Washington University Specialized Program of Research Excellence (SPORE) in Leukemia
Washington University
Principal Investigator(s):
Daniel Link, MD
- Principal Investigator(s) Contact Information
- Overview
- Project 1: Molecular Determinants of Decitabine Responsiveness
- Project 2: Targeted Therapies for T Cell Acute Lymphoblastic Leukemia (T-ALL)
- Project 3: Novel Therapies for Splicesome-Mutant MDS
- Project 5: Memory-Like NK Cell Augmented Hematopoietic Cell Transplantation for AML
- Project 6: Bispeficic Antibody-Based Therapies for AML After Allogeneic Hematopoietic Stem Cell Transplantation
- Biospecimen Processing Core
- Biostatistics Core
- Administrative Core
- Developmental Research Program
- Career Enhancement Program
- Institutional SPORE Website
Principal Investigator(s) Contact Information
Daniel Link, MD
Alan A. and Edith L. Wolff Professor of Medicine
Washington University
729 Southwest Tower CB 8007
660 South Euclid Avenue
St. Louis, MO 63110
(314) 362-8771
Overview
The Washington University SPORE in Leukemia is a highly dynamic translational cancer research program that focuses specifically on leukemias and myelodysplastic syndromes. We have assembled an outstanding group of investigators with complementary expertise in basic and clinical leukemia research. In this SPORE, we leverage expertise in cancer genomics, immunology, and hematopoiesis to develop innovative translational research in leukemia. Our long-term goal is to develop novel biomarkers and treatments for leukemias and myelodysplastic syndromes and to develop and promote innovative translational leukemia research. To achieve these goals, the following specific aims are proposed.
Aim 1. We will exploit institutional expertise in cancer genomics, immunology, and hematopoiesis to develop novel biomarkers and treatments for leukemias and myelodysplastic syndromes. Basic research at WUSM has led to the development of the following five translational research projects, all featuring innovative investigator-initiated therapeutic trials for leukemias or MDS.
- Project 1. Molecular determinants of decitabine responsiveness
- Project 2. Targeted therapies for T cell acute lymphoblastic leukemia (T-ALL)
- Project 3. Novel therapies for splicesome-mutant MDS
- Project 5. Memory-like NK cell augmented hematopoietic cell transplantation for AML
- Project 6. Targeting AML using novel bispecific and antibody drug conjugates
Aim 2. We will enhance the infrastructure that supports translational leukemia research. This SPORE will support the following Shared Research Resources: 1) Core A. Biospecimen Processing; 2) Core B. Biostatistics; and 3) Core C. Administration.
Aim 3. We will recruit and train new investigators in translational research. This SPORE will support a Career Enhancement Program (CEP) to recruit and mentor new investigators in translational leukemia research. The SPORE has established a successful minority post-baccalaureate training program. The SPORE also will support a Developmental Research Program (DRP) to support innovative translational concepts.
Aim 4. We will facilitate inter-SPORE collaboration. Three of the SPORE projects include multi-institutional clinical trials. We have established CEP educational exchange and grant review programs with peer Leukemia SPORE institutions. We will continue to organize and participate in joint meetings with other Leukemia SPOREs.
Project 1: Molecular Determinants of Decitabine Responsiveness
Project Co-Leaders:
Timothy Ley, MD (Basic Co-Leader)
John Welch MD, PhD (Clinical Co-Leader)
The long-term goal of this project is to identify the patients with acute myeloid leukemia (AML) who are the most likely to respond to decitabine therapy, and to determine the molecular mechanisms of decitabine responses. TP53 mutated AML has the worst outcomes of all AML subgroups, with 1-year survival rates <20%. We recently reported that TP53 mutated AML and MDS patients respond consistently to decitabine, a hypomethylating agent that can be given as an outpatient. The molecular mechanisms associated with decitabine responses are currently unclear. To extend these findings, we conducted a clinical trial focused on AML patients with TP53 mutations, and with disease that is relapsed or refractory after cytotoxic induction therapy (NCT01687400). We also will explore the genomic and epigenomic signatures associated with decitabine responses, by performing whole-genome bisulfite sequencing (WGBS) and RNA-Seq on all patients (as shown below), to determine whether decitabine causes specific patterns of DNA hypomethylation, whether these changes result in consistent transcriptional signatures, and whether these patterns correlate with clinical outcomes.
Project 2: Targeted Therapies for T Cell Acute Lymphoblastic Leukemia (T-ALL)
Project Co-Leaders:
Daniel C. Link, MD (Basic Co-Leader)
Geoffrey Uy, MD (Clinical Co-Leader)
The long-term goal of this project is to develop novel targeted therapies for T-cell acute lymphoblastic leukemia (T-ALL). T-ALL is an aggressive hematologic malignancy that comprises 15% of pediatric ALL and 25% of adult-ALL. Current treatment consists of intense chemotherapy that is associated with acute and chronic life-threatening or debilitating toxicities. Five-year event-free survival is 70-75% for children, 30-40% for adults under 60, and less than 10% for adults over age 60. The prognosis after relapse is dismal, with 3-year event-free survival of only 10-15%. There is compelling evidence that increased MYC activity is central to the pathogenesis of most cases of T-ALL. Although MYC is a potent oncogene, it has an Achilles heel. In addition to providing a proliferative signal, MYC strongly induces apoptosis, in part, through an ARF/MDM2/TP53 pathway. In T-ALL this negative feedback loop is disrupted due to inactivating mutations of CDKN2A (encoding ARF). This project will explore the hypothesis that T-cell acute lymphoblastic leukemia (T-ALL) will be sensitive to drugs that interfere with MYC-survival signaling. This project includes a clinical trial of a novel CXCR4 antagonist (BL-8040) in combination with chemotherapy to treat patients with relapsed/refractory T-ALL (NCT02763384).
Project 3: Novel Therapies for Splicesome-Mutant MDS
Project Co-Leaders:
Timothy Graubert, MD (Basic Co-Leader)
Matthew Walter, MD (Clinical Co-Leader)
The long-term goal of this project is to develop novel mechanism-based therapies targeting myeloid malignancies with splicing factor mutations. We and others identified frequent, recurrent mutations in RNA splicing factors (e.g., U2AF1, SF3B1, SRSF2) in patients with myeloid malignancies, including myelodysplastic syndrome (MDS), acute myeloid leukemia (AML) and chronic myelomonocytic leukemia (CMML). The canonical hotspot mutations in U2AF1 (S34F), SF3B1 (K700E), or SRSF2 (P95H) alter RNA splicing. We recently reported that expression of mutant splicing factors or pharmacologic perturbation of splicing increase the abundance of R loops, which are structures containing DNA:RNA hybrids and displaced single-strand DNA. R loops trigger an ATR-dependent DNA damage checkpoint response that mediates resolution of the R loop to protect cells from genomic instability and cell death. Our preliminary data suggest that spliceosome mutant cells are more sensitive to ATR inhibition than wild-type cells. This project will explore the hypothesis that splicing factor mutations may create a vulnerability to ATR inhibition that can be exploited for the development of novel therapeutic strategies. It includes a clinical trial of an oral ATR inhibitor, AZD6728, in relapsed/refractory MDS (NCT03770429).
Project 5: Memory-Like NK Cell Augmented Hematopoietic Cell Transplantation for AML
Project Co-Leaders:
Todd Fehniger, MD, PhD (Basic Co-Leader)
Amanda Cashen, MD (Clinical Co-Leader)
The long-term goal of this project is to develop novel NK cell-based therapeutic strategies that will lead to clinical benefit for patients with leukemia. Hematopoietic cell transplantation was the first curative cellular immunotherapy for leukemia. These clinical remissions are achieved through immune response by the donor’s immune system, in particular, T cell and natural killer (NK) cells. The aim of this project is to test the ability of functionally-amplified donor NK cells, transferred into the patient, to eliminate leukemia. We identified a highly translatable strategy to induce memory-like natural killer (NK) cells using combined interleukin (IL)-12, IL-15, and IL-18 pre-activation, which results in multiple enhanced anti-leukemia properties. First-in-human phase 1 testing performed at Washington University demonstrated the safety, feasibility, and capability of memory-like NK cell therapy from an MHC-haploidentical donor to induce complete remissions in patients with relapsed or refractory acute myeloid leukemia (AML). Further, donor memory-like NK cells expanded in the patients, trafficked to the bone marrow, and exhibited potent anti-leukemia functions. However, since donor NK cells are foreign cells to the patient (allogeneic), they are eventually rejected by the patient’s immune system, resulting in only a brief 2- to 3-week window of opportunity for the NK cells to eliminate leukemia. To address this barrier of NK cell persistence, we hypothesized that augmenting MHC-haploidentical hematopoietic cell transplantation with same-donor memory-like NK cells would provide an ideal immune compatible environment that would allow for long term memory-like NK cell response. This Project tests this hypothesis in a phase 2 clinical trial of hematopoietic cell transplantation, followed within days by same-donor memory-like NK cell infusion for patients with AML not in remission (NCT02782546). The safety, feasibility, and ability to achieve remission and improve leukemia-free survival will be tested in this high-risk subset of AML patients. In addition, cutting-edge immunomonitoring will be used to track memory-like NK cells in patients, and discovery mechanisms of response and resistance to this immunotherapy. These studies will lead to new strategies to enhance NK cell anti-leukemia responses.
