Adrian Wiestner, M.D., Ph.D.

I am leading the lymphoid malignancies section of the Hematology Branch, supported by the intramural research program of the NHLBI, NIH. As senior investigator on clinical trials and principal investigator of the laboratory program, I combine clinical and laboratory investigation that aim to improve treatment for patients with B-cell malignancies, in particular Chronic Lymphocytic Leukemia (CLL). I am pursuing three major goals: First, identify pathogenic mechanisms to assist the development of targeted therapy. Second, evaluate novel agents and treatment concepts in clinical trials and investigate resistance mechanisms through pharmacodynamic and genetic studies in patients enrolled on our clinical trials. Third, study the impact of treatment on immune function, response to vaccines, the interplay between the immune system and the progression of CLL, and how we can harness immune mechanisms to improve treatment.

1. Pathogenesis of Chronic Lymphocytic Leukemia (CLL)
Past research indicated a possible role for antigen in the pathogenesis of CLL and identified numerous interactions between tumor cells and the tissue microenvironment. I lead work in my group that identified the lymph node microenvironment as a key site of CLL cell activation through B-cell receptor and NF-ĸB signaling. These studies provide a framework for targeted therapy in CLL. Using heavy water labeling of proliferating CLL cells in patients we provided direct evidence that the lymph node is the site of tumor proliferation. Extending these observations we recently employed single cell sequencing to identify a distinct minor subpopulation of activated and proliferating CLL cells in the lymph node microenvironment that interface with the immune milieu, and promote disease progression. Using exome sequencing of matched samples from blood and lymph nodes, we found that clonal evolution primarily occurred in the lymph node and associated with a suppressed T-cell inflammatory response.

• Sun C, Chen YC, Martinez AZ, Baptista MJ, Pittaluga S, Liu D, Rosebrock D, Gohil SH, Saba NS, Davies-Hill T, Herman SEM, Getz G, Pirooznia M, Wu CJ, Wiestner A. The Immune Microenvironment Shapes Transcriptional and Genetic Heterogeneity in Chronic Lymphocytic Leukemia. Blood Adv. 2023 Jan 10;7(1):145-158. PMC9811214
• Dadashian EL, McAuley EM, Liu D, Shaffer AL 3rd, Young RM, Iyer JR, Kruhlak MJ, Staudt LM, Wiestner A*, Herman SEM*. TLR Signaling Is Activated in Lymph Node-Resident CLL Cells and Is Only Partially Inhibited by Ibrutinib. Cancer Res. 2019 Jan 15;79(2):360-371. PMC6342512.
• Herndon TM, Chen SS, Saba NS, Valdez J, Emson C, Gatmaitan M, Tian X, Hughes TE, Sun C, Arthur DC, Stetler-Stevenson M, Yuan CM, Niemann CU, Marti GE, Aue G, Soto S, Farooqui MZ, Herman SE, Chiorazzi N, Wiestner A. Direct in vivo evidence for increased proliferation of CLL cells in lymph nodes compared to bone marrow and peripheral blood. Leukemia. 2017 Jun;31(6):1340-1347. PMC5462849.
• Herishanu Y, Pérez-Galán P, Liu D, Biancotto A, Pittaluga S, Vire B, Gibellini F, Njuguna N, Lee E, Stennett L, Raghavachari N, Liu P, McCoy JP, Raffeld M, Stetler-Stevenson M, Yuan C, Sherry R, Arthur DC, Maric I, White T, Marti GE, Munson P, Wilson WH, Wiestner A. The lymph node microenvironment promotes B-cell receptor signaling, NF-kB activation, and tumor proliferation in chronic lymphocytic leukemia. Blood. 2011 Jan 13;117(2):563-74. PMC3031480.

2. Inhibitors of B-cell receptor signaling to treat CLL
I lead a clinical program investigating inhibitors of BCR signaling to treat CLL. We completed a phase II single center study with ibrutinib in CLL patients showing excellent tolerability and activity in elderly patients and in high-risk disease characterized by deletion of chromosomal arm 17p. We demonstrated to on-target effects of ibrutinib on BCR and NF-ĸB signaling in blood and lymph node in vivo, revealed the impact of ibrutinib on platelet aggregation, and identified improvements in both humoral and cellular immunity on treatment. Investigating mechanisms of resistance to ibrutinib, we identified mutations in BTK and PLCG2 in most patients with CLL progressing on ibrutinib, showed that these mutations are often detectable long before the diagnosis of clinical relapse, and identified emergence of multiple subclones carrying different mutations. Based on our study results, we developed and validated a prognostic model for patients being treated with BTK inhibitors. In our phase 2 study of acalabrutinib, a more BTK selective inhibitor than ibrutinib, we found that BID dosing maintains near complete occupancy of BTK in blood and tissues and more profoundly inhibits oncogenic signaling than QD dosing. We also measured the rate of BTK turnover and estimated the rate of BTK synthesis to be 15% per day, indicating complete reversal of target inhibition within a week of last dose of drug. Pre-pandemic we initiated studies investigating vaccine responses in patients treated with BTK inhibitors and showed a reduced rate of humoral and cellular immune responses in patients on treatment.

