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Last Updated: 10/10/18

Memorial Sloan Kettering SPORE in Lymphoma

Principal Investigators:
Anas Younes, M.D.
Andrew Zelenetz, M.D., Ph.D.

Principal Investigator Contact Information

Anas Younes, MD
Chief, Lymphoma Service
Memorial Sloan-Kettering Cancer Center
Division of Hematologic Oncology
Department of Medicine
1275 York Ave
New York, NY 10065
Phone: 212-639-5059
Email: younesa@mskcc.org

Andrew Zelenetz MD, PhD
Memorial Sloan-Kettering Cancer Center
Department of Hematology
1275 York Ave
New York, NY 10021
Phone: 212-639-2656
Email: a-zelenetz@ski.mskcc.org

SUMMARY

The goal of the Memorial Sloan Kettering (MSK) SPORE in Lymphoma is to improve the cure rate of patients with diffuse large B cell lymphoma, through a collaborative effort between three New York City institutions: 1) Memorial Sloan Kettering Cancer Center, 2) Weill Cornell Medical College (WCMC), and 3) Herbert Irving Comprehensive Cancer Center (HICCC) of Columbia University. The overall approach for this SPORE in Lymphoma seeks to shift current treatment paradigms and clinical practice by introducing, developing, and applying new concepts, methods, and technologies to address several DLBCL subgroups with a clear unmet medical need. Our overall broad aims are:

Specific Aim 1. To develop novel treatments for DLBCL based on targeting specific genetic and molecular alterations that contribute to the oncogenic process.

Specific Aim 2. Identify potential biomarkers of antitumor efficacy using tissue specimens from patients enrolled on four clinical trials developed in the SPORE.

We plan to identify and utilize biologic, genetic, and clinical biomarkers to select patients with DLBCL for novel therapeutic approaches.

Project 1, we will develop novel treatments to target the oncogenic cooperation between Myc and Bcl2. Such therapy can subsequently be evaluated in patients enriched for high Myc+/Bcl2+ expression in DLBCL using standard immunohistochemistry methods. These patients have a clear unmet medical need, as they have a poor prognosis with standard chemotherapy.

Project 2, we will investigate the safety and clinical efficacy of genetically modified T cells to express chimeric antigen receptors (CARs) targeting CD19 in elderly patients with relapsed DLBCL who are not candidates for stem cell transplant. These patients have a dismal prognosis, with a median overall survival rarely exceeding one year.

Project 3, we will investigate the safety and efficacy of the first Tumor Enriched-Hsp90 (TE-Hsp90) inhibitor PU-H71 in patients with relapsed DLBCL.21,22 A novel PET-based molecular imaging using radiolabeled I-124 PU-H71 will be used to examine in vivo targeting of HSP90 by PU-H71, and to guide dosing and patient selection. Because c-Myc and intrinsic apoptosis pathway proteins are client proteins of TE-Hsp90, the efficacy of this treatment will be retrospectively assessed in patients with Myc+/Bcl2+ DLBCL.

Project 4, we will elucidate the normal and pathologic role of CBP and p300 in B cells, establish pre-clinical models for their therapeutic targeting, and test the activity of the novel HDAC inhibitor mocetinostat in a phase II clinical trial. We will use targeted sequencing strategies to select patients with DLBCL that carry mutations in the CBP/p300 histone acetyltransferase (HAT) genes for therapy with novel HDAC inhibitors. Our goal is to identify safe and active new agents in biomarker-defined patients with relapsed DLBCL.

Project 1: Development of Mechanism-Based Therapy for Myc+/Bcl2+ Diffuse Large B Cell Lymphoma (MSK)

Project Co-Leaders:
Anas Younes (Clinical/Translational)
Hans Guido Wendel (Basic)

Fig 1. Targeting the oncogenic cooperation between Myc, PI3K/AKT/mTOR pathway and Bcl2 provides opportunities for the development of mechanism-based targeted therapy of Myc+/Bcl2+ DLBCL.
Fig 1. Targeting the oncogenic cooperation between Myc, PI3K/AKT/mTOR pathway and Bcl2 provides opportunities for the development of mechanism-based targeted therapy of Myc+/Bcl2+ DLBCL. Drugs in red color either have proven clinical activity in patients with DLBCL, or currently in clinical trials in patients with lymphoma.

