, and Lucas, David M., additional

Published
2016
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20. Generation of a poor prognostic chronic lymphocytic leukemia-like disease model: PKC subversion induces up-regulation of PKC II expression in B lymphocytes

Author

Nakagawa, Rinako, Vukovic, Milica, Tarafdar, Anuradha, Cosimo, Emilio, Dunn, Karen, Mccaig, Alison M., Holroyd, Ailsa, McClanahan, Fabienne, Ramsay, Alan G., Gribben, John G., and Michie, Alison

Abstract

Overwhelming evidence identifies the microenvironment as a critical factor in the development and progression of chronic lymphocytic leukemia, underlining the importance of developing suitable translational models to study the pathogenesis of the disease. We previously established that stable expression of kinase dead protein kinase C alpha in hematopoietic progenitor cells resulted in the development of a chronic lymphocytic leukemia-like disease in mice. Here we demonstrate that this chronic lymphocytic leukemia model resembles the more aggressive subset of chronic lymphocytic leukemia, expressing predominantly unmutated immunoglobulin heavy chain genes, with upregulated tyrosine kinase ZAP-70 expression and elevated ERK-MAPK-mTor signaling, resulting in enhanced proliferation and increased tumor load in lymphoid organs. Reduced function of PKCα leads to an up-regulation of PKCβII expression, which is also associated with a poor prognostic subset of human chronic lymphocytic leukemia samples. Treatment of chronic lymphocytic leukemia-like cells with the selective PKCβ inhibitor enzastaurin caused cell cycle arrest and apoptosis both in vitro and in vivo, and a reduction in the leukemic burden in vivo. These results demonstrate the importance of PKCβII in chronic lymphocytic leukemia-like disease progression and suggest a role for PKCα subversion in creating permissive conditions for leukemogenesis.

Published
2015

21. RASGRP1 deficiency causes immunodeficiency with impaired cytoskeletal dynamics

Author

Salzer, Elisabeth, primary, Cagdas, Deniz, additional, Hons, Miroslav, additional, Mace, Emily M, additional, Garncarz, Wojciech, additional, Petronczki, Özlem Yüce, additional, Platzer, René, additional, Pfajfer, Laurène, additional, Bilic, Ivan, additional, Ban, Sol A, additional, Willmann, Katharina L, additional, Mukherjee, Malini, additional, Supper, Verena, additional, Hsu, Hsiang Ting, additional, Banerjee, Pinaki P, additional, Sinha, Papiya, additional, McClanahan, Fabienne, additional, Zlabinger, Gerhard J, additional, Pickl, Winfried F, additional, Gribben, John G, additional, Stockinger, Hannes, additional, Bennett, Keiryn L, additional, Huppa, Johannes B, additional, Dupré, Loïc, additional, Sanal, Özden, additional, Jäger, Ulrich, additional, Sixt, Michael, additional, Tezcan, Ilhan, additional, Orange, Jordan S, additional, and Boztug, Kaan, additional

Published
2016
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30. Trisomy 12 chronic lymphocytic leukemia cells exhibit upregulation of integrin signaling that is modulated by NOTCH1 mutations

Author

Riches, John C., primary, O’Donovan, Conor J., additional, Kingdon, Sarah J., additional, McClanahan, Fabienne, additional, Clear, Andrew J., additional, Neuberg, Donna S., additional, Werner, Lillian, additional, Croce, Carlo M., additional, Ramsay, Alan G., additional, Rassenti, Laura Z., additional, Kipps, Thomas J., additional, and Gribben, John G., additional

Published
2014
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31. Intraclonal Complexity Of CLL Fractions In Cell Proliferation Rates, Gene Expression Signatures, and Responses To Autologous T-Cell Help In Peripheral blood and Secondary Lymphoid Tissues

Author

Chen, Shih-Shih, primary, Herndon, Thomas M., additional, Emson, Claire, additional, Riches, John C., additional, McClanahan, Fabienne, additional, Tong, Timothy, additional, Yan, Xiao-Jie, additional, Patten, Piers E.M., additional, Gribben, John, additional, Wiestner, Adrian, additional, and Chiorazzi, Nicholas, additional

Published
2013
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40. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and diffusion-weighted imaging of bone marrow in healthy individuals

Author

Hillengass, Jens, primary, Stieltjes, Bram, additional, Bäuerle, Tobias, additional, McClanahan, Fabienne, additional, Heiss, Christiane, additional, Hielscher, Thomas, additional, Wagner-Gund, Barbara, additional, Habetler, Verena, additional, Goldschmidt, Hartmut, additional, Schlemmer, Heinz-Peter, additional, Delorme, Stefan, additional, and Zechmann, Christian M, additional