• Baptista MJ, Baskar S, Gaglione EM, Keyvanfar K, Ahn IE, Wiestner A, Sun C. Select Antitumor Cytotoxic CD8+ T Clonotypes Expand in Patients with Chronic Lymphocytic Leukemia Treated with Ibrutinib. Clin Cancer Res. 2021 Aug 15;27(16):4624-4633. PMID: 33875521; PMCID: PMC8364883.
• Pleyer C, Ali MA, Cohen JI, Tian X, Soto S, Ahn IE, Gaglione EM, Nierman P, Marti GE, Hesdorffer C, Lotter J, Superata J, Wiestner A*, Sun C. Effect of Bruton tyrosine kinase inhibitor on efficacy of adjuvanted recombinant hepatitis B and zoster vaccines. Blood. 2021 Jan 14;137(2):185-189. PMID: 33259596; PMCID: PMC7820878.
• Ahn IE, Tian X, Ipe D, Cheng M, Albitar M, Tsao LC, Zhang L, Ma W, Herman SEM, Gaglione EM, Soto S, Dean JP, Wiestner A. Prediction of Outcome in Patients With Chronic Lymphocytic Leukemia Treated With Ibrutinib: Development and Validation of a Four-Factor Prognostic Model. J Clin Oncol. 2021 Feb 20;39(6):576-585. PMID: 33026937.
• Ahn IE, Tian X, Wiestner A. Ibrutinib for Chronic Lymphocytic Leukemia with TP53 Alterations. N Engl J Med. 2020 Jul 30;383(5):498-500. PMID: 32726539; PMC7456330
• Sun C, Nierman P, Kendall EK, Cheung J, Gulrajani M, Herman SEM, Pleyer C, Ahn IE, Stetler-Stevenson M, Yuan C, Maric I, Gaglione EM, Harris HM, Pittaluga S, Wang MH, Patel P, Farooqui MZ, Izumi R, Hamdy A, Covey T, Wiestner A. Clinical and biological implications of target occupancy in CLL treated with the BTK inhibitor acalabrutinib. Blood. 2020 Mar 20. PMID: 32202637. PMC7332900
• Ahn IE, Farooqui MZH, Tian X, Valdez J, Sun C, Soto S, Lotter J, Housel S, Stetler-Stevenson M, Yuan CM, Maric I, Calvo KR, Nierman P, Hughes TE, Saba NS, Marti GE, Pittaluga S, Herman SEM, Niemann CU, Pedersen LB, Geisler CH, Childs R, Aue G, Wiestner A. Depth and durability of response to ibrutinib in CLL: 5-year follow-up of a phase II study. Blood. 2018 May 24;131(21):2357-2366. PMC5969380.
• Landau DA, Sun C, Rosebrock D, Herman SEM, Fein J, Sivina M, Underbayev C, Liu D, Hoellenriegel J, Ravichandran S, Farooqui MZH, Zhang W, Cibulskis C, Zviran A, Neuberg DS, Livitz D, Bozic I, Leshchiner I, Getz G, Burger JA, Wiestner A*, Wu CJ*. The evolutionary landscape of chronic lymphocytic leukemia treated with ibrutinib targeted therapy. Nat Commun. 2017 Dec 19;8(1):2185. PMC5736707.
• Ahn IE, Underbayev C, Albitar A, Herman SE, Tian X, Maric I, Arthur DC, Wake L, Pittaluga S, Yuan CM, Stetler-Stevenson M, Soto S, Valdez J, Nierman P, Lotter J, Xi L, Raffeld M, Farooqui M, Albitar M, Wiestner A. Clonal evolution leading to ibrutinib resistance in chronic lymphocytic leukemia. Blood. 2017 Mar 16;129(11):1469-1479. PMC5356450.
• Sun C, Tian X, Lee YS, Gunti S, Lipsky A, Herman SE, Salem D, Stetler-Stevenson M, Yuan C, Kardava L, Moir S, Maric I, Valdez J, Soto S, Marti GE, Farooqui MZ, Notkins AL, Wiestner A*, Aue G. Partial reconstitution of humoral immunity and fewer infections in patients with chronic lymphocytic leukemia treated with ibrutinib. Blood. 2015 Nov 5;126(19):2213-9. PMC4635117
• Herman SE, Mustafa RZ, Gyamfi JA, Pittaluga S, Chang S, Chang B, Farooqui M, Wiestner A. Ibrutinib inhibits B-cell receptor and NF-κB signaling and reduces tumor proliferation in tissue-resident cells of patients with chronic lymphocytic leukemia. Blood. 2014 Mar 22;123(21):3286-95. PMC4046423.

3. Immunotherapy and monoclonal antibodies for treatment of CLL
We initiated a clinical trial with the second generation, fully humanized anti-CD20 mAb ofatumumab, a more potent inducer of CDC than rituximab. In addition to loss of CD20 through trogocytosis following the administration of standard doses of ofatumumab similar to previous reports with rituximab, we also observed that the transient binding of ofatumumab was sufficient to opsonize all tumor cells with C3d. These observations led us to hypothesize that C3d constitutes a neoantigen that could be exploited to re-target cells that have escaped from anti-CD20 mAb therapy, an approach that we are currently pursuing further. Previous studies in CLL indicated that lenalidomide can repair defective T-cell function in vitro. We identified changes in the immune microenvironment in patients with CLL treated with single-agent lenalidomide and observed prominent T cell activation and Th1-type polarization in the lymph node of patients responding to treatment. Deep sequencing of T-cell receptor genes revealed an expansion of select clonotypes in responders. These data link lenalidomide induced Th1 immunity in the lymph with clinical response. To exploit overexpression of the IgM Fc-receptor on CLL cells for the selective delivery of cytotoxic therapy we engineered a Fcμ-drug conjugate that was selectively toxic for FcµR expressing cell lines and CLL cells but not autologous normal T cells in vitro and in patient derived xenografts in vivo, establishing the FcµR as a valuable therapeutic target in CLL. More recently, we focused on T-cell engaging bispecific antibodies (bsAb) targeting CD19 or CD20 on the surface of CLL cells. We found that BTK inhibitors, independent of ITK inhibition, downregulated immunosuppressive effectors in CLL cells and that bispecific antibody-induced cytotoxicity was enhanced in PBMCs from patients treated with BTKis. For the CD20xCD3 bsAb epcoritamab we showed that killing of CLL cells by autologous T cells correlated with effctor:target cell ratio, but not CD20 expression. Efficacy of epcoritamab was increased by concurrent use of a BTK inhibitor or venetoclax, supporting its combination with targeted therapy.

• Mhibik M, Gaglione EM, Eik D, Herrick J, Le J, Ahn IE, Chiu C, Wielgos-Bonvallet M, Hiemstra IH, Breij EC, Chen J, Reilly EB, Epling-Burnette PK, Szafer Glusman E, Sun C, Wiestner A. Cytotoxicity of the CD3xCD20 bispecific antibody epcoritamab in CLL is increased by concurrent BTK or Bcl-2 targeting. Blood Adv. 2023 May 23. Online ahead of print. PMID: 37219524
• Mhibik M, Gaglione EM, Eik D, Kendall EK, Blackburn A, Keyvanfar K, Baptista MJ, Ahn IE, Sun C, Qi J, Rader C, Wiestner A. BTK Inhibitors, Irrespective of ITK Inhibition, Increase Efficacy of a CD19/CD3 Bispecific Antibody in CLL. Blood. 2021 Nov 11;138(19):1843-1854.
• Robinson HR, Qi J, Cook EM, Nichols C, Dadashian EL, Underbayev C, Herman SEM, Saba NS, Keyvanfar K, Sun C, Ahn IE, Baskar S, Rader C, Wiestner A. A CD19/CD3bispecific antibody for effective immunotherapy of chronic lymphocytic leukemia in the ibrutinib era. Blood. 2018 Aug 2;132(5):521-532. PMC6073325.
• Aue G, Sun C, Liu D, Park JH, Pittaluga S, Tian X, Lee E, Soto S, Valdez J, Maric I, Stetler-Stevenson M, Yuan C, Nakamura Y, Muranski P, Wiestner A. Activation of Th1 Immunity within the Tumor Microenvironment Is Associated with Clinical Response to Lenalidomide in Chronic Lymphocytic Leukemia. J Immunol. 2018 Oct 1;201(7):1967-1974. PMC6143435.
• Vire B, Skarzynski M, Thomas JD, Nelson CG, David A, Aue G, Burke TR Jr, Rader C, Wiestner A. Harnessing the Fcμ receptor for potent and selective cytotoxic therapy of chronic lymphocytic leukemia. Cancer Res. 2014 Dec 15;74(24):7510-20. PMC4268434.
• Beursken F, Lindorfer M, Farooqui M, Beum P, Engelberts P, Mackus P, Parren P, Wiestner A, Taylor R. Exhaustion of cytotoxic effector systems may limit mAb-based immunotherapy in cancer patients. J. Immunol. 2012. Apr 1;188(7):3532-3541. PMC3311731.

Full list of published work: https://www.ncbi.nlm.nih.gov/myncbi/adrian.wiestner.1/bibliography/public/

Dr. Adrian Wiestner leads the Laboratory of Lymphoid Malignancies, Hematology Branch, National Heart, Lung, and Blood Institute, NIH. Dr. Wiestner earned his M.D. from the University of Basel Medical School in Switzerland in 1992, and a Ph.D. in genetics in 1998. He joined the NIH with the NHLBI Hematology Fellowship Program in 2000. In September 2004, Dr. Wiestner was appointed as a Tenure Track Investigator with the NHLBI Hematology Branch and was promoted to Senior Investigator in December 2013. As senior investigator on clinical trials and principal investigator of the laboratory program, he combines clinical and laboratory investigation that aim to improve treatment for patients with B-cell malignancies, in particular Chronic Lymphocytic Leukemia (CLL). He is pursuing three major goals: First, identify pathogenic mechanisms to assist the development of targeted therapy. Second, evaluate novel agents and treatment concepts in clinical trials. Third, investigate resistance mechanisms through pharmacodynamic and genetic studies in patients enrolled on our clinical trials.