Recent studies demonstrated that ~35% of DLBCL tumors co-express high levels of Myc and Bcl2 proteins (hereafter will be referred to as Myc+/Bcl2+ DLBCL). Except for the few cases involving Myc and Bcl2 translocations or genetic amplifications, mechanisms responsible for Myc and Bcl2 protein overexpression in DLBCL remain undetermined. Patients with Myc+/Bcl2+ DLBCL have a poor prognosis when treated with standard RCHOP regimen. Thus, Myc+/Bcl2+ DLBCL represents a biomarker-defined subset of patients with a clear unmet medical need. The major goal of this project is to develop novel, mechanism-based, treatment strategies to improve treatment outcome of patients with Myc+/Bcl2+ DLBCL. Based on preclinical data from our group and others, DLBCL cells frequently depend on severl maechanisms to promote their growth and survival. Our focus will be on designing treatment strategies aimed at disrupting the oncogenic cooperation between Myc, and Bcl2, or Myc and activated PI3K signaling pathway (Fig 1). Our aims are:

Aim 1. To investigate the contribution of protein translation to Myc/Bcl2 expression In DLBCL.

Except for the few cases involving Myc and Bcl2 translocations or genetic amplifications, the mechanisms responsible for Myc and Bcl2 protein overexpression in DLBCL remain undetermined. Understanding the mechanism responsible for Myc and Bcl2 expression may provide opportunities for novel treatment strategies.

Aim 2. To develop mechanism-based treatment strategies for Myc+/Bcl2+ DLBCL

  1. Targeting Myc and Bcl2 oncogenic cooperation in DLBCL
  2. Targeting Myc and PI3K/AKT/mTOR pathway oncogenic cooperation in DLBCL

Aim 3. To evaluate the safety and efficacy of novel therapies developed and prioritized from Aims 1 and 2 in phase I/II studies in patients with Myc+/Bcl2+ DLBCL

Project 2: Optimizing Adoptive Therapy of Relapsed DLCBL with Cd19 Targeted T Cells (MSK)

Project Co-Leaders:
Renier Brentjens (Basic)
Connie Batlevi (Clinical)

Fig 2. A model for targeting DLBCL cells using CAR T cells targeting CD19 antigen and immune checkpoint inhibitors targeting PD1
Fig 2. A model for targeting DLBCL cells using CAR T cells targeting CD19 antigen and immune checkpoint inhibitors targeting PD1

Despite currently available chemotherapy regimens, patients with relapsed diffuse large B cell lymphoma (DLBCL) ineligible for autologous stem cell transplant (ASCT) have a very poor prognosis and represent an area of unmet need. One novel approach is the adoptive transfer of T cells genetically modified to express artificial T cell receptors termed CARs designed to recognize target antigens expressed on the tumor cell surface. A patient’s own T cells may be isolated and modified to express the CAR thereby redirecting T cell specificity to the tumor associated antigen. Most B cell non-Hodgkins lymphomas (NHL), including DLBCL, express the B cell specific antigen CD19. We and several other groups have recently reported initial clinical outcomes of patients with both low grade as well as aggressive B cell cancers treated with CAR T cells targeted to the CD19 antigen. To date, these clinical studies have reported marked anti-tumor responses in a variety of B cell malignancies especially in patients with low grade B cell CLL as well as even more impressive clinical outcomes in patients with relapsed B-ALL. However, there is a limited data on patients with aggressive DLBCL treated with CD19 targeted CAR T cells. An additional and relevant immune-based approach to cancer therapy not yet fully explored in the setting of B cell malignancies in general, and specifically in the setting of DLBCL is immune-checkpoint blockade through infusion of antagonistic monoclonal antibodies (MAb’s) targeted to the T cell PD-1 receptor, which when engaged with either the PD-L1 or PD-L2 ligand induces T cell anergy. As a result, blockade of this T cell checkpoint pathway with PD-1 specific MAbs in turn enhances the anti-tumor function of tumor targeted T cells. The goal of this project is to initially apply our CD19 targeted CAR T cell approach to relapsed ASCT ineligible DLBCL patients in a clinical trial as a single agent therapy following salvage chemotherapy. We will next investigate the rationale of combining 19-28z CAR T cell therapy with PD-1 checkpoint inhibition wherein the latter immune-based approach may protect the CD19 targeted CAR T cells from PD-L1 and PD-L2 mediated anergy. We will initially study this hypothesis in a clinically relevant syngeneic immune competent model of disease with subsequent translation in a planned second clinical trial targeting the same patient population. The specific aims of Project 2 are:

Aim 1. To conduct a Phase I/II clinical trial treating elderly transplant ineligible patients with relapsed DLBCL with salvage chemotherapy followed by CD19 targeted 19-28z CAR modified autologous T cells.

Aim 2. To optimize the efficacy of CAR modified T cell therapy through additional PD-1 checkpoint blockade.

Aim 3. To conduct a Phase I/II clinical trial treating elderly transplant ineligible relapsed DLBCL patients with salvage chemotherapy followed by CD19 targeted CAR T cells in combination with PD-1 blocking MAb.

Project 3: Translating Stress Response Targeted Therapy for B-Cell Lymphomas (Weill Cornell Medical College and MSK)

Project Co-Leaders:
Gabriela Chiosis (Clinical)
Ari Melnick (Translational/Basic)

DLBCL are subjected to substantial levels of stress. Sources of stress for these cells include massive proliferation, genomic instability, starvation, hypoxia, and suppression of checkpoint proteins that normally maintain homeostasis. Stress pathway activation enables B-cells to survive long enough for sub-population of B-cells to emerge acquiring many genetic mutations that facilitate malignant transformation. Our data indicate that DLBCLs are often addicted to a stress protein called tumor enriched Hsp90 (TE-Hsp90). TE-Hsp90, which is essential for the actions of multiple oncoproteins. Along these lines the Chiosis lab developed PUH71, an inhibitor with selective activity against TE-Hsp90. In pre-clinical studies PUH71 was shown to potently kill DLBCLs without toxicity to other organs. PUH71 preferentially accumulates in tumors but not in normal tissues in animals and in humans. Indeed PUH71 distribution and tissue concentration can be precisely measured in humans using a novel PET scan method. PUH71 phase 0 and phase I studies are nearing completion, and have proven that PUH71 PET imaging provides an accurate measurement of tumor drug concentration and exposure (area under the curve), which in turn correlates with tumor responsiveness. Hence PUH71 is a potentially unique personalized companion biomarker for drug activity that may allow treatment to be individually tailored to patients. Herein we propose to perform the first phase II trial of PUH71, in patients with relapsed refractory DLBCL, accompanied by PUH71 PET non-invasive imaging, as well as correlative science to evaluate putative biomarkers that have emerged from pre-clinical laboratory studies.

Aim 1. Perform a PUH71 phase II clinical trial in patients with DLBCL

Aim 2. Compare and contrast spectrum of activity among DLBCLs to Hsp90 and Hsp70 inhibitors.

Aim 3. Build rational combinatorial regimens anchored on PUH71 and Hsp70 inhibitors.

Project 4: Role of Acetyltransferase Gene Inactivation In DLBCL (Columbia University and MSK)

Project Co-Leaders:
Riccardo Dalla-Favera (Basic)
Andrew Zelenetz (Clinical)

Figure 3. Most common genetic lesions associated with the two major cell-of-origin based DLBCL subtypes.
Figure 3. Most common genetic lesions associated with the two major cell-of-origin based DLBCL subtypes.

Diffuse Large B-cell Lymphoma (DLBCL) represents the most common form of B-cell non-Hodgkin Lymphoma (B-NHL), accounting for ~30% of the de-novo diagnoses54. A significant fraction of DLBCL remains incurable, underscoring the need to identify molecular mechanisms that are responsible for disease development and that can be targeted therapeutically. Toward this end, we have integrated next-generation whole-exome sequencing analysis and high-density single nucleotide polymorphism (SNP) array analysis for the genome-wide detection of mutations and gene copy number changes in DLBCL. This combined approach has shown that DLBCL is frequently associated with structural alterations inactivating CREBBP (CBP) and, more rarely, EP300 (p300), two highly related histone and non-histone acetyltransferases (HATs) that act as transcriptional co-activators in multiple signaling pathways. Overall, ~37% of DLBCL and 36% of follicular lymphoma (FL) cases display genomic deletions and/or somatic point mutations that remove or inactivate the HAT-coding domain of these two genes. Moreover, 64% (n=25/39) of DLBCL derived from FL transformation harbor genetic lesions affecting these two loci. Notably, CBP lesions appear to represent early events acquired during the clonal expansion of a common mutated precursor cell, suggesting a role in the initial phases of tumorigenesis. We have demonstrated that CBP/p300 inactivation leads to specific defects in the acetylation-mediated inactivation of the BCL6 onco-protein and activation of the p53 tumor suppressor, therefore suggesting one possible mechanism by which these lesions may contribute to cell transformation. Based on these results, the general objectives of this project are to elucidate the normal and pathologic role of CBP and p300 in mature B cells, to establish pre-clinical models for their therapeutic targeting, and to assess the efficacy of drugs targeting deacetylation mechanisms in clinical trials. To achieve these objectives, the following Specific Aims will be pursued:

Aim 1. Identify the full complement of genetic and epigenetic lesions affecting CBP/p300 and investigate their pathogenetic and clinical impact in DLBCL.

Aim 2. Identify biomarkers of CBP/p300 activity in GC B cells that are deregulated in patients harboring CBP/p300 functional loss

Aim 3. Elucidate the role of CBP inactivation in lymphomagenesis in vivo.

Aim 4. Evaluate the safety and efficacy of novel therapies developed from Aims 1 and 2 in patients with relapsed DLBCL

Administrative Core

Directors:
A. Younes
A. Zelenetz

The purpose of the Administrative Core is to coordinate the activities of the Projects and Cores and to provide oversight and leadership of the scientific, administrative, and fiscal aspects of the MSK Lymphoma SPORE. The Core will oversee the coordination of the various clinical and translational studies outlined, and will integrate scientific and clinical efforts within and between Projects and Cores, and assure the timely enrollment of patients on clinical trials and performance of the translational studies. The Core will provide support to ensure seamless communication and exchange of data between Projects and Cores. This Core will facilitate exchange of information among the all investigators, as well as the Internal and External Advisory Board members. It will ensure compliance with institutional policies to protect human subjects, and will encourage participation of women and minorities on the proposed clinical trials. The Core will oversee all financial expenditures, and will ensure compliance with institutional and regulatory agencies. The work of the Core is organized into three Aims:

Aim 1. To coordinate all meetings to evaluate and monitor the SPORE scientific activities

Aim 2. To coordinate communications among Projects, Cores, and internal and external programs

Aim 3. To provide administrative and financial support for the Projects and Cores