Project 6: Bispeficic Antibody-Based Therapies for AML After Allogeneic Hematopoietic Stem Cell Transplantation
Project Co-Leaders:
John F. DiPersio, MD, PhD (Basic Co-Leader)
Peter Westervelt, MD, PhD (Clinical Co-Leader)
Flotetuzumab is a CD123 x CD3 bispecific antibody designed to target CD123-positive cells for recognition and elimination by CD3-expressing T lymphocytes. Data from our early phase studies have shown that flotetuzumab is relatively well-tolerated, with the most common adverse event being cytokine release syndrome (CRS). We hypothesize that flotetuzumab for relapsed AML following allogenic hematopoietic cell transplantation (alloHCT) will be safe, tolerable and facilitate preferential T cell killing of leukemic cells, resulting in improved patient outcomes. Furthermore, administration of a donor lymphocyte infusion (DLI) in combination with flotetuzumab will be safe, tolerable and may provide additional therapeutic efficacy. Specific Aim 1: To conduct a Phase II clinical trial of flotetuzumab in patients with relapsed or refractory AML after alloHCT (NCT04582864). This is an open-label, single-arm, single-center Phase 2 study to evaluate for efficacy, safety and tolerability of flotetuzumab administered as a single agent and/or in combination with DLI in patients with relapsed AML post-alloHCT. Specific Aim 2: To determine the immunophenotype and transcriptional profiles of AML and T cells before and after treatment with of flotetuzumab. Specific Aim 3: To identify novel approaches to mitigate flotetuzumab-associated (CRS) while maintaining anti-leukemia activity using in vitro and in vivo preclinical models.
Project 6. CD123 x CD3 DART therapy to clear AML through both direct cytotoxic effects and by augmenting bystander immune responses through local cytokine production
Biospecimen Processing Core
Core Directors:
Peter Westervelt, MD, PhD (Director)
Mark Watson, MD, PhD (Co-Director)
The Biospecimen Processing Core (Core A) is responsible for the identification and enrollment of every patient referred to the Siteman Cancer Center with newly diagnosed and relapsed hematologic malignancy (excluding multiple myeloma). The pathologic material from these patients will be banked using the existing Siteman Cancer Center (SCC) Tissue Processing Core (TPC), and clinical data will be tracked prospectively in a clinical database.
Biostatistics Core
Core Directors:
Graham Colditz, MD, DrPH
The Biostatistics Core provides resources to assist in the planning, conduct and analysis of the proposed research in such a way that quantitative analyses are appropriate and illuminating. The Core also assists in the dissemination of appropriate information both within and external to the SPORE and the Siteman Cancer Center (SCC). The Core is staffed by a dedicated biostatistician for each of the 4 projects. In addition, a designated faculty member is devoted to collaborations concerning specialized bioinformatics issues. The Biostatistics Core will serve as a resource and collaborator for the four main projects proposed in this application, Career Development Program and Developmental Research Program projects and the SPORE Cores.
Administrative Core
Core Directors:
Daniel Link, MD
The Administration Core provides executive oversight and administrative support for all of the projects and cores that comprise the Leukemia SPORE. The goal of the Administration Core is to monitor the activities of all of the program components, to comply with all local and federal guideline for grant administration, and to facilitate communication and collaboration among the program members.
Developmental Research Program
Program Directors:
Daniel Link, MD (Director)
Laura Schuettpelz (Co-Director)
The goal of this program is to recruit and support developmental research projects in leukemia for future peer-reviewed funding and/or future independent SPORE projects. The types of studies to be supported include projects in basic research, clinical research, epidemiologic studies, and cancer prevention and control research in leukemia. Projects supported under the DRP will expand the scope of translational research and increase the number of investigators committed to leukemia research.
Career Enhancement Program
Program Directors:
Matthew Walter (Director)
Geoffrey Uy (Co-Director)
The goal of this program is to recruit and support new independent investigators in the field of translational leukemia research. To accomplish this objective, the CEP program will provide financial support, didactic training and mentored research for investigators to prepare them for independent careers in translational leukemia research. The proposed CEP program will also extend current efforts to promote diversity through the recruitment of women, minority and disabled faculty to the field of leukemia research