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2. PP2A is a therapeutically targetable driver of cell fate decisions via a c-Myc/p21 axis in human and murine acute myeloid leukemia

Author

Goswami, Swagata, Mani, Rajeswaran, Nunes, Jessica, Chiang, Chi-Ling, Zapolnik, Kevan, Hu, Eileen, Frissora, Frank, Mo, Xiaokui, Walker, Logan A., Yan, Pearlly, Bundschuh, Ralf, Beaver, Larry, Devine, Raymond, Tsai, Yo-Ting, Ventura, Ann, Xie, Zhiliang, Chen, Min, Lapalombella, Rosa, Walker, Alison, Mims, Alice, Larkin, Karilyn, Grieselhuber, Nicole, Bennett, Chad, Phelps, Mitch, Hertlein, Erin, Behbehani, Gregory, Vasu, Sumithira, Byrd, John C., and Muthusamy, Natarajan

Published
2022
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3. Efficacy, safety, and biomarker analyses of bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in patients with advanced non-small cell lung cancer

Author

Rajan, Arun, primary, Abdul Sater, Houssein, additional, Rahma, Osama, additional, Agajanian, Richy, additional, Lassoued, Wiem, additional, Marté, Jennifer L, additional, Tsai, Yo-Ting, additional, Donahue, Renee N, additional, Lamping, Elizabeth, additional, Bailey, Shania, additional, Weisman, Andrew, additional, Walter-Rodriguez, Beatriz, additional, Ito, Rena, additional, Vugmeyster, Yulia, additional, Sato, Masashi, additional, Machl, Andreas, additional, Schlom, Jeffrey, additional, and Gulley, James L, additional

Published
2024
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4. AB016. Phase 2 clinical trial of PT-112 in patients with thymic epithelial tumors

Author

McAdams, Meredith, primary, Swift, Shannon, additional, Donahue, Renee N., additional, Celades, Carolina, additional, Tsai, Yo-Ting, additional, Bingham, Molly, additional, Szabo, Eva, additional, Zhao, Chen, additional, Sansone, Susan, additional, Feierabend, Christine, additional, DaSilva, Laercio, additional, Shelat, Meenakshi, additional, O’Donnell, Joseph, additional, Ames, Tyler D., additional, Raphael, Brooke, additional, Steinberg, Seth M., additional, Gulley, James L., additional, Schlom, Jeffrey, additional, and Rajan, Arun, additional

Published
2023
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5. A T cell receptor β chain–directed antibody fusion molecule activates and expands subsets of T cells to promote antitumor activity

Author

Hsu, Jonathan, primary, Donahue, Renee N., additional, Katragadda, Madan, additional, Lowry, Jessica, additional, Huang, Wei, additional, Srinivasan, Karunya, additional, Guntas, Gurkan, additional, Tang, Jian, additional, Servattalab, Roya, additional, Moisan, Jacques, additional, Tsai, Yo-Ting, additional, Stoop, Allart, additional, Palakurthi, Sangeetha, additional, Chopra, Raj, additional, Liu, Ke, additional, Wherry, E. John, additional, Su, Zhen, additional, Gulley, James L., additional, Bayliffe, Andrew, additional, and Schlom, Jeffrey, additional

Published
2023
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6. 781 A phase II, open-label trial of bintrafusp alfa (M7824) in subjects with thymoma and thymic carcinoma (trial in progress)

Author

McAdams, Meredith, primary, Swift, Shannon, additional, Donahue, Renee N, additional, Celades, Carolina, additional, Tsai, Yo-Ting, additional, Bingham, Molly, additional, Szabo, Eva, additional, Choradia, Nirmal, additional, Zhao, Chen, additional, Sansone, Susan, additional, Feierabend, Christine, additional, Shelat, Meenakshi, additional, Steinberg, Seth M, additional, Schlom, Jeffrey, additional, Gulley, James L, additional, and Rajan, Arun, additional

