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2016 in Review


The Experimental Hematology Laboratory at The Ohio State University Wexner Medical Center led by John C. Byrd, MD would like to sincerely thank you for your support of our research mission. We have accomplished many things that are having a direct impact on patient care, and we would like to share with you some highlights of 2016 as we get prepared for an even bigger and more impactful 2017.

Team Expansion: Our ever-growing research team is currently made up of 9 faculty researchers, 3 Clinical Research Fellows (MD), 9 postdoctoral fellows (PhD), 28 technicians, and 14 graduate students, as well as undergraduates and visiting students. We work to procure, process, and study thousands of samples that come directly from patients on experimental therapies not only at Ohio State, but from all over the country. While the main focus of our team remains on Chronic Lymphocytic Leukemia (CLL), we have been expanding and diversifying, and are excited to be studying acute myeloid leukemia, hairy cell leukemia, multiple myeloma, and sickle cell anemia.

New Clinical Trials: We are one of the main sites working on the Leukemia & Lymphoma Society “Beat AML” master trial. This is a new clinical trial model designed to speed up the testing of new treatments for acute myeloid leukemia. This study, led by the LLS, performs rapid turnaround genomic analysis on patients upon diagnosis. As soon as results are available, the patient is assigned to a specific drug regimen based on those results. The idea behind this strategy is that AML is a complex disease with many subtypes. This trial uses the individual patient’s genomic makeup to direct them to experimental treatments that have a higher likelihood of efficacy. We believe this new approach will accelerate the evaluation of new therapies and their transition to broader use. In addition to this, we are working on new trials to move away from chemotherapy whenever possible and to use targeted or immune drugs that lack serious side effects associated with older therapies used for this disease.  An example of this are the trials with entospletinib, an oral drug taken daily by patients which we have seen complete remissions even as monotherapy.  At this time we are working hard to decipher out who this drug works best in.  There are several other targeted agents to which our group will test as well and move the most promising ones forward to clinical trials. 

Scientific Presentations: The largest scientific meeting for hematology investigators is The American Society of Hematology (ASH) annual meeting. This year our combined team had 21 presentations (9 oral presentations and 12 poster presentations) on the disease types we currently study, the most we have ever had. Titles and authors of these presentations are listed at the end.   The Beat AML trial was featured at this meeting as well.   Five a year follow up studies of ibrutinib were presented where many patients remain well and in remission on this therapy.  In addition, patients on ibrutinib were shown to have a highly functional immune system as compared to patients treated with other CLL therapies.  The success of other agents such as venetoclax and MOR0028 in patients who have stopped responding to ibrutinib was also presented by members of OSU.  Finally, a more selective and potentially better BTK inhibitor acalabrutinib was presented and shown to be tolerated even when ibrutinib is not.  This is important because it provides an avenue for patients not tolerant of ibrutinib to receive another effective drug in this class.   Ibrutinib, acalabrutinib, and MOR0028 all were developed in the Experimental Hematology laboratory.

New Technology: One of the challenges of research in hematologic disease is to isolate live tumor cells away from other cell types in the blood so each cell type can be studied individually. Through generous investments in 2016 by both grateful patients and also the Division of Hematology, we were able to purchase an Aria Fusion cell sorter. This instrument uses lasers and small electrical pulses, first to detect different cell types labeled with fluorescent molecules (“tags”), then to physically pull these cells away from the others, intact. With different combinations of fluorescent tags, we will be able to physically separate out up to six different cell types from the same sample. Before we had this instrument we could observe the cells, but we could not study them in isolation. With this major advancement, we will be able to identify AND to isolate individual cell subsets to study if and how each contributes to tumor cell survival. The Aria cell sorter also allows us to separate out leukemia progenitor cells that could give us clues to how disease develops. In our current understanding, cancer arises from abnormal progenitor (or “stem”) cells - to cure leukemia, we need to understand how these cells function and what makes them abnormal. We can also use this technology to isolate cells that were not eliminated with treatment, to study why they are resistant and design therapies that are more effective. Renovations to our building are underway to accommodate the cell sorter, and we will be looking for a highly skilled technician in the next few months to run this sensitive machine. We are very much looking forward to putting it to use very soon. Another exciting technology that we have obtained in collaboration with the College of Pharmacy is a BioMek FXP automated work station which provides the capability to do high throughput drug screening. The most important aspect of this system is the ability to screen large libraries of compounds to identify existing therapies which can be repurposed to treat leukemia and lymphoma. Many compounds in these libraries are FDA approved and available for immediate clinical translation. This system can also be used to identify novel drug combinations, and explore the mechanism of action of new drugs in a very efficient manner. 