Published
2011
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41. Correlation of Bone Marrow Cellularity, Plasma Cell Infiltration and Microcirculation with Apparent Diffusion Coefficient of Diffusion Weighted Imaging In Patients with Monoclonal Plasma Cell Disease

Author

Hillengass, Jens, primary, Stieltjes, Bram, additional, Baeuerle, Tobias, additional, McClanahan, Fabienne, additional, Heiss, Christiane, additional, Andrulis, Mindaugas, additional, Bartl, Reiner, additional, Shah, Rajiv, additional, Simon, Dirk, additional, Hose, Dirk, additional, Ho, Anthony D., additional, Schlemmer, Heinz Peter, additional, Goldschmidt, Hartmut, additional, and Delorme, Stefan, additional

Published
2010
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42. Early Autologous Stem Cell Transplantation (autoSCT) May Overcome the Adverse Impact of Del 11q- in Poor-Risk Chronic Lymphocytic Leukemia (CLL): Results From the GCLLSG CLL3 Trial.

Author

Dreger, Peter, primary, Döhner, Hartmut, additional, Greinix, Hildegard, additional, McClanahan, Fabienne, additional, Hensel, Manfred, additional, Hertenstein, Bernd, additional, Dührsen, Ulrich, additional, Hentrich, Markus, additional, Trümper, Lorenz, additional, Sonnen, Ruth, additional, Emmerich, Bertold, additional, Knauf, Wolfgang Ulrich, additional, Hopfinger, Georg, additional, Hallek, Michael, additional, Kneba, Michael, additional, Schmitz, Norbert, additional, and Stilgenbauer, Stephan, additional

Published
2009
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43. How Much Rituximab Do We Need: A Multicenter, Randomized Trial Comparing 1, 3 or 6 Infusions of Rituximab Combined with 6 Cycles of CHOP Chemotherapy in Untreated Patients with Advanced Follicular Lymphoma (HD2000-Trial).

Author

McClanahan, Fabienne, primary, Hielscher, Thomas, additional, Rieger, Michael, additional, Hensel, Manfred, additional, Bentz, Martin, additional, Schmidt-Wolf, Ingo, additional, Kaebisch, Andreas, additional, Salwender, Hans-Jürgen, additional, Dürk, Heinz, additional, Staiger, Hans Juergen, additional, Mandel, Thomas, additional, Neben, Kai, additional, Hillengass, Jens, additional, Ho, Anthony D., additional, and Witzens-Harig, Mathias, additional

Published
2009
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44. Rituximab Maintenenance Therapy in CD20+ B-Cell Non-Hodgkin-Lymphoma – Final Results of a Multicenter Prospective Randomised Phase II Study.

Author

Witzens-Harig, Mathias, primary, Benner, Axel, additional, Rieger, Michael, additional, McClanahan, Fabienne, additional, Hensel, Manfred, additional, Neben, Kai, additional, Dreger, Peter, additional, Lengfelder, Eva, additional, Schmidt-Wolf, Ingo, additional, Alwin, Krämer, additional, and Ho, Anthony D., additional

Published
2009
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48. BRAF(V600E) Accelerates Disease Progression and Increases Immune Suppression in a Mouse Model of B-Cell Leukemia

Author

Tsai, Yo-Ting, Lakshmanan, Aparna, Lehman, Amy M., Sass, Ellen J., Minh Tran, Mcclanahan, Fabienne, Long, Meixiao, Harrington, Bonnie K., La Perle, Krista, Vincenzo Coppola, Lozanski, Gerard, Muthusamy, Natarajan, Byrd, John C., Grever, Michael R., and Lucas, David M.