Published
2023
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8. First-in-human phase Ib trial of M9241 (NHS-IL12) plus avelumab in patients with advanced solid tumors, including dose expansion in patients with advanced urothelial carcinoma

Author

Strauss, Julius, primary, Deville, Jean-Laurent, additional, Sznol, Mario, additional, Ravaud, Alain, additional, Maruzzo, Marco, additional, Pachynski, Russell K, additional, Gourdin, Theodore S, additional, Maio, Michele, additional, Dirix, Luc, additional, Schlom, Jeffrey, additional, Donahue, Renee N, additional, Tsai, Yo-Ting, additional, Wang, XiaoZhe, additional, Vugmeyster, Yulia, additional, Beier, Frank, additional, Seebeck, Joerg, additional, Schroeder, Andreas, additional, Chennoufi, Sarah, additional, and Gulley, James L, additional

Published
2023
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9. Efficacy and tolerability of anti-programmed death-ligand 1 (PD-L1) antibody (Avelumab) treatment in advanced thymoma

Author

Rajan, Arun, Heery, Christopher R., Thomas, Anish, Mammen, Andrew L., Perry, Susan, O’Sullivan Coyne, Geraldine, Guha, Udayan, Berman, Arlene, Szabo, Eva, Madan, Ravi A., Ballester, Leomar Y., Pittaluga, Stefania, Donahue, Renee N., Tsai, Yo-Ting, Lepone, Lauren M., Chin, Kevin, Ginty, Fiona, Sood, Anup, Hewitt, Stephen M., Schlom, Jeffrey, Hassan, Raffit, and Gulley, James L.

Published
2019
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12. 1337 Preclinical evaluation of STAR0602, a novel, first-in-class anti-TCR Vb targeted bispecific antibody with potent anti-tumor activity for PD-1 refractory solid tumors

Author

Su, Zhen, primary, Gulley, James, additional, Schlom, Jeffrey, additional, Siu, Lillian, additional, Sullivan, Ryan, additional, John Wherry, E, additional, Liu, Ke, additional, Donahue, Renee, additional, Katraggada, Madan, additional, Chopra, Rajesh, additional, Moisan, Jacques, additional, Hsu, Jonathan, additional, and Tsai, Yo-Ting, additional

Published
2022
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16. A Randomized Phase II Trial of mFOLFOX6 + Bevacizumab Alone or with AdCEA Vaccine + Avelumab Immunotherapy for Untreated Metastatic Colorectal Cancer

Author

Redman, Jason M, primary, Tsai, Yo-Ting, additional, Weinberg, Benjamin A, additional, Donahue, Renee N, additional, Gandhy, Shruti, additional, Gatti-Mays, Margaret E, additional, Abdul Sater, Houssein, additional, Bilusic, Marijo, additional, Cordes, Lisa M, additional, Steinberg, Seth M, additional, Marte, Jennifer L, additional, Jochems, Caroline, additional, Kim, Sunnie S, additional, Marshall, John L, additional, McMahon, Sheri, additional, Redmond, Erica, additional, Schlom, Jeffrey, additional, Gulley, James L, additional, and Strauss, Julius, additional

Published
2022
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20. Phase I study of a multitargeted recombinant Ad5 PSA/MUC-1/brachyury-based immunotherapy vaccine in patients with metastatic castration-resistant prostate cancer (mCRPC)

Author

Bilusic, Marijo, primary, McMahon, Sheri, additional, Madan, Ravi A, additional, Karzai, Fatima, additional, Tsai, Yo-Ting, additional, Donahue, Renee N, additional, Palena, Claudia, additional, Jochems, Caroline, additional, Marté, Jennifer L, additional, Floudas, Charalampos, additional, Strauss, Julius, additional, Redman, Jason, additional, Abdul Sater, Houssein, additional, Rabizadeh, Shahrooz, additional, Soon-Shiong, Patrick, additional, Schlom, Jeffrey, additional, and Gulley, James L, additional

Published
2021
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22. Joint-Predominant Rheumatic Complications of Immune Checkpoint Inhibitor Therapy in Patients with Thymic Epithelial Tumors.

Author

Mullenix, Cristina, Ballman, Madison, Chen, Haobin, Swift, Shannon, McAdams, Meredith J, Tsai, Yo-Ting, Donahue, Renee N, Poretta, Trina, Gupta, Sarthak, Loehrer, Patrick J, Schlom, Jeffrey, Gulley, James L, and Rajan, Arun

Subjects
ADVERSE health care events, EPITHELIAL cell tumors, IMMUNE checkpoint inhibitors, INFECTIOUS arthritis, JOINT diseases, RISK assessment, CANCER patients, POLYMYALGIA rheumatica, RHEUMATISM, MYOSITIS, IMMUNOTHERAPY, DISEASE risk factors
Abstract

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced cancers. However, activation of the immune system can occasionally cause life-threatening toxicity involving critical organs. Induction of immune-mediated toxicity is a significant concern for patients with thymic epithelial tumors (TETs) due to defects in immune tolerance. An increased risk of skeletal and cardiac muscle inflammation following treatment with ICIs is well recognized in patients with advanced TETs. However, uncommon musculoskeletal and rheumatic complications can also occur. The cases presented in this report highlight the spectrum of presentation of immune-mediated, joint-predominant musculoskeletal adverse events in patients with advanced TETs treated with ICIs, including polymyalgia rheumatica-like illness and inflammatory arthritis. [ABSTRACT FROM AUTHOR]

Published
2022
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26. Randomized Phase II Trial of mFOLFOX6 + Bevacizumab Alone or with AdCEA Vaccine + Avelumab Immunotherapy for Untreated Metastatic Colorectal Cancer.

Author

Redman, Jason M, Tsai, Yo-Ting, Weinberg, Benjamin A, Donahue, Renee N, Gandhy, Shruti, Gatti-Mays, Margaret E, Sater, Houssein Abdul, Bilusic, Marijo, Cordes, Lisa M, Steinberg, Seth M, Marte, Jennifer L, Jochems, Caroline, Kim, Sunnie S, Marshall, John L, McMahon, Sheri, Redmond, Erica, Schlom, Jeffrey, Gulley, James L, and Strauss, Julius

Subjects
CONFIDENCE intervals, CANCER chemotherapy, METASTASIS, MONOCLONAL antibodies, COLORECTAL cancer, RANDOMIZED controlled trials, BEVACIZUMAB, CANCER vaccines, STATISTICAL sampling, PROGRESSION-free survival, IMMUNOTHERAPY
Abstract

Background FOLFOX plus bevacizumab is a standard of care (SOC) for first-line treatment of microsatellite-stable metastatic colorectal cancer (MSS mCRC). This study randomized patients to SOC or SOC plus avelumab (anti-PD-L1) plus CEA-targeted vaccine. Methods Patients with untreated MSS mCRC enrolled to a lead-in arm assessing safety of SOC + immuno-oncology agents (IO). Next, patients were randomized to SOC or SOC + IO. The primary endpoint was progression-free survival (PFS). Multiple immune parameters were analyzed. Results Six patients enrolled to safety lead-in, 10 randomized to SOC, and 10 to SOC + IO. There was no difference in median PFS comparing SOC versus SOC + IO (8.8 months (95% CI: 3.3-17.0 months) versus 10.1 months (95% CI: 3.6-16.1 months), respectively; hazard ratio 1.061 [ P =.91; 95% CI: 0.380-2.966]). The objective response rate was 50% in both arms. Of patients analyzed, most (8/11) who received SOC + IO developed multifunctional CD4+/CD8+ T-cell responses to cascade antigens MUC1 and/or brachyury, compared to 1/8 who received SOC alone (P =.020). We detected post-treatment changes in immune parameters that were distinct to the SOC and SOC + IO treatment arms. Accrual closed after an unplanned analysis predicted a low likelihood of meeting the primary endpoint. Conclusions SOC + IO generated multifunctional MUC1- and brachyury-specific CD4+/CD8+ T cells despite concurrent chemotherapy. Although a tumor-directed immune response is necessary for T-cell–mediated antitumor activity, it was not sufficient to improve PFS. Adding agents that increase the number and function of effector cells may be required for clinical benefit. [ABSTRACT FROM AUTHOR]

