Each year, the Developmental Research Program supports pilot projects that take maximum advantage of new research opportunities in lymphoma. Through the DRP, the MSK SPORE in Lymphoma provides multidisciplinary resources to advance novel scientific ideas and support innovative pilot projects in translational lymphoma research. Projects are intended to rapidly advance a new idea or concept that has the potential to substantially impact our understanding of lymphoma and advance treatment of the disease.
“Targeting oncoprotein expression in follicular lymphoma and mantle cell lymphoma patients with indolent disease: a biomarker-driven proof-of-concept clinical trial”
Weill Cornell Medicine
Abstract: Follicular Lymphoma (FL) usually presents with disseminated disease and follows an indolent, although incurable, clinical course. During the indolent phase, rather than increased proliferation, accumulation of FL cells is a consequence of the almost universal expression of BCL2 that make these cells resist apoptosis. Mantle cell lymphoma (MCL) is another type of lymphoma that can have an indolent course. It is characterized by (11,14) translocation which leads to cyclin D1 (CCND1) overexpression.
We and others identified eIF4E as a critical factor for the nuclear export and preferential translation of lymphoma oncogenic mRNAs. Accordingly, eIF4E inhibition using the antiviral ribavirin results in decreased production of BCL2, CCND1, BCL6, LYN and AKT among others proteins. The advantage of oncogenic mRNA translation as a therapeutic target is that iFL cells require constant production of these proteins to survive even if they are not proliferating. We therefore postulate that ribavirin could constitute a therapeutic strategy for lymphoma patients with indolent disease.
Our specific aim is to conduct a proof-of-mechanism clinical trial (Phase 0) to determine the tolerability and biological effect of ribavirin in patients with iFL and iMCL. The main endpoint will be a change in a pharmacodynamics biomarker (i.e. amount of DNA with BCL2 or CCND1 translocation in cell-free circulating DNA). We will enroll iFL and iMCL patients with BCL2 or CCND1 translocations and expression of eIF4E in the nucleus of lymphoma cells. Patients will be followed by serial assessment of BCL2/CCND1 translocation in cf-DNA. We expect that ribavirin treatment will lead to a decrease of BCL2/CCND1 presence in cf-DNA that will be followed by clinical benefit.
“Genetic determinants of primary chemoresistance in diffuse large B cell lymphoma”
Columbia University Institute for Cancer Genetics
Abstract: Diffuse large B-cell lymphoma (DLBCL) represents the most common B cell lymphoma in adulthood, accounting for 30-40% of all diagnoses. Despite significant advances in the management and treatment of this disease, a significant proportion of patients are not cured; prognosis is especially dismal in patients progressing during first-line therapy or early after treatment (primary-refractory DLBCL), with 4-yr overall survival of only 13%. The molecular basis and the specific mechanisms that are responsible for this poor therapeutic response are currently unknown. The general goal of this project is to provide pilot data toward the identification of genetic determinants of primary chemo-resistance in DLBCL, with the following specific aims:
1) Identify genetic alterations associated with primary-refractory DLBCL, by integrating state-of-the-art genomic profiling approaches and computational methods in clinically-annotated, pre-treatment tumor specimens from rigorously defined chemoresistant (CR) and chemo-sensitive (CS) DLBCL patients; 2) Provide initial functional characterization of the top scoring mutant alleles, including the DTX1 candidate gene identified in a preliminary discovery screen. The results of this study are expected to provide insights into the genetic landscape of CR-DLBCL, with relevant implications for the diagnosis and clinical management of this poor prognostic category of patients.
“Potentiating Antibody-Dependent Killing of Lymphomas by Use of a CAR T Cell that Blocks CD47”
Memorial Sloan Kettering Cancer Center
Abstract: CAR T cells have emerged as an effective therapy for B-cell hematopoietic cancers. However, greater potency and mechanisms to defeat resistance are still needed. This includes antigen loss variant escape and relapse. To mitigate this problem, we propose an innovative strategy that overcomes tumor resistance by modifying CAR T cells to constitutively express and secrete a drug that activates macrophages and vastly stimulates their ability to kill via antibody mediated phagocytosis (ADCP), which is the major mechanism of antibody mediated killing in vivo. Selective synthesis and local secretion of the activating drug at the lymphoma by the CAR T cell should reduce systemic toxicity of the combination. The mechanism of action of these advanced CAR T cells is that the drug, CV1, blocks the phagocytosis and ADCP-inhibiting protein, CD47, on the lymphomas. CD47 transduces an anti-phagocytic signal via binding to its cognate ligand, SIRPα, expressed on macrophages, neutrophils and NK cells. CV1 is a soluble, truncated SIRPα protein variant that potently blocks binding of tumor cell CD47 to phagocyte SIRPα, and improves macrophage-mediated ADCP of cancer cells in vitro and in mice. Here we plan to construct a CAR T cell that secretes CV1 to increase the phagocytic function of macrophages locally and more specifically to engage targets of infused antibodies such as CD20. Orexigenic drugs stimulate the appetite; thus CV1 is orexigenic to macrophages. Accordingly, we term this new CAR T cell technology as, “OrexiCARs.” Local CV1 secretion should improve potency through synergy with antibody therapy, and reduce systemic toxicity compared to CD47 antibody therapies.
“Characterization of clonal evolution using cell free DNA from lymphoma patients”
Abstract: Cell free DNA is known to be elevated in malignant conditions and has been applied to solid tumors to monitor tumor dynamics. Analysis of cell free tumor DNA is a young field with early successes of tracking minimal residual disease by high throughput sequencing of the immunoglobulin gene. However this approach does little to reveal clonal evolution and heterogeneity throughout a disease course. Analysis of genomic dynamics through cell free tumor DNA sequencing will subsequently aid biomarker development by non-invasive molecular stratification, monitoring treatment responses and identifying genomic mechanisms of resistance. This proposal is a proof of principle study using cell free DNA in patients with lymphoma to study tumor dynamics.
“Characterizing and modulating the immune evasion landscape in Primary CNS Lymphoma disease models and patients”
Abstract: Diffuse large-B-cell lymphoma represents the most common type of malignant lymphoma and is heterogeneous in its clinical presentation. Involvement of the central nervous system (CNS) occurs as primary CNS lymphoma (PCNSL), with exclusive disease manifestation in the CNS, or as secondary CNS dissemination (SCNSL). Patients with disease that does not respond to or recurs after initial therapy have a poor prognosis. As PCNSL tissue samples are mainly collected through biopsies, there is a paucity of tumor material with a lack of detailed pathophysiologic investigations. Therefore, the mechanisms of immune evasion in PCNSL are largely unknown. We have established a large PCNSL tissue bank with more than 170 tumor samples. We will characterize immune checkpoint markers in our tumor bank with a novel multiplexing immunofluorescence technology platform (MultiOmyx) allowing to quantify the expression of >60 proteins at single cell resolution in a single tissue section. All PCNSL tumor samples have been sequenced with the MSK-HemePACT panel and immune checkpoint marker protein expression can be associated with underlying genomic alterations. Unique PCNSL xenografts established by our group will be used to modulate immune evasion in vivo. The Bruton Tyrosine Kinase (BTK) inhibitor ibrutinib was been used in the MSKCC IRB#14-184 trial and shown to be effective in CNS lymphoma. Furthermore it has been shown to trigger tumor growth inhibition independent of its BTK function through immune modulation. We will build on these findings and propose a combination trial with ibrutinib and an immune checkpoint inhibitor to further improve clinical outcome.
“Mechanisms of response and resistance to checkpoint inhibitor-based treatments in lymphomas”
Abstract: Relapsed lymphomas are typically incurable in the absence of a stem cell transplant, underscoring the need for durable, well-tolerated treatments. Recently, treatments aimed at amplifying the anti-tumor immune response through blockade of the inhibitory immunoreceptor PD-1 have shown activity in multiple lymphoma subtypes; however, complete remissions remain infrequent. As a result, a series of combination strategies have recently been developed at MSKCC with the goal of deepening responses to immunotherapy across multiple lymphoma subtypes. These include facilitation of antigen release (by combining anti-PD-1 therapy with radiation therapy) as well as increasing antigen and co-stimulatory machinery while depleting inhibitory regulatory T-cells (by combining with histone deacetylase inhibition).
I propose to investigate the mechanisms by which combination immunotherapeutic strategies promote anti-tumor responses in relapsed and refractory lymphomas through a series of correlative analyses performed on primary patient samples obtained as part of 3 clinical trials opening in the coming year at MSKCC. Specifically, through a combination of immunohistochemistry, T-cell immunophenotyping, and high throughput T cell receptor sequencing, I will determine biomarkers of response and resistance to these therapeutic strategies. These analyses are critical to gaining a better understanding of how anti- PD-1 therapy functions in lymphoma and will lead to both identification of clinically applicable biomarkers as well as development of next-generation, biologically tailored treatment strategies.
“Dissecting SHMT2 function as a metabolic driver of lymphomagenesis”
Collaborator: Sara Parsa
Abstract: We find that the serine hydroxymethyltransferase-2 gene (SHMT2) is amplified in approx. 30% of human B cell lymphomas including follicular and diffuse large B cell lymphomas. Moreover, our preliminary data show that SHMT2 can act as a driver of lymphoma development in a mouse lymphoma model in vivo. To our knowledge SHMT2 is therefore a first metabolic enzyme that can act as an oncogene in vivo. We propose a study to dissect the metabolic effects of SHMT2 activation in lymphoma, its contribution to lymphoma progression, and we will explore therapeutic implications of SHMT2 activity. Specifically, we have developed a murine model of follicular lymphoma that captures the early stages of the disease and is ideally suited to study genetic drivers of lymphoma development and progression and characterize their biochemical and gene expression effects as well as test new therapies in genetically engineered tumors. We will further investigate the mechanistic effect of SHMT2 activation on lymphomagenesis using a combination of metabolomics and in vivo CRISPR-Cas9 based genetic screening approaches. A better understanding of the role of SHMT2 in Myc amplified lymphoma cells will enable identification of new therapies directed towards aberrant metabolism in these cancers. Metabolic aspects of lymphoma biology and their immediate goal is to strengthen the existing preliminary data towards a full research project.