Integrin αvβ3 Presents a Possible Therapeutic Target for Patients with T-cell Lymphomas

lecBy Leandro Cerchietti, MD

Malignant T-cell proliferation, survival, and drug resistance are dependent on a combination of external stimuli delivered by the micro-environment. Previous research has shown that the transmembrane receptor integrin αvβ3 plays a crucial role in mediating the interaction of T-cell lymphoma (TCL) cells with external signals. Integrin αvβ3 ligands include extracellular matrix-associated signaling proteins and soluble factors such as thyroid hormones (TH). Having previously shown that TH stimulate the proliferation of TCL through complimentary intracellular pathways involving the αvβ3 integrin, we hypothesized that targeting integrin αvβ3 could represent a novel strategy in treating TCL patients in an abstract presented during ASH.

In determining whether αVβ3 integrin is of therapeutic benefit for TCL, xenografts were developed in SCID mice using CUTLL1 cells transfected with si-control, si-αV and si-β3, and monitored tumor growth and angiogenesis. CUTLL1 was found to transfect with si-αV and si-β3 developed significant smaller tumors than si-control. The translational impact of this strategy was determined through the effect of cilengitide, a selective αVβ3 integrin inhibitor in phase 3 for glioma, in pre-clinical models of PTCL-NOS,  ALCL-ALK+ and  ALCL-ALK-. Similarly to si-αV and si-β3 treated mice, the anti-lymphoma effect of cilengitide correlated with lower levels of angiogenesis and NFkB activation.

This allowed us to elucidate the mechanisms by which integrin αvβ3 activation increases TCL proliferation through the activation of pro-survival pathways in malignant T-cells, while promoting angiogenesis. In the course of our research we also found that the genetic and pharmacological targeting of integrin αvβ3 induces an anti-lymphoma effect in TCL, including ALCL-ALK + and ALCL-ALK- PDT models obtained from treatment refractory patients. Both of these findings present potentially new therapeutic targets for the treatment of patients with T-cell lymphoma.

Circulating Memory T-cell Isolated from Hodgkin Lymphoma Patients Display Evidence of Exhaustion and Chronic Activation

Picture2By Jia Ruan, MD, PhD

Although Hodgkin Reed-Sternberg (HRS) cells comprise only a small number of tumor cells, their number is outweighed by their relative importance as the orchestrators of an inflammatory microenvironment that allows for the growth of Hodgkin Lymphoma (HL). The peritumoral CD4 and CD8 cells in patients with HL, display high expression of the receptor programmed death-1 (PD-1). PD-1 is involved in the functional impairment and “exhaustion” of T-cells. Recent data confirms that the effects of HL-mediated immune suppression may stretch beyond the tumor microenvironment, with reports of high levels of inflammatory cytokines and chemokines in patients with both newly diagnosed and relapsed HL.

In results presented from an abstract presented during the 2014 American Society of Hematology conference (ASH), we found that HL patients have evidence of chronic activation/exhaustion in their central memory and effector T-cells. Informed consent was requested for correlative blood testing was obtained from patients with both newly diagnosed and relapsed HL. For patients with progressive disease persistence of this phenotype is worthy of further investigation as to whether immune dysfunction results from or is caused by resistance to therapy. An answer to this question may provide the rationale for an immune targeted therapy in patients with relapsed or resistance HL.

ASH 2014 – WCMC Related Abstracts

It has been another productive year for research in the Lymphoma Program at Weill Cornell Medical College. Listed below are the abstracts we were involved in whole or in part to be presented at this year’s 56th Annual Meeting of the American Society of Hematology (ASH).

Look to this space for future updates about developments at ASH 2014.

Anaplastic Large Cell Lymphoma
781 – Convergent Mutations and New Kinase Fusions Lead to Oncogenic STAT3 Activation in Anaplastic Large Cell Lymphoma
1679 – Identification of a New Subclass of ALK Negative Anaplastic Large Cell Lymphoma Expressing Aberrant Levels of ERBB4 Transcripts

CLL/SLL
327 – Efficacy and Safety of Ibrutinib in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Leukemia with 17p Deletion: Results from the Phase II RESONATE™-17 Trial
330 – Second Interim Analysis of a Phase 3 Study of Idelalisib (ZYDELIG®) Plus Rituximab (R) for Relapsed Chronic Lymphocytic Leukemia (CLL): Efficacy Analysis in Patient Subpopulations with Del(17p) and Other Adverse Prognostic Factors
1990 – Pattern of Use of Anticoagulation and/or Antiplatelet Agents in Patients with Chronic Lymphocytic Leukemia (CLL) Treated with Single-Agent Ibrutinib Therapy
3316 – Extracellular Nicotinamide Phosphoribosyltransferase (NAMPT) Shapes the CLL Microenvironment Promoting Macrophage M2 Polarization Via a Non-Enzymatic Mechanism
3331 – Updated Efficacy Including Genetic and Clinical Subgroup Analysis and Overall Safety in the Phase 3 RESONATETM Trial of Ibrutinib Versus Ofatumumab in Previously Treated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
4615 – Cancer-Associated Mutations in SF3B1 Exhibit Neomorphic Splicing Activity and Block Erythroid Differentiation
3343 – Long-Term Follow-up of a Phase 1 Trial of Idelalisib (ZYDELIG®) in Combination with Bendamustine (B), Bendamustine/Rituximab (BR), Fludarabine (F), Chlorambucil (Chl), or Chlorambucil/Rituximab (ChlR) in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL)

DLBCL
59 – Demethylase Activity of Aid during Germinal Center B Cell Maturation Could Contribute to Lymphomagenesis
143 – Akt Activation Confers an Inferior Survival in Patients with Activated B-Cell Subtype of Diffuse Large B-Cell Lymphoma: A Report from the International DLBCL Rituximab-CHOP Consortium Program
567 – BCL6 Mediates a Stress Tolerance Phenotype through Its BTB Domain
864 – Strand-Specific Total RNA Sequencing Establishes the Complete Transcriptome and Alternative Splicing Repertoire in Diffuse Large B Cell Lymphoma
928 – A Virtual B Cell Lymphoma Model to Predict Effective Combination Therapy
1620 – NF-κB Subunit c-Rel Cooperates with Myc and Mutated p53 to Confer Significantly Worse Survival in Patients with Diffuse Large B-Cell Lymphoma: A Report from the International DLBCL Rituximab-CHOP Consortium Program
1692 – Genetic Mechanisms of Immune Escape in Diffuse Large B Cell Lymphoma
1764 – Hsp90 at the Hub of Metabolic Homeostasis in Malignant B Cells
2032 – Whole-Genome Epigenomic Analysis in Multiple Myeloma Reveals DNA Hypermethