AML Stem Cell Heterogeneity: Implications for Gemtuzumab Ozogomicin-based Therapy

Summary

Principal Investigator: Roland Walter
Abstract: DESCRIPTION (provided by applicant): This candidate is committed to a career in clinical/translational research in the field of acute myeloid leukemia (AML). His long-term goal is to become an independent investigator capable of bringing bench research to the bedside, leading appropriate clinical trials, and then using the clinical information back in the laboratory to further unravel underlying biologic processes. Over the award period, he will develop his career by performing clinical research with the objective of science accomplishment and independence. He will complement his practical research training as Principal Investigator of clinical trials with formal coursework leading to a Master in Science degree in Clinical Research, conduct of correlative studies associated with his clinical trials, and participation in research- and ethics-related educational sessions while maintaining minimal but critical patient care responsibilities. During this critical stage of career development, the candidate will receive mentorship from Drs. F. Appelbaum and I. Bernstein, leading experts in clinical AML trials and leukemia stem cell (LSC) biology. In his proposal, the candidate seeks to develop novel therapies for AML, in particular for older adults. Specifically, he aims to improve the anti-AML efficacy of gemtuzumab ozogamicin (GO), an immunoconjugate between an anti-CD33 antibody and a toxic calicheamicin-31 derivative. Since GO has limited activity as single agent, novel pharmacological approaches are needed to improve its clinical efficacy. The candidate's preclinical studies demonstrated the quantitative importance of CD33 expression and drug efflux for GO efficacy. His studies further revealed an inverse maturation stage-dependent expression of CD33 and drug transporter proteins, an observation that provided the rationale for the use of cellular differentiation agents to enhance GO efficacy by increasing CD33 expression and drug uptake and/or reducing drug efflux. Indeed, his in vitro studies indicated that drugs that are under active clinical investigation to induce AML cell differentiation such as epigenetic therapeutics modulate these characteristics and lower the apoptotic threshold for GO toxicity. To test his hypothesis that these agents improve clinical GO efficacy, he proposes two clinical trials of GO in combination with epigenetic therapeutics in older adults with AML. He will then determine the factors associated with response to these GO-based regimens. The candidate predicts that beneficial outcome after GO-containing therapy is restricted to a subset of AML that predominantly involves more mature CD33+ progenitors. He therefore uses specimens from his trials to characterize leukemic progenitor and stem cells with regard to CD33 expression and to determine the association between maturation stage of these cells and susceptibility to GO. He also tests whether modulation of cellular characteristics of AML cells by epigenetic therapeutics associates with increased sensitivity to GO in vivo. Findings from his proposed studies may provide the rationale for further testing in randomized trials. Furthermore, his studies will identify patients with varying probabilities of response to GO-based therapy and thereby lead to optimized use of this targeted anti- AML agent through the ability of restricting treatment to patients with the greatest likelihood of response. PUBLIC HEALTH RELEVANCE: A novel approach to treat acute myeloid leukemia (AML), a blood cancer mainly seen in older people, uses an antibody called GO (a short term for gemtuzumab ozogamicin or Mylotarg") that recognizes leukemia cells and directs cell kill towards these cells while leaving most normal cells unaffected. As GO's effectiveness is limited when used alone, this application seeks to study GO in combination with other leukemia drugs with the ultimate goal of developing novel, more effective treatments for AML in older patients. Research will also be performed to find out which patients benefit most from these therapies and to see how these drug combinations precisely work together with GO to kill leukemia cells.
Funding Period: 2009-09-29 - 2012-08-31
more information: NIH RePORT

Top Publications

  1. pmc Effect of complete remission and responses less than complete remission on survival in acute myeloid leukemia: a combined Eastern Cooperative Oncology Group, Southwest Oncology Group, and M. D. Anderson Cancer Center Study
    Roland B Walter
    Clinical Research Division and Southwest Oncology Group Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA 98109 1024, USA
    J Clin Oncol 28:1766-71. 2010
  2. pmc Pretargeted radioimmunotherapy for hematologic and other malignancies
    Roland B Walter
    Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109 1024, USA
    Cancer Biother Radiopharm 25:125-42. 2010
  3. pmc Comparison of matched unrelated and matched related donor myeloablative hematopoietic cell transplantation for adults with acute myeloid leukemia in first remission
    R B Walter
    Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109 1024, USA
    Leukemia 24:1276-82. 2010

Scientific Experts

Detail Information

Publications3

  1. pmc Effect of complete remission and responses less than complete remission on survival in acute myeloid leukemia: a combined Eastern Cooperative Oncology Group, Southwest Oncology Group, and M. D. Anderson Cancer Center Study
    Roland B Walter
    Clinical Research Division and Southwest Oncology Group Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA 98109 1024, USA
    J Clin Oncol 28:1766-71. 2010
    ..Although the significance of CRp for survival remains unclear, reports of AML trials frequently combine CR with CRp rather than considering CR as a separate entity...
  2. pmc Pretargeted radioimmunotherapy for hematologic and other malignancies
    Roland B Walter
    Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109 1024, USA
    Cancer Biother Radiopharm 25:125-42. 2010
    ..With continued research, PRIT-based treatment strategies promise to become cornerstones to improved outcomes for cancer patients despite their complexities...
  3. pmc Comparison of matched unrelated and matched related donor myeloablative hematopoietic cell transplantation for adults with acute myeloid leukemia in first remission
    R B Walter
    Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109 1024, USA
    Leukemia 24:1276-82. 2010
    ..16 (0.52-2.61), P=0.71). These data indicate that URD HCT can provide long-term survival for CR1 AML; outcomes for 10/10 URD HCT, and possibly 9/10 URD HCT, suggest that this modality should be considered in the absence of a suitable MRD...