Four projects currently are underway within the Lymphoma SPORE:
- Project 1: Epigenetic-based therapy of Hodgkin lymphoma
- Project 2: Development of 8-chloro-adenosine therapy
- Project 3: Non-genotoxic p53 activation as novel therapeutic concept for lymphomas
- Project 4: Gene expression profiling and pathway targeted therapy in peripheral T-cell lymphoma (PTCL)
Project 1: Epigenetic-based therapy of Hodgkin lymphoma
Co-Principal Investigator: Yasuhiro Oki, M.D. (clinical)
Molecular analysis has demonstrated that the malignant Hodgkin and Reed-Sternberg (HRS) cells of HL are of B-cell origin, yet they infrequently express B-cell antigens. The loss of the B-cell phenotype has been reported to be epigenetically regulated and is believed to enable HRS cells to evade immunosurveillance.
We have recently evaluated the single-agent activity and safety of the oral isotype selective HDAC inhibitor MGCD-0103 in patients with relapsed HL, which demonstrated for the first time the potential clinical benefit of epigenetic-based therapy in this patient population in a phase II study. Our preliminary in vitro data, in addition to emerging clinical data in other hematologic malignancies, suggest that combined epigenetic therapy using an HDAC inhibitor and a hypomethylating agent have synergistic antitumor activity. Furthermore, our preliminary data and results from correlative studies conducted on specimens from HL patients treated with the single agent MGCD-0103 indicate that HDAC inhibition may have a direct antitumor effect, in addition to altering cytokine and chemokine expression and secretion, suggesting that HDAC inhibition may alter the inflammatory process in the HL microenvironment.
Our central hypothesis is that epigenetic-based therapy has a dual therapeutic effect in HL, directly, in the form of an antiproliferative effect on the malignant HRS cells, and indirectly, through inducing a favorable antitumor immune response. To test this hypothesis, this project includes clinical trials that evaluate rationally designed epigenetic-based combination therapy, examination of biomarkers on specimens obtained from patients participating in these clinical trials, and in vitro experiments to rationally design future epigenetic-based combination therapies for patients with relapsed HL.
Our work is organized into three specific aims:
- Aim 1: Determine the safety and efficacy of HDACi-based therapy in patients with relapsed and refractory classical HL.
- Aim 2: Determine the in vivo effect of MGCD-0103 plus azacytidine therapy on targeted pathways and identify potential biomarkers of antitumor efficacy and treatment toxicity using blood and tissue specimens from patients enrolled on the study in Aim 1.
- Aim 3: Examine novel epigenetic-based combination therapy in vitro to rationally design a second generation of clinical trials.
Project 2: Next generation T-cell therapy targeting CD19+ lymphoma
Principal Investigator: Laurence Cooper, M.D, Ph.D. (clinical and translational)
Co-Principal Investigator: Richard Champlin, M.D. (clinical)
T cells can be genetically modified to target tumor associated antigens (TAA’s) such as CD19 on B-lineage lymphomas. The adoptive transfer of T cells that express a chimeric antigen receptor (CAR) to target CD19 on chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL) has resulted in anti-tumor responses in humans. At MD Anderson Cancer Center we have trials underway that are also infusing CD19-specific CAR+ T cells. However, we differ from others as we have advanced, for the first time in humans, a new approach to gene therapy based on the Sleeping Beauty (SB) transposon/transposase system and an ability to propagate clinically appealing numbers of T cells on artificial presenting cells (aAPC). These two platform technologies provide an opportunity to now further advance the field of immune-based therapies through testing of new CAR designs that target CD19+ NHL.
The prototypical CAR is able to activate T cells for proliferation, cytokine production, and killing by combining the specificity of a monoclonal antibody (for CD19) with activation motifs, such as CD3- combined with CD28 and CD3- combined with CD137. However, it is not yet known which endodomain design is superior to providing an anti-tumor effect for CD19+ NHL. This will be answered in this SPORE Project. In Specific Aim 1 we seek to undertake a clinical trial enrolling patients who are undergoing autologous a hematopoietic stem-cell transplantation and co-infuse two types of CD19-specific T cells that differ in their CAR design. One CAR design signals through CD137 and the other through CD28. In Specific Aim 2 we seek to determine the trial’s primary objectives to evaluate safety, feasibility, and persistence, of the two populations of administered T cells. In Specific Aim 3 we seek to address the trial’s secondary objectives to determine whether there is a recipient immune response that comprises the survival of the CAR+ T cells, the ability of the T cells to traffic to sites of NHL, the emergence of subpopulations of T cells with improved persistence, and the ability of T cells recovered from the patient to participate in effector functions.
In aggregate, this Project and trial tests an immune based therapy that will advance the field for the treatment of NHL and the results can be broadly applied to the targeting of other CD19+ malignancies as well as the human application of CAR+ T cells that address other TAA’S.
To achieve our overall goal and to test our hypothesis, we will pursue the following specific aims:
- Aim 1: Seeks to develop the two CD19-specific CARs
- Aim 2: Seeks to undertake clinical trial infusing autologous CD19-specific T-cells after hematopoietic stem-cell transplantation
- Aim 3: Seeks to undertake correlative studies
Project 3: Non-genotoxic p53 activation as novel therapeutic concept for lymphomas
Principal Investigator: Michael Andreeff, M.D, Ph.D. (translational and basic science)
Co-Principal Investigator: Susan O’Brien, M.D. (clinical)
Co-Investigator: Marina Konopleva, M.D., Ph.D.
The main therapeutic challenge in the treatment of lymphomas is the development of strategies that maximize the induction of CLL cell apoptosis before resistance to chemotherapy develops. The p53 molecule is the master switch that determines whether a stressed cell undergoes apoptosis, thus acting as a tumor suppressor. Mutations of p53 lead to inactivation of this suppressor function and are found in approximately 50% of solid tumors. Alternatively, Mouse Double Minute 2 (MDM2, human homolog HDM2), and its homolog HDMX can also render p53 inactive through different mechanisms; while HDM2 is an ubiquitin ligase that mediates degradation of p53 by ubiquitin-mediated proteolysis, HDMX inhibits the transcriptional activity of p53. These p53 mutations leading to p53 inactivation, while frequent in solid tumors, are rare in newly diagnosed and relapsed CLL/lymphomas. However, we and others have reported loss of p53 function through over-expression of HDM2 in approximately 50% of hematological malignancies, while expression levels of HDMX have not been investigated in CLL.
We have recently reported that the restoration of p53 activity, by inhibiting HDM2/p53 interaction utilizing non-genotoxic small molecule inhibitors (Nutlin 3a, MI 63), induces apoptosis in Hodgkin and non-Hodgkin lymphomas and in acute myeloid and chronic lymphocytic leukemias/SCL with unmutated p53. While these HDM2 inhibitors increase p53 levels which in turn initiate transcription of p53 targets, we have also demonstrated transcription-independent direct interactions of p53 with Bcl-2 family members. Furthermore, we reported striking synergisms with conventional chemotherapeutic agents such as fludarabine, cytarabine, and daunorubicin, and with BH3 mimetics.
Here we propose to investigate the molecular and clinical effects of a phase I clinical trial with a small molecule inhibitor of HDM2 (Nutlin 3a from Roche), and to develop a better understanding of the mechanisms regulating p53 activation and the observed synergism with chemotherapy. We have recently discovered that MAPK signaling regulates the subcellular localization of p53 and that MAPK inhibition enhanced the proapoptotic function of p53 by inhibiting induction of anti-apoptotic p21 and regulating intracellular trafficking of p53. We therefore propose to correlate response to HDM2 inhibition with MAPK signaling status in CLL.