Published
2022
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27. Phase I Trial of a Modified Vaccinia Ankara Priming Vaccine Followed by a Fowlpox Virus Boosting Vaccine Modified to Express Brachyury and Costimulatory Molecules in Advanced Solid Tumors

Author

Collins, Julie M., primary, Donahue, Renee N., additional, Tsai, Yo-Ting, additional, Manu, Michell, additional, Palena, Claudia, additional, Gatti-Mays, Margaret E., additional, Marté, Jennifer L., additional, Madan, Ravi A., additional, Karzai, Fatima, additional, Heery, Christopher R., additional, Strauss, Julius, additional, Abdul-Sater, Houssein, additional, Cordes, Lisa, additional, Schlom, Jeffrey, additional, Gulley, James L., additional, and Bilusic, Marijo, additional

Published
2019
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28. Phase I trial of a modified vaccinia ankara (MVA) priming vaccine followed by a fowlpox virus (FPV) boosting vaccine modified to express brachyury and costimulatory molecules in advanced solid tumors.

Author

Collins, Julie Marie, primary, Donahue, Renee Nicole, additional, Tsai, Yo-Ting, additional, Palena, Claudia, additional, Marte, Jennifer L., additional, Madan, Ravi Amrit, additional, Karzai, Fatima, additional, Heery, Christopher Ryan, additional, Strauss, Julius, additional, Gatti-Mays, Margaret Elena, additional, Cordes, Lisa M., additional, Schlom, Jeffrey, additional, Gulley, James L., additional, and Bilusic, Marijo, additional

Published
2019
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29. Abstract 1029: MAPK-mediated immunomodulation in disseminated murine Emu-TCL1 chronic lymphocytic leukemia

Author

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

Published
2017
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30. 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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32. Preliminary efficacy, safety, and immunomodulatory effects of PT-112 from a phase 2 proof of concept study in patients (pts) with thymic epithelial tumors (TETs).

Author

McAdams, Meredith, Swift, Shannon, Donahue, Renee N., Celades, Carolina, Tsai, Yo-Ting, Bingham, Molly, Szabo, Eva, Zhao, Chen, Sansone, Susan, Choradia, Nirmal, Shelat, Meenakshi, O'Donnell, Joseph Francis, Ames, Tyler David, Raphael, Brooke, Steinberg, Seth M., Gulley, James L., Schlom, Jeffrey, and Rajan, Arun

Published
2023
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34. BRAFV600Eaccelerates disease progression and enhances immune suppression in a mouse model of B-cell leukemia

Author

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

Abstract

Mutated mitogen-activated protein kinase (MAPK) pathway components promote tumor survival, proliferation, and immune evasion in solid tumors. MAPK mutations occur in hematologic cancers as well, but their role is less clear and few models are available to study this. We developed an in vivo model of disseminated BRAFV600EB-cell leukemia to determine the effects of this mutation on tumor development and immune evasion. Mice with B-cell–restricted BRAFV600Eexpression crossed with the Eµ-TCL1 model of chronic lymphocytic leukemia (CLL) developed leukemia significantly earlier (median, 4.9 vs 8.1 months; P≮ .001) and had significantly shorter lifespan (median, 7.3 vs 12.1 months; P≮ .001) versus BRAF wild-type counterparts. BRAFV600Eexpression did not affect B-cell proliferation but reduced spontaneous apoptosis. BRAFV600E-mutant leukemia produced greater T-cell effects, evidenced by exhaustion immunophenotype and CD44+T-cell percentage, as well as increased expression of PD-L1 on CD11b+cells. Results were confirmed in syngeneic mice engrafted with BRAFV600Eleukemia cells. Furthermore, a BRAFV600E-expressing CLL cell line more strongly inhibited anti-CD3/CD28–induced T-cell proliferation, which was reversed by BRAFV600Einhibition. These results demonstrate the immune-suppressive impact of BRAFV600Ein B-cell leukemias and introduce a new model to develop rational combination strategies targeting both tumor cells and tumor-mediated immune evasion.