Core 1: Biospecimens

Director:
A. Dogan

The purpose of the Memorial Sloan Kettering Cancer Center (MSK) Lymphoma SPORE is to support the proposed research aim of improving the cure rate of patients with diffuse large B cell lymphoma (DLBCL). The main role of the Biospecimen Core is to collect, characterize, annotate, bank and distribute biospecimens including primary tumor tissue and cells, bone marrow, peripheral blood white cells, serum and plasma in support of SPORE projects. The core is led by two senior MSK hematopathologists with vast experience in clinical diagnostic and translational research, and biospecimen processing. The core will administer all biospecimen related activities primarily using existing state-of-the-art institutional infrastructure, biospecimen banking processes, CLIA-based laboratories, and research core facilities. There is an established strong collaborative network among investigators of the MSK lymphoma research group and participating institutions, with the ability to share data and biospecimens across institutions, as evident by joint publications in high profile journals. The Biospecimen Core will be based at MSK, and will provide services and support to SPORE investigators in the three participating institutions. The Biospecimen core will provide the Lymphoma SPORE program with tissue, blood, nucleic acid, and proteomic derivatives essential to achieving the aims of the 4 proposed projects focusing on diffuse large B cell lymphoma (DLBCL). This shared resource for SPORE investigators will allow for expanding correlative studies, interrogating gene networks, specific signaling pathways, and serve as a hypothesis-generating tool. The following specific aims are proposed:

Aim 1. To collect, process, bank, and distribute biospecimens from patients with DLBCL to SPORE investigators and collaborators in support of their research projects.

Aim 2. To provide comprehensive diagnostic characterization of lymphoma specimens collected from patients enrolled on SPORE clinical trials.

Aim 3. To process and perform integral and integrated biomarker analysis on biospecimens collected from patients enrolled on SPORE clinical trials.

Core 2: Biostatistics and Bioinformatics

Director:
Venkatramen Seshan

The role of the Biostatistics and Bioinformatics Core is to support the investigators of the SPORE in Lymphoma in their research efforts, including laboratory experiments, molecular studies and the design and analysis of clinical trials. In laboratory experiments, core members will assist in the formulation of the experimental design and in the analysis and interpretation of the data at the conclusion of the study. In molecular studies, core members will closely interface with the members of the Biospecimen Core, and will have primary responsibility of merging molecular and clinical data, followed by appropriate statistical analysis and reporting. In the clinical trial design phase, a core member will conduct a protocol review with the principal investigator. Based on this, a statistical section for the protocol will be provided, outlining major scientific objectives, population to be studied, primary and secondary endpoints, experimental design, a randomization procedure if necessary, analysis plans, and a targeted sample size justified in probabilistic terms. At the conclusion of the trial, data analyses will be performed to assess outcomes of the primary and secondary endpoints stated in the protocol. If current statistical methodology does not adequately address a research question in this SPORE, alternative methodologies will be explored. The Biostatistics Core assists the research efforts of the investigators of the MSKCC SPORE in Lymphoma, contributing to the design and analysis of clinical and laboratory research and the development of valid conclusions. The core provides statistical analysis and consultancy as well as ongoing quality assurance. The core has also established a data quality working group to improve the quality of data that will be generated by the SPORE projects. The analytical methods necessary to search for new markers, investigate patterns of gene expression, predict patient outcomes, and assess therapeutic trial results are becoming increasingly complex. Many analyses cannot be done by the basic scientists or clinicians themselves, and dedicated methodological collaborators are necessary. We anticipate that the services of the Biostatistics and Bioinformatics Core will be used by all research projects and will also interact with the other cores. These services include preclinical and molecular studies as well as clinical trials. The benefit of having this core is that it provides a consistent team of dedicated personnel to efficiently support these activities. The Core’s aims are:

Specific Aim 1: To provide statistical and bioinformatic expertise in experimental design, data analysis and interpretation. The core will be involved in the studies from the conception stage all the way to its completion and dissemination.

Specific Aim 2: To develop and/or adapt and implement novel statistical and bioinformatic methodologies to meet need when standard methods are less than optimal.

Specific Aim 3: To provide informatics infrastructure to enable collaboration and data sharing among the various projects and the three institutions that constitute this SPORE.

Developmental Research Program (DRP)

Directors:
J. Leonard
A. Younes

The DRP Committee is responsible for the initial review and ranking of all proposed DRP applications. Detailed review and selection criteria are provided in the DRP Section of the SPORE. The SPORE Executive Committee will finalize the selection based on scientific merit, innovation, and programmatic needs. The PIs of funded DRP applications will be required to present progress report at least every 6 months at the monthly SPORE scientific and working group meeting. Funded DRPs will be reviewed annually during the IAB/EAB meeting. The evaluation process will result in one of the following outcomes: 1) continued funding for meritorious projects for an additional year; 2) discontinuation of funding, 3) recommendation to become a full SPORE project. Recommendations from the EAB will be ratified by a majority vote of the Executive Committee members. An important measure of success will be incorporation of a Developmental Project into a SPORE project, becoming a full SPORE project, securing external peer-reviewed funding, and outstanding publication record.

Career Enhancement Program (CEP)

Directors:
Riccardo Dalla-Favera
A. Zelenetz

The CEP Committee is responsible for the initial review and ranking of all proposed CEP applications. The SPORE Executive Committee will finalize the selection based on scientific merit, innovation, mentorship plans, and programmatic needs (Full description is provided in the CEP Section of the SPORE). The recipients of CEP awards will be required to present progress reports at least every 6 months at the monthly SPORE scientific and working group meeting. Funded CEP applications will be reviewed annually during the IAB/EAB meetings. The evaluation process will include its ability to recruit and train investigators who will continue to contribute to translational lymphoma research, participation of CEP awardees in SPORE projects, publication of translational lymphoma research in peer-reviewed journals, and securing external peer-reviewed funding. More details are provided in the description of the CEP.

SPORE LEADERSHIP

Anas Younes, M.D.

Anas Younes, M.D. (Core Director, SPORE Director) is currently the Chief of the Lymphoma Service at Memorial Sloan Kettering Cancer Center (MSK) and a Professor of Medicine at Weill Cornell College of Medicine. He joined MSK in February 2013, after being on the faculty of MD Anderson Cancer Center for 20 years. He was the PI of the MDACC Lymphoma SPORE and has extensive experience in both translational lymphoma research and clinical investigations in lymphoma. His research currently focuses on the development of targeted therapy for lymphoma, and identifying predictive biomarkers for response. At the national and international level, Dr. Younes is a member of the Scientific Advisory Board of the Lymphoma Research Foundation, and a past member of the NCI lymphoma Steering Committee. He served as a member of the Lymphoma Committee of the Southwest Oncology Group (SWOG), and he is currently a member of the Scientific Advisory Committee for the International Symposium on Hodgkin Lymphoma (Cologne, Germany) and the International Congress on Malignant Lymphoma (Lugano). He is an external advisor to the Iowa/Mayo Lymphoma SPORE. As the SPORE Director and Administrative Core Director, Dr. Younes has the overall administrative, fiscal, and scientific responsibility for the Lymphoma SPORE. Dr. Younes’ duties as the Core Director include serving as the Chair of the SPORE Executive Committee, chairing monthly SPORE investigator meetings, coordinating the annual progress reports submitted to the NCI, coordinating participation with the annual NCI Translational Science meetings, and coordinating the annual SPORE IAB/EAB meeting.

Andrew Zelenetz, M.D., Ph.D.

Andrew Zelenetz, M.D., Ph.D. (Core Co-Director, SPORE Co-Director) is the former Chief of Memorial Sloan Kettering’s Lymphoma Service. He is an internationally known lymphoma clinical investigator who participated in the development of several new agents for the treatment of lymphoma, including 131I-tosituomab/tositumomab, bortezomib, and pralatrexate. He has published more than 100 papers on lymphoma research in journals such as Blood, Journal of Clinical Oncology, and Clinical Cancer Research. Dr. Zelenetz is involved in several national organizations that provide information about lymphoma treatment and fund laboratory and clinical research. He is the chairperson of the Non-Hodgkin Lymphoma Guidelines panel of the National Comprehensive Cancer Network and vice chairperson of the Lymphoma Core Committee of the Cancer and Leukemia Group B. He is also a member of the scientific advisory board of the Lymphoma Research Foundation. Dr. Zelenetz’s research interests include understanding the molecular biology of lymphoma and assessment of minimal residual disease.