Subjects
Immunology, Cell Biology, Hematology, Biochemistry
Abstract

Background: Mitogen-activated protein kinase (MAPK) pathway components are frequently mutated in cancer, and abnormal MAPK signaling can drive malignancy by promoting tumor survival and proliferation. Furthermore, work in solid tumors shows that the presence of BRAFV600E further enhances tumor-induced immune suppression, but if and how this occurs in a disseminated disease such as leukemia is unknown. MAPK mutations occur in nearly 100% of classic hairy cell leukemia (HCL) and approximately 10% of chronic lymphocytic leukemia (CLL). Furthermore, up to 30% of B cell lymphomas exhibit activated MAPK signaling via expression of a BRAF pseudogene. However, the pathomechanisms of these abnormalities and the clinical utility of MAPK inhibitors in hematologic malignancies are unclear, and few models are available to evaluate this. To study these aspects, we developed in vitro and in vivo models of BRAF-mutated B cell malignancy. Methods: To mechanistically interrogate the role of BRAFV600E in malignant B cells, we transfected the CLL cell line OSUCLL with doxycycline-inducible constructs containing normal BRAF or BRAFV600E and incubated the cells -/+ doxycycline. These cells were also co-cultured with healthy donor T cells pre-incubated with anti-CD3/anti-CD28, and T cell proliferation was measured by flow cytometry. Cytokines and surface proteins were assessed by flow cytometry. To mimic human HCL, we developed a transgenic mouse model of BRAFV600E B cell leukemia. Mice with Cre-activatable BRAFV600E expression were crossed with mice carrying Cre under the control of the CD19 promoter. CD19-Cre x BRAFV600E or CD19-Cre only mice were then crossed with the well-characterized Eµ-TCL1 model of CLL to generate mice with spontaneous B cell leukemia expressing either wild-type BRAF (CD19-Cre x TCL1) or BRAFV600E (BRAFVE x CD19-Cre x TCL1) under the native BRAF promoter. B cell restricted expression of BRAFV600E was confirmed by immunoblots of purified B and T cells using a BRAFV600E specific antibody. Blood and spleen cells were examined by flow cytometry. For adoptive transfer experiments, leukemia cells (2x10^7) from transgenic mice were introduced intravenously into syngeneic healthy adult animals. Results: OSUCLL cells expressing BRAFV600E showed no significant changes in growth vs. wild-type BRAF expressing cells, but more strongly inhibited anti-CD3/CD28-induced proliferation of normal donor T cells. Transwell assays showed this effect was due both to soluble and contact-dependent factors. Expression of PD-L1 was not different between cells expressing normal and mutated BRAF, indicating this common checkpoint molecule is not the reason for greater immune suppression in this context. TNF levels were higher in BRAFV600E expressing cells and reduced by vemurafenib, but a TNF neutralizing antibody did not alter the inhibitory effect of BRAFV600E expressing cells on T cell proliferation. BRAFV600E x CD19-Cre x TCL1 mice developed B cell leukemia significantly earlier (median 4.9 vs. 8.1 months; P10% CD5+/CD19+ cells in blood) sooner than CD19-Cre x TCL1 tumor cells. In mice matched for disease load, BRAFV600E B cells produced a greater negative impact on T cells as evidenced by lower overall percentage of T cells, increased expression of T cell exhaustion markers PD-1, CD244, and CD160, and higher percentage of CD44+ memory T cells. Current studies are investigating the mechanism of these effects in vivo as well as the potential for pharmacologic reversal. Conclusions: Together, these results demonstrate the immune-suppressive impact of BRAFV600E in B-cell leukemias and introduce a novel mouse model to develop rational combination strategies to both directly target the tumor cell and overcome tumor-mediated immune evasion. Disclosures Lozanski: Genentech: Research Funding; Stemline Therapeutics Inc.: Research Funding; Beckman Coulter: Research Funding; Boehringer Ingelheim: Research Funding.

49. Immunotherapeutic Approaches Have the Potential to Brighten the Future Not Only for Patients With del(17pl3.1), but for All CLL Patients.

Author

Mcclanahan, Fabienne and Gribben, John G.

Abstract

The authors review an article by Drs. Stephens and Byrd which outline pathophysiology associated with del(17pl3.1) responsible for chronic lymphocytic leukemia (CLL). They state that Stephens and Byrd have summarized the poor outcome of these patients across different treatment regimens and clinical studies. According to the authors the clinical management of these patients poses enormous challenges, and patients should be included in clinical trials whenever possible.

Published
2012

50. BRAFV600EAccelerates Disease Progression and Increases Immune Suppression in a Mouse Model of B-Cell Leukemia

Author

Tsai, Yo-Ting, Lakshmanan, Aparna, Lehman, Amy M., Sass, Ellen J., Tran, Minh, McClanahan, Fabienne, Long, Meixiao, Harrington, Bonnie K., La Perle, Krista, Coppola, Vincenzo, Lozanski, Gerard, Muthusamy, Natarajan, Byrd, John C., Grever, Michael R., and Lucas, David M.

Abstract

Background:Mitogen-activated protein kinase (MAPK) pathway components are frequently mutated in cancer, and abnormal MAPK signaling can drive malignancy by promoting tumor survival and proliferation. Furthermore, work in solid tumors shows that the presence of BRAFV600Efurther enhances tumor-induced immune suppression, but if and how this occurs in a disseminated disease such as leukemia is unknown. MAPK mutations occur in nearly 100% of classic hairy cell leukemia (HCL) and approximately 10% of chronic lymphocytic leukemia (CLL). Furthermore, up to 30% of B cell lymphomas exhibit activated MAPK signaling via expression of a BRAF pseudogene. However, the pathomechanisms of these abnormalities and the clinical utility of MAPK inhibitors in hematologic malignancies are unclear, and few models are available to evaluate this. To study these aspects, we developed in vitroand in vivomodels of BRAF-mutated B cell malignancy.

Published
2016
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