Published
2017
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36. Phase I Trial of a Modified Vaccinia Ankara Priming Vaccine Followed by a Fowlpox Virus Boosting Vaccine Modified to Express Brachyury and Costimulatory Molecules in Advanced Solid Tumors.

Author

Collins, Julie M., Donahue, Renee N., Tsai, Yo‐Ting, Manu, Michell, Palena, Claudia, Gatti‐Mays, Margaret E., Marté, Jennifer L., Madan, Ravi A., Karzai, Fatima, Heery, Christopher R., Strauss, Julius, Abdul‐Sater, Houssein, Cordes, Lisa, Schlom, Jeffrey, Gulley, James L., and Bilusic, Marijo

Subjects
ANTIGENS, CLINICAL trials, DRUG side effects, GENE expression, PROTEINS, TUMORS, VIRAL vaccines, CANCER vaccines, TREATMENT effectiveness, PHARMACODYNAMICS
Abstract

Lessons Learned: Modified vaccinia Ankara‐Bavarian Nordic (MVA‐BN)‐Brachyury followed by fowlpox virus‐BN‐Brachyury was well tolerated upon administration to patients with advanced cancer.Sixty‐three percent of patients developed CD4+ and/or CD8+ T‐cell responses to brachyury after vaccination.BN‐Brachyury vaccine also induced T‐cell responses against CEA and MUC1, which are cascade antigens, that is, antigens not encoded in the vaccines. Background: Brachyury, a transcription factor, plays an integral role in the epithelial–mesenchymal transition, metastasis, and tumor resistance to chemotherapy. It is expressed in many tumor types, and rarely in normal tissues, making it an ideal immunologic target. Bavarian Nordic (BN)‐Brachyury consists of vaccination with modified vaccinia Ankara (MVA) priming followed by fowlpox virus (FPV) boosting, each encoding transgenes for brachyury and costimulatory molecules. Methods: Patients with metastatic solid tumors were treated with two monthly doses of MVA‐brachyury s.c., 8 × 108 infectious units (IU), followed by FPV‐brachyury s.c., 1 × 109 IU, for six monthly doses and then every 3 months for up to 2 years. The primary objective was to determine safety and tolerability. Results: Eleven patients were enrolled from March 2018 to July 2018 (one patient was nonevaluable). No dose‐limiting toxicities were observed. The most common treatment‐related adverse event was grade 1/2 injection‐site reaction observed in all patients. Best overall response was stable disease in six patients, and the 6‐month progression‐free survival rate was 50%. T cells against brachyury and cascade antigens CEA and MUC1 were detected in the majority of patients. Conclusion: BN‐Brachyury vaccine is well tolerated and induces immune responses to brachyury and cascade antigens and demonstrates some evidence of clinical benefit. [ABSTRACT FROM AUTHOR]

Published
2020
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37. 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.

38. Dysregulation of Mitogen-Activated Protein Kinases Signaling and Immune Suppression in B-cell Leukemia

Author

Tsai, Yo-Ting

Subjects
Pharmaceuticals, Biomedical Research
Abstract

Mutant mitogen-activated protein kinases (MAPK) components-mediated dysregulation of the pathway is commonly exhibited in cancers and can drive malignancies by promoting tumor survival and proliferation. Tumor-mediated immune suppression in both solid tumors and hematologic malignancies is significant and the activated MAPK signaling pathway is evident in solid tumors to enhance immune suppression. The improvement of current therapies in chronic lymphocytic leukemia (CLL) controls disease development to a greater extent, but the leukemia-induced immune suppression remains one of the leading causes of death. The refractory/relapse cases and the severe immune-deficiency provide a strong justification to identify the effect(s) of genetic lesions and to develop strategies to reverse it in CLL. Activating mutation of MAPK components including BRAF occurs in approximately 10% of CLL and nearly 100% of hairy cell leukemia (HCL), and a BRAF pseudogene-mediated MAPK activation presents in up to 30% of B-cell lymphomas. However, the contribution of the mutant BRAF-activated MAPK signaling in B-cell malignancies remains unclear in respects of disease development and tumor-induced immune suppression, and few models of mutant BRAF-mediated MAPK activation are available to address these. We therefore generate both cellular and mouse models of BRAFV600E mutant B-cell leukemia to study these aspects.The work presented here focuses on the evaluation of the pathomechanism of BRAFV600E in B-cell leukemias. Chapter one introduces the background of B-cell development, B-cell receptor (BCR) and MAPK signaling in B-cell malignancies, and MAPK signaling-mediated immune suppression in cancers. In addition, animal models of leukemia with MAPK activation and/or immune suppression are referred. Chapters two evaluates the pathologic effects of BRAFV600E in a CLL cell line, OSUCLL, using a doxycycline transduction manner. We found that transduction of BRAFV600E increases growth rate and enhances activation of OSUCLL cells. Moreover, it leads to changes in transcripts in OSUCLL cells including ABCB1 (aka p-glycoprotein), an ATP-dependent efflux pump and often mediated anti-cancer drug resistance. The mechanism of the ABCB1 induction is evidenced by inhibition of BRAFV600E and MEK kinases using pharmacological agents, and the key mediators are the activated MAPK pathway-induced AP-1 transcription factors. Chapter three introduces a novel mouse model of B-cell leukemia harboring the B-cell restricted BRAFV600E mutation. This new mouse model with B-cell specific BRAFV600E expression was characterized to shorten the leukemia onset and overall survival. The early B-cell development and the proliferation of leukemia B cells were not affected by this mutation. The reduction of B-cell apoptosis and mutant BRAF leukemia-enhanced immune suppression in the microenvironment contributed to the more aggressive disease seen in this B-cell leukemia mouse model. Chapter four concludes the findings, addresses the unanswered questions in this work, and proposes future perspectives, especially the applications of the new mouse model in future preclinical studies.Together, this work, for the first time, employs a transgenic mouse model of B-cell leukemia with B-cell lineage-restricted BRAFV600E expression and demonstrates the immune-suppressive impact of BRAFV600E in B-cell leukemias. Importantly, this mouse model can be utilized to develop rational combination strategies to both directly target the tumor cells and overcome tumor-mediated immune evasion.

Published
2017

39. 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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40. BRAFV600EInduces ABCB1/P-Glycoprotein Expression and Drug Resistance in B-Cells Via AP-1 Activation

Author

Tsai, Yo-Ting, Lozanski, Gerard, Lehman, Amy M., Sass, Ellen, Hertlein, Erin K., Salunke, Santosh, Chen, Ching-Shih, Grever, Michael R., Byrd, John C., and Lucas, David M.

Abstract

A subset of patients with chronic lymphocytic leukemia (CLL) and nearly all patients with classic hairy cell leukemia (HCL) harbor somatic BRAF activating mutations. However, the pathological role of activated BRAF in B-cell leukemia development and progression remains unclear. In addition, although HCL patients respond well to the BRAFV600E inhibitor vemurafenib, relapses are being observed, suggesting the development of drug resistance in patients with this mutation.

Published
2015
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