The recent development and early promising clinical data in CLL/SLL with ABT-737 provides the opportunity to efficiently and selectively inhibit the function of anti-apoptotic Bcl-2 family members. We have contributed to the development of ABT-737 and have extensively analyzed its mechanisms of action. We therefore combined Nutlin-3a and ABT-737 and reported profound synergism in the induction of apoptosis.
These studies will guide the clinical development of HDM2 inhibitors and are supported by our observation that increased HDM2 levels correlate with apoptosis induced by Nutlin 3a in CLL.
The following are our aims:
- Aim 1: Identify the molecular determinants of apoptosis induced by non-genotoxic small molecule inhibitors of HDM2 (Nutlin-3a, MI-63) in lymphoma cell lines and primary CLL/SLL cells
- Aim 2: Determine mechanisms by which HDM2 inhibition synergizes with BH3 mimetics, MAPK inhibitors, and chemotherapy
- Aim 3: Conduct first-in-man phase I trial of an HDM2 inhibitor (Nutlin-3a analog RO5045337) in CLL/SLL
Project 4: Gene expression profiling and pathway targeted therapy in peripheral T-cell lymphoma (PTCL)
Principal Investigator: John (Wing) C. Chan, M.D. (translational and basic science)
Co-Principal Investigator: Julie M. Vose, M.D. (clinical)
University of Nebraska Medical Center
In the United States, B-cell NHL encompasses about 90% of all lymphomas. For the most part, T-cell NHL and a very small percentage of NK-cell lymphomas comprise the remainder. However, a higher prevalence of T- and NK-cell lymphomas is present in Asia. The current WHO classification recognizes nine distinct clinicopathological peripheral T-cell lymphoma (PTCL) subtypes. These lymphomas have a very poor clinical outcome with current therapies, and further elucidation of the pathogenesis of this heterogeneous group of lymphomas–as well as the mechanisms responsible for their varied clinical behavior–is essential.
Gene expression profiling (GEP) has been a useful tool in identifying biologically and clinically distinctive entities, constructing molecular predictors of survival, and delineating pathogenetically important pathways in different classes of B-cell NHL. Due to the rare nature of PTCL, GEP studies on only a small series of PTCL have been performed. We have put together a large international consortium that has contributed clinical and pathologic materials from 1,320 cases of PTCL and NK-cell lymphoma. With materials from this source and other PTCL studies, we propose to perform GEP studies on the PTCL cryopreserved tissue. In addition to classification, important molecular characteristics of PTCL, including pathways that may contribute to oncogenesis, will be identified. Novel therapeutic approaches will be evaluated based upon these results.
Based upon preliminary data, NF-κB has been identified as a potential target in PTCL. A phase II study of CEP-18770, a novel orally active proteasome inhibitor with a tumor-selective pharmacological profile, has been planned for patients with relapsed PTCL. As part of the planned study, specimens from the patients on the trial will be analyzed for NF-κB activity, which will be correlated with the outcomes of the patients on the trial. Additional phase I/II trials will be planned based upon the subsequent results of the GEP and the pathway analysis performed during the first 2 years of this project.
We hypothesize that gene expression profiling analysis will allow us to construct robust and biologically meaningful classifiers for PTCL. It will also allow us to identify therapeutically relevant oncogenic pathways and tumor/host interactions that would lead to improvement in the management of patients with PTCL.
To test our hypotheses, we propose the following specific aims:
- Aim 1: Identify key molecular signatures in peripheral T-cell lymphoma (PTCL) and natural killer (NK)-cell malignancies to construct a more robust and biologically meaningful classification
- Aim 2: Identify oncogenic pathways and tumor/host interactions that contribute to the development of the neoplastic clone, tumor-induced immunosuppression, and the outcome of PTCL patients with particular emphasis on angioimmunoblastic T-cell lymphoma (AITL)
- Aim 3: Perform a phase I/II trial in patients with relapsed PTCL with agents that are directed at oncogenic pathways identified by GEP