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Last Updated: 08/15/19

University of Texas/MD Anderson Cancer Center Leukemia SPORE

Principal Investigators:
Marina Konopleva, MD, PhD
Jean-Pierre Issa, MD


Marina Konopleva, MD, PhD
Department of Leukemia
Division of Cancer Medicine
University of Texas M.D. Anderson Cancer Center
1515 Holcombe Blvd Unit 0428
Houston, TX 770304009
Phone: 713-794-1628

Jean-Pierre Issa, MD
Coriell Institute for Medical Research
403 Haddon Ave
Camden, NJ 08103
Phone: 856-757-4821


MD Anderson Cancer Center’s Specialized Program of Research Excellence (SPORE) in Leukemia aims to develop novel biomarkers and treatments for leukemias and myelodysplastic syndromes. In this SPORE, we expand on several areas of successful research in the previous funding period, and explore novel biologic and therapeutic ideas that have emerged recently. Our goal remains to discover new therapies and actionable targets in leukemia.

Our SPORE includes four major translational research projects.
Project 1: New epigenetic therapy targets
Project 2: Anti-PR1 Immune Therapy for Myeloid Leukemia
Project 4: Off-the-shelf engineered cord blood-derived natural killer cells for the treatment acute leukemia
Project 5: Targeting Oxidative Phosphorylation in AML

These projects are supported by three shared resources: Core 1. Administrative Core; Core 2. Pathology & Tissue; and Core 3. Biostatistics, Data Management & Bioinformatics. This SPORE also supports a Career Enhancement Program to recruit and mentor new investigators in translational leukemia research and a Developmental Research Program to support innovative translational concepts.

New epigenetic therapy targets

Basic Science Co-Leader: Jean-Pierre Issa, MD
Clinical Science Co-Leader: Hagop Kantarjian, MD

Epigenetic therapy aims to reprogram gene expression in cancer cells to achieve a therapeutic effect. To date, DNMT inhibition is the most effective form of epigenetic therapy in myeloid leukemias. Through SPORE funding, Project 1 investigators developed (and validated) a live cell assay to screen for drugs that achieve the same degree of epigenetic reprogramming as DNMTi. Using this screen, they discovered a new class of epigenetic drugs that activate silenced expression through inhibition of CDK9. CDK9 is a transcriptional regulator previously linked to gene activation through the pTEFb complex that phosphorylates RNAPII and promotes elongation. The new data place CDK9 at the heart of a node that regulates both gene silencing and activation. As such, targeting CDK9 has pleotropic effects on gene expression that appear ideal from an anti-tumor perspective: One observes simultaneous gene activation (of tumor suppressors), repression (of oncogenes), and induction of an interferon response which may be immune-sensitizing.

Known CDK9 inhibitors (flavopiridol, SNS-032) have activity in leukemias but are marred by serious chemotherapy like toxicities. Examining published PK/PD data, the investigators found that doses in use clinically were at least an order of magnitude higher than what is needed to inhibit CDK9, and speculate that the toxicity observed is typical of cross-target inhibition of CDK1/2. Thus, much lower doses of CDK9 inhibitors may preserve activity (through epigenetic effects of CDK9 inhibition) while reducing toxicity (by avoiding other CDKs). This is similar to the development of decitabine where switching from cytotoxic doses (abandoned in the 1980s because of severe delayed and unpredictable myelosuppression) to low “epigenetic” doses (100 mg/m2/ course versus 1,000-2,0000 mg/m2/course) uncovered its remarkable activity in AML and MDS. By analogy, Project 1 investigators hypothesize that low doses of CDK9 selective drugs may preserve activity (through epigenetic effects of CDK9 inhibition) while reducing toxicity (by avoiding other CDKs). In this SPORE renewal, Project 1 investigators will elucidate the mechanism of epigenetic effects of CDK9, determine the downstream effects of CDK9 inhibition on cellular function and immune responses, and conduct a clinical trial of a newly developed CDK9 selective drug in myeloid leukemias.

Specific Aim 1. Elucidate the mechanisms of CDK9 mediated epigenetic silencing effects

Translational goal. Clarify the contribution of CDK9 inhibition to the potential of improving epigenetic therapy; this can be readily exploited as a novel therapy in clinical trials in leukemia and MDS

Specific Aim 2. Study the functional consequences of CDK9 inhibition alone and in combination with DNMT3A inhibition

Translational goal. Develop rational strategies and new combinations involving CDK9 inhibition, in preparation for clinical trials of a novel, CDK9 selective drug.

Specific Aim 3. Pre-clinical and early clinical studies of MC180295, a new selective CDK9 inhibitor.

Translational goal. Perform IND enabling studies to introduce a new CDK9 selective drug into clinical trials, and bring this drug to a first-in-human trial using dual endpoints of MTD and biologically optimal dose, as done for hypomethylating drugs.

Anti-PR1 Immune Therapy for Myeloid Leukemia

Basic Science Co-Leader: Jeffrey Molldrem, MD
Clinical Science Co-Leader: Richard Champlin, MD

The long-term goal of Project 2 is to develop immune therapies that target aberrantly expressed proteases in blasts and leukemia stem cells. The investigators identified a T cell receptor (TCR)-like antibody (8F4) with specificity for a conformational epitope of PR1 (VLQELNVTV), a peptide derived from leukemia-associated protease antigens (LAAs) P3 and NE, that are bound to HLA-A2. 8F4 induces complement-dependent cytolysis (CDC) of AML and leukemia stem cells (LSC) and inhibits AML progenitor cell growth but not normal bone marrow progenitors, which supports further study of 8F4 as a potential therapeutic monoclonal antibody for AML. The preliminary data generated by Project 2 investigators showed that 8F4 prevented AML engraftment in vivo, and that humanized 8F4 eliminated established human AML in a xenogeneic animal model. Thus, 8F4 is the first TCR-like monoclonal antibody that inhibits growth of AML and LSC and eliminates AML in vivo. In the previous Leukemia SPORE period, Project 2 investigators have characterized the activity of 8F4 against human AML, performed pre-clinical treatment validation studies of 8F4, and secured cGMP material of 8F4 monoclonal antibody for phase I clinical trials, in collaboration with the drug industry (Astellas). Thus, the work in this project supports the overall goal of the SPORE grant to discover, develop and clinically test novel therapies for leukemia.

While studies of 8F4 appear promising, a significant reduction of LSC required prolonged treatment with 8F4 in PDX-bearing mice. Antibodies for the treatment of cancer, including leukemia, have limited effectiveness as single agents. Also, additional studies in PDX models showed that 8F4 treatment of some primary AML resulted in the growth of a population of blasts with low PR1 expression but without changes in overall HLA-A2 expression. This potential mechanism of 8F4 resistance or escape suggests that increasing the potency of 8F4-based therapy will be important for its successful clinical application. In the current proposal, the investigators seek to characterize the mechanism of PR1 down-regulation on AML after 8F4 treatment, and to explore alternative approaches to increase the potency of 8F4, based on established treatment strategies that have demonstrated significant clinical activity as single agents in patients with CD19+ leukemia, (e.g. treatment with CD19xCD3 bispecific antibody blinatumomab; CD19 CAR T cells). The hypothesis is that AML will be more effectively eliminated by redirecting polyclonal T cells to target PR1/HLA-A2 through modifying T cells with an 8F4-CAR or with treatment using an 8F4xCD3 bispecific antibody. To test this hypothesis, they propose the following Specific Aims:

Aim 1. Conduct a first-in-human Phase I clinical trial of 8F4 in HLA-A2+ refractory/relapsed AML

Translational goal. Evaluate the safety and potential efficacy of h8F4 therapy in AML. If successful, expand this investigation into phase II-III pivotal clinical trial as indicated by the efficacy-toxicity and translational results on serial samples evaluating response-resistance mechanisms.

Aim 2. Characterize AML blasts and leukemic stem cells in patients treated with 8F4.

Translational goal. Evaluate mechanisms of resistance on 8F4 therapy to decide whether such mechanisms can be potentially circumvented with new forms of 8F4 targeted therapies (bispecific monoclonal antibody constructs; CART cellular therapy targeting 8F4).

Aim 3. Characterize mechanisms of PR1 cross-presentation, and characterize alternative treatment approaches to address resistance to 8F4 treatment.

SubAim 3A. Characterize mechanism of PR1 down-regulation after 8F4 treatment.

SubAim 3B. Study the preclinical activity of 8F4-CAR T cells on AML.

SubAim 3C. Conduct pre-clinical validation and safety studies of 8F4-CAR T cells in animal models.

Translational goal. Develop alternative forms of 8F4 targeting therapies that can overcome potential mechanisms of resistance to h8F4 monoclonal antibody therapy, in order to move them into clinical trials as indicated by the developing results.

Off-the-shelf engineered cord blood-derived natural killer cells for the treatment acute leukemia

Basic Science Co-Leader: Katy Rezvani, MD, PhD
Clinical Science Co-Leader: Elizabeth Shpall, MD

Adoptive cell therapy has emerged as a powerful treatment modality for advanced cancers refractory to conventional therapy. Remarkable responses have been achieved in patients receiving autologous CD19-redirected T cells for the treatment of acute lymphoblastic leukemia (ALL) and other B lymphoid malignancies. CAR-modified T-cells have limitations: 1) The generation of autologous products for individual patients is logistically cumbersome and restrictive for widespread clinical use 2) The manufacturing of CAR T-cells often takes several weeks, making it impractical for patients with rapidly advancing disease. 3) It is not always possible to generate clinically relevant doses of CAR T-cells from heavily pre-treated patients.

A previously collected allogeneic product could overcome these limitations; but allogeneic T-cells (even if HLA-matched) carry the risk of graft-versus-host disease (GVHD), mediated through native aΒ T-cell receptor. Natural killer (NK) cells provide an attractive alternative to T cells for CAR engineering. Functional NK cells can be derived from several sources. Autologous NK cells can be reproducibly generated in vitro, but have limited activity against autologous tumors, which is unlikely to be overcome by CAR engineering. Cord blood (CB) is a readily available source of allogeneic NK cells with clear advantages. CB is available as an off-the-shelf frozen product, an advantage bolstered by methods to generate large numbers of highly functional NK cells from frozen CB units ex vivo. This holds promise for widespread scalability that cannot be replicated with individual adult donors who require screening and leukapheresis. One disadvantage of NK cells is their lack of persistence after adoptive transfer in the absence of cytokine support. Although CAR-engineered NK cells may improve their persistence, they may also exert potentially serious toxicity, such as cytokine release syndrome (CRS) or off-tumor/on-target toxicity, as reported with CAR T-cells.

The long-term objective of Project 4 research is to develop novel cell-based therapies using CB-derived NK cells, and to enhance their effector function against ALL by genetically engineering them to redefine their specificity and enhance their potency and safety. Project 4 investigators have developed a novel strategy to redirect the specificity of CB-derived NK cells to target CD19+ malignancies by genetically modifying them with a retroviral vector (iC9-2A-CD19.CAR-CD3zeta-2A-IL-15) that; 1) incorporates the gene for CAR.19 to redirect their specificity; 2) ectopically produces IL-15, to support their survival and proliferation; and 3) expresses a suicide gene, inducible caspase-9 (iC9), that can be pharmacologically activated to eliminate transduced cells. Using this approach, they showed that engineered CB-derived NK cells exhibited striking efficacy, and proliferated and persisted in vivo. They can also be efficiently eliminated to limit toxicity. These pre-clinical data provide the rationale to take this approach to the clinic.

Based on these data, the investigators hypothesize that the antileukemic activity of NK cells against ALL can be enhanced by engineering them to express a CAR against CD19 and by protecting them from the immunosuppressive cytokine TGF-beta. To test the hypothesis, they propose the following Specific Aims:

Specific Aim 1. Test the safety and anti-leukemic efficacy of CB-NK cells engineered to express CAR.CD19 to redirect their specificity, IL-15 to enhance their in vivo persistence and a suicide gene based on iC9 as a safety measure.

Translational goal. Obtain clinical toxicity and efficacy results to guide further development and expansion of this novel NK-CAR cellular therapy.

Specific Aim 2. Trace the fate of genetically modified CB-derived NK cells after adoptive transfer and study their expansion and reconstitution in vivo.

Translational goal. Validate the long-term viability, efficacy and safety of the transferred NK-CAR cells.

Specific Aim 3. Determine if a novel CAR construct based on iC9-2A-CAR19-zeta-2A-IL15 that also includes the dominant-negative TGF-Β type II can protect NK cells from the TGF-Β rich immunosuppressive tumor microenvironment.

Translational goal. Establish if targeting the TGF-Β/SMAD signaling axis using a novel retroviral construct that, in addition to CAR.CD19 and IL-15, includes the gene for the dominant-negative version of human TGFΒ receptor II (TGFΒ-DNRII), can protect the transduced NK cells from the immunosuppressive tumor microenvironment for next-generation clinical studies.

Targeting Oxidative Phosphorylation in AML

Basic Science Co-Leader: Giulio Draetta, MD, PhD
Clinical Science Co-Leader: Marina Konopleva, MD, PhD

Metabolic reprogramming of the key energy-generating pathways is one of the key oncogenic properties of cancer, including leukemia. While accelerated glycolysis is considered to be most common feature of tumors, the SPORE Project 5 investigators and others have shown that AML cells are unique in their mitochondrial characteristics and have an increased reliance on oxidative phosphorylation (OxPhos). Unlike normal cells, AML cells, including leukemia-initiating cells, overexpress anti-apoptotic BCL-2 protein and are unable to upregulate glycolysis sufficiently after OxPhos is inhibited due to a low spare reserve capacity. This unique metabolic and mitochondrial biology makes AML vulnerable to strategies that target OxPhos and BCL-2. Inhibition of cellular respiration with IACS-010759, a novel inhibitor of OxPhos identified in-house in collaboration with the Institute of Advanced Cancer Science (IACS)/MD Anderson, causes a metabolic catastrophe in AML subsets and induces profound growth-inhibitory effects in primary CD34+ AML cells, with minimal toxicity against normal bone marrow (BM) cells. Preliminary data by Project 5 investigators further indicate that resistance to BCL-2 inhibition is associated with altered OxPhos, and that a combination of OxPhos inhibitors and the BCL-2 inhibitor venetoclax is synergistic in parental and in venetoclax-resistant cells. In orthotopic xenografts of primary AML cells, daily dosing with IACS-010759 delayed disease progression, suppressed OxPhos and inhibited hypoxia. A first-in-human Phase I clinical trial of IACS-010759 in AML is ongoing at MD Anderson (PI-Konopleva), and preliminary pharmaco-dynamic studies indicate reduction of oxygen consumption consistent with on-target activity. In this proposal, the investigators will leverage the expertise of the drug discovery unit at MD Anderson with the PI’s extensive focus on tumor metabolism and experience with in-depth analyses of primary patients-derived AML tumors using a battery of cellular, biochemical and genetic methodologies. They will establish combinations of the OxPhos inhibitor with standard chemotherapy and with the BCL-2 inhibitor, venetoclax. The central hypothesis is that key metabolic dependencies of the leukemia and leukemia-initiating cells, such as oxidative phosphorylation, affect leukemia survival and chemosensitivity; and that combined blockade of mitochondrial respiration by OxPhos and BCL-2 inhibitors will eliminate leukemia-initiating cells and enhance anti-leukemic efficacy. To test the hypothesis they propose the following Specific Aims:

Specific Aim 1. Characterize molecular subsets of AML that depend on OxPhos for survival, and examine the combined efficacy of IACS-010759 with BCL-2 inhibitor venetoclax.

Translational goal. To examine sensitivity and RNA signatures of the genomically defined AML subsets (primary AML samples in vitro), and investigate molecular mechanisms of synergy between OxPhos inhibition and BCL-2 blockade

Specific Aim 2. Investigate whether residual AML cells surviving standard chemotherapy or BCL-2 inhibition require OxPhos, and test the impact of IACS-010759 on the residual cells in the in vivo AML PDX models.

Translational Goal. Based on pre-clinical data, optimize the sequential administration of a combination of OxPhos and BCL-2 inhibition or standard chemotherapy, and characterize biomarkers of response, with the goal of the translation into Phase I clinical trials.

Specific Aim 3. Conduct a Phase 1/2 Study of standard chemotherapy and of BCL-2 inhibitor Venetoclax combined with IACS-010759 in patients with salvage 1 or 2 AML.

Translational Goal. The study will pave the way for the future phase II and phase III pivotal combination clinical trials with IACS-010759, with the goal to improve survival in AML.

Administrative Core

The Administrative Core provides leadership and administrative support for all SPORE-related activities, including Projects, Cores, and the SPORE Career Enhancement and Developmental Research Programs (CEP and DRP, respectively). The Administrative Core accommodates the complex interdisciplinary nature of the SPORE and integration between the two participating institutions (MDACC and Temple University/Fox Chase Cancer Center). This Core provides essential, centralized administration to integrate the needs of and synergize research potential among investigators representing various scientific disciplines and focused on research in hematologic malignancies. It oversees the conduct of proposed research and provides core services for a unified translational leukemia research program. Responsibilities of this Core include: planning for and monitoring scientific activities; evaluating future science directions for the SPORE, ensuring emphasis on translational research; and facilitating interdisciplinary and inter-project integration, including assistance in the establishment of collaborations with other SPOREs and other major leukemia programs. The Administrative Core will also coordinate activities associated with clinical trials including, but not limited to, protocol design and submission, approval by regulatory bodies, prioritization, implementation, and conduct of studies, identification of eligible patients and development and submission of required regulatory reports. The Administrative Core assumes overall fiscal responsibility for the SPORE, including the employment of key personnel to deliver cost-effective and efficient use of resources, and cost-sharing with other available resources when appropriate. This Core prepares all required reports and assurances for compliance with governmental regulations and requirements, and provides timely communications, consultations, and meeting coordination within the SPORE, and preparation of progress reports to the National Cancer Institute (NCI). The Core coordinates frequent communications with NCI Program Director and staff, including discussions regarding developments that affect the SPORE management or the fulfillment of its research mission. Given the multi-institutional nature of the SPORE, the Administrative Core coordinates the use of its established and available Web-based, video- and teleconferencing capabilities, e-mail, and password-protected web-based databases to facilitate communications and data-sharing.

Pathology and Tissue Core

The MD Anderson Leukemia SPORE consists of four translational research Projects directed towards translating the basic understanding of the biology of AML into patient care. All Projects require either fresh or archival tissue and surrogate materials. Morphologic, cytogenetic, immunophenotypic, and molecular evaluation and characterization of cells is fundamental to understanding the biology of leukemia development and progression, and are the foundation for designing new therapeutic approaches and for interpretation of results of clinical trials. Therefore, prompt, organized and reproducible handling, careful separation of important and relevant cells, and preservation of tissue specimens are of utmost importance. In addition, the correlation of laboratory measurements with clinical endpoints is critical for translational research, especially for samples from clinical trials. The Pathology and Tissue Core will collect and distribute tissue samples and linked clinical data, and therefore is a critical infrastructure for the clinical and population-based translational studies proposed in this application.

The Pathology and Tissue Core has the following objectives:

  1. Develop and maintain a repository of intact cells, serum, DNA, RNA and protein from blood and bone marrow specimens obtained from AML patients at MDACC.
  2. Maintain a comprehensive, prospective, interactive online database with detailed clinical and pathologic data for the samples received by the Core.
  3. Provide Reverse Phase Protein Arrays (RPPA) from AML patient samples for screening of protein expression in bulk leukemia cells, leukemia stem cells, and mesenchymal stromal cells (MSC).
  4. Provide RNA-Seq data interpretation for gene expression profiling (GEP).
  5. Facilitate inter- and extra- Leukemia Spore collaborations through sharing of blood and marrow resources.

Biostatistics, Data Management & Bioinformatics

The Biostatistics, Data Management, and Bioinformatics Core (Core 3) for the Leukemia SPORE will be a comprehensive, multilateral resource for data acquisition and management, design of laboratory experiments and clinical trials, development of innovative statistical methodology, statistical analysis, and publishing translational research generated through the Leukemia SPORE.

Core 3 will incorporate sound experimental design principles within all Projects, carry out data analyses using appropriate statistical methodology, and contribute to the interpretation of results through written reports and frequent interaction with Project investigators. Core 3 will provide an integrated data management system to facilitate communication among all Projects and Cores, which will be customized to meet the needs of the Leukemia SPORE and the Department of Leukemia. This process includes prospective data collection, data quality control, data security, and patient confidentiality. Thus, from inception to reporting, translational experiments will benefit from SPORE resources that will be used to augment existing MD Anderson biostatistics resources.

To serve all proposed SPORE Projects, as well as the Career Enhancement Program (CEP) and the Developmental Research Program (DRP), Core 3 has the following objectives:

  1. Provide guidance in the design and conduct of clinical trials and other experiments (including high-dimensional genomic and proteomic studies) that arise from the ongoing research of the SPORE.
  2. Facilitate prospective collection, entry, quality control, and integration of data for the basic science, pre-clinical, and clinical studies associated with the SPORE.
  3. Provide bioinformatic data analysis of high-throughput and high-dimensional genomic data, including whole genome/exome and transcriptome sequencing data.
  4. Provide innovative and tailored statistical modeling, simulation techniques, and data analyses for the main Projects, DRP and CEP, and Cores to achieve their specific aims.
  5. Prepare statistical reports for all experiments within all Projects; ensure that the results of all projects are based on well-designed experiments and are appropriately interpreted; and assist all Project investigators in the publication of scientific results.
  6. Be a resource for intra- and inter-SPORE collaborations, including study design and developing databases for multi-center clinical trials.