Animal Models: As we are beginning to expand our focus into new disease types, new mouse models of disease are being acquired or created right here at Ohio State. A study published from our lab recently forms the basis for clinical trials using drug coupled antibody therapy in CLL and lymphoma, which was accomplished using mice engineered to express human targets. This will facilitate the evaluation of patient directed therapies in the lab. Also, we are establishing patient derived xenograft (PDX) models of leukemia, which involves the transfer of patient samples and potential leukemia stem cells directly into immunocompromised mice to establish the disease in mice. These models are currently being used to understand how disease develops as well as test novel human directed therapies in mice. We have also recently acquired several new AML mouse models which represent common mutations that have been identified to drive human disease. Perhaps the greatest benefit of these mouse models is the fact that these mice have intact immune systems. This provides the ability to study not only the impact of the immune system on disease development, but also how the immune cells either contribute to or antagonize the efficacy of the novel therapeutic agents.[HE1] [GA2]    In addition to our mouse models, we have active collaboration with the school of veterinary medicine studying spontaneous dog lymphoma in companion pets.   Dogs that develop lymphoma are enrolled in clinical trials with agents tested in the laboratory.   This provides an outstanding way to screen compounds to determine their potential promise for helping patients.  Drugs that work in dog lymphoma almost always work in humans.  As our goal is to avoid bringing ineffective drugs forward to the clinic, the canine model provides another helpful tool to select the best candidate therapies.

Research Published: An upcoming publication in the Journal of Clinical Oncology will demonstrate a direct impact on patient care that our group developed this past year. Our team was able to show that by testing for BTK gene mutations in residual tumor cells from patients receiving Ibrutinib, we could predict Ibrutinib relapse well before the patient showed any signs or symptoms. This allows a much greater time window to identify and implement alternatives, saving a great deal of stress and uncertainty.

Separately, our group published a study concept using an engineered antibody for AML treatment. This work, published in the hematology journal ‘Blood’, has transitioned to a first-in-human clinical trial at OSU.  This antibody is also being tested in the Beat AML trial.  Other publications from the group include studies of new leukemia treatments such as the second-generation BTK inhibitor Acalabrutinib and a new experimental inhibitor of nuclear export. Our group is also very interested in the effects of cancer and cancer treatments on the immune system and published several articles on this important topic as well. Overall, we are to prioritizing projects we believe will have the maximum benefit for patients and continue to work hard on each of these areas.   This work would not be possible had it not been for the continued investment of patients and their families in our work through providing blood tumor cells, participating in trials and providing resources for our work

Thanks again to each of your for the difference you make!

 

Sincerely,

The entire Experimental Hematology Laboratory team

 

 

American Society of Hematology Annual Meeting, 2016

Poster presentations:

Jennifer A. Woyach, Peter Hillmen, Jennifer R. Brown, Steven E. Coutre, Paul M. Barr, Susan M. O'Brien, Jacqueline C. Barrientos, Stephen Devereux, Neil E. Kay, Nishitha Reddy, Stephen Mulligan, Alessandra Tedeschi, Cathy Zhou, Joi Ninomoto, Danelle F. James, John C. Byrd, and Jan Burger. “Outcomes of Ibrutinib Therapy by Age in Patients with CLL/SLL: Analyses from Phase 3 Trial Data (RESONATE and RESONATE-2)”

Tracy E Wiczer, Lauren B Levine, Jessica Brumbaugh, Jessica Coggins, Qiuhong Zhao, Amy S. Ruppert, Anli McCoy, Kami J. Maddocks, Beth A Christian, Kerry A. Rogers, Leslie Andritsos, Samantha Jaglowski, Steven M Devine, Pierluigi Porcu, Jennifer A. Woyach, Jeffrey Jones, Michael R. Grever, John C. Byrd, and Farrukh T. Awan. “Management and Outcomes of Atrial Fibrillation in Patients Receiving Ibrutinib for Hematologic Malignancies at a Single Center”

Cecelia R. Miller, Amy S. Ruppert, Nyla A. Heerema, Kami J. Maddocks, Jadwiga Labanowska, Heather Breidenbach, Gerard Lozanski, Weiqiang Zhao, Amber Gordon, Jeffrey Jones, Joseph M. Flynn, Samantha Jaglowski, Leslie A. Andritsos, Farrukh T. Awan, Kristie A. Blum, Michael R. Grever, Amy J. Johnson, Lynne V. Abruzzo, Erin K. Hertlein, Jennifer A. Woyach, and John C. Byrd. “Near-Tetraploidy Is Strongly Associated with Development of Richter’s Transformation in Chronic Lymphocytic Leukemia Patients Receiving Ibrutinib”

Priscilla Do, Kyle A. Beckwith, Larry Beaver, Brittany G. Griffin, Xiaokui Mo, Jeffrey Jones, Erin K. Hertlein, Natarajan Muthusamy, John C. Byrd. “Leukemic Cell Expressed CTLA-4 Suppresses T Cells via Down-Modulation of CD80 by Trans-Endocytosis”

Jeffrey P. Sharman, Andrei R. Shustov, Mitchell Smith, Christopher T. Hagenstad, Kathryn S. Kolibaba, Esteban Abella-Dominicis, Danjie Zhang, Siddhartha Mitra, Christopher A. Yasenchak and Farrukh T. Awan. “Updated Results on the Clinical Activity of Entospletinib (GS-9973), a Selective Syk Inhibitor, in Patients with CLL Previously Treated with an Inhibitor of the B-Cell Receptor Signaling Pathway”

Sean D. Reiff, Rose Mantel, Lisa L. Smith, Samantha McWhorter, Virginia M. Goettl, Amy J. Johnson, Sudharsan Eathiraj, Giovanni Abbadessa, Brian Schwartz, John C. Byrd, Jennifer A. Woyach. “The Bruton’s Tyrosine Kinase Inhibitor ARQ 531 Effectively Inhibits Wild Type and C481S Mutant BTK and Is Superior to Ibrutinib in a Mouse Model of Chronic Lymphocytic Leukemia”

Meixiao Long, Kyle A. Beckwith, Priscilla Do, Mundy L Bethany, Amy M. Lehman, Kami J. Maddocks, Carolyn Cheney, Jeffrey Jones, Leslie A. Andritsos, Farrukh T. Awan, Joseph A. Fraietta, Carl H June, Marcela V. Maus, Jennifer A. Woyach, Michael A. Caligiuri, Amy J. Johnson, Natarajan Muthusamy, John C. Byrd. “Ibrutinib Represents a Novel Class of Immune Modulating Therapeutics That Enhances the Survival of Activated T Cells in Vitro and In Vivo through a Non-BTK Mediated Mechanism”

Nicole R. Grieselhuber, Shaneice R. Mitchell, Shelley Orwick, Bonnie K. Harrington, Virginia M. Goettl, Alison R. Walker, Bhavana Bhatnagar, Alice S. Mims, Rebecca B. Klisovic, Sumithra Vasu, William Blum, James S. Blachly, David M. Lucas, Ramiro Garzon, Rosa Lapalombella, John C. Byrd. “The Novel BET Inhibitor PLX51107 Has In Vitro and In Vivo Activity against Acute Myeloid Leukemia”

Kerry A. Rogers, Amy M. Lehman, Carolyn Cheney, Virginia M. Goettl, Rose Mantel, Lisa L. Smith, Minh Tran, Amy J. Johnson, John C. Byrd, Jennifer A. Woyach. “Inhibitors of Bruton's Tyrosine Kinase Reduce Anti-Red Blood Cell Response in a Murine Model of Autoimmune Hemolytic Anemia”

Swagata Goswami, Rajeswaran Mani, Chi-Ling Chiang, Frank W Frissora, Xiaokui Mo, Zhiliang Xie, Donna Bucci, Amber Gordon, David M. Lucas, William Blum, Alison R. Walker, Alice S. Mims, Rebecca B Klisovic, Ching-Shih Chen, Robert J Lee, John C. Byrd, Mitch A. Phelps, Sumithira Vasu, Natarajan Muthusamy. “CD33 Targeted Immunoliposomal Delivery of OSU-2S, a Non-Immunosuppressive FTY720 Derivative, Mediates Selective Cytotoxicity in Acute Myeloid Leukemia”

Nyla A. Heerema, Qiuhong Zhao, Amy S. Ruppert, Heather Breidenbach, Jeffrey Jones, Leslie A. Andritsos, Jennifer A. Woyach, Farrukh T. Awan, Meixiao Long, Amber Gordon, Caitlin Coombes, John C. Byrd, Natarajan Muthusamy. “Presence of a Translocation Is Associated with Short Time to Treatment from Diagnosis in IGHV Mutated Chronic Lymphocytic Leukemia (CLL) Patients”

Deborah M Stephens, Kyle A. Beckwith, Priscilla Do, Carolyn Cheney, Xiaokui Mo, Karilyn Larkin, Jeffrey Jones, Farrukh T. Awan, Laura Grosmaire, Randy Jones, Julie DiPaolo, Stacey Tannheimer, Karl-Heinz Heider, John C. Byrd, Natarajan Muthusamy. “BI 836826, a Novel Fc-Engineered Antibody in Combination with Phosphoinositide-3-Kinase Inhibitor for Treatment of High Risk Chronic Lymphocytic Leukemia and Lymphoma”

 

Oral Presentations:

Brian Giacopelli, Amy S. Ruppert, Yue-Zhong Wu, Laura Z. Rassenti, William G. Wierda, Kanti R Rai, Neil E. Kay, Jennifer R. Brown, Thomas J. Kipps, John C. Byrd, Christopher C Oakes. “Comparative Evaluation of Prognostic Factors That Assess the Natural History of Chronic Lymphocytic Leukemia”

Zachary A. Hing, James S. Blachly, Virginia M. Goettl, Guramrit Singh, John C. Byrd, Rosa Lapalombella. “Exploring the Role of the Recurrent Exportin 1 (XPO1/CRM1) Mutations E571G and E571K in Chronic Lymphocytic Leukemia”

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

Rajeswaran Mani, Swagata Goswami, Bhavani Gopalakrishnan, Rahul Ramaswamy, Ronni Wasmuth, Minh Tran, Xiaokui Mo, Amber Gordon, Donna Bucci, David Lucas, Christopher L. Brooks, Alison R. Walker, William Blum, John C. Byrd, Gerard Lozanski, Sumithra Vasu, Natarajan Muthusamy. “SL-401 Mediates Potent Cytotoxicity against CD123+ AML and MDS with Excess Blasts and Demonstrates Therapeutic Benefit in PDX Model”

Yo-Ting Tsai, Aparna Lakshmanan, Amy M. Lehman, Ellen J. Sass, Minh Tran, Fabienne McClanahan, Meixiao Long, Bonnie K. Harrington, Krista La Perle, Vincenzo Coppola, Gerard Lozanski, Natarajan Muthusamy, John C. Byrd, Michael R. Grever, David M. Lucas. “BRAFV600E Accelerates Disease Progression and Increases Immune Suppression in a Mouse Model of B-Cell Leukemia”

Jennifer A. Woyach, Daphne Guinn, Amy S. Ruppert, James S. Blachly, Arletta Lozanski, Nyla A. Heerema, Weiqiang Zhao, Joshua Coleman, Daniel Jones, Lynne V. Abruzzo, Amber Gordon, Rose Mantel, Lisa L. Smith, Samantha McWhorter, Melanie Davis, Tzyy-Jye Doong, Fan Ny, Margaret S. Lucas, Weihong Chase, Jeffrey Jones, Joseph M. Flynn, Kami J. Maddocks, Samantha Jaglowski, Leslie A. Andritsos, Farrukh T. Awan, Kristie Blum, Michael R. Grever, Gerard Lozanski, John C. Byrd, Amy J. Johnson. “The Development and Expansion of Resistant Subclones Precedes Relapse during Ibrutinib Therapy in Patients with CLL”

Farrukh T. Awan, Anna Schuh, Jennifer R. Brown, Richard R. Furman, John M. Pagel, Peter Hillmen, Deborah M. Stephens, Ahmed Hamdy, Jane Huang, Raquel Izumi, Priti Patel, Min Hui Wang, John C. Byrd. “Acalabrutinib Monotherapy in Patients with Ibrutinib Intolerance: Results from the Phase 1/2 ACE-CL-001 Clinical Study”

Jeffrey A. Jones, Jennifer Woyach, Farrukh T. Awan, Kami J. Maddocks, Thomas Whitlow, Amy Ruppert, John C. Byrd. “Phase 1b Results of a Phase 1b/2 Study of Obinutuzmab, Ibrutinib, and Venetoclax in Relapsed/ Refractory Chronic Lymphocytic Leukemia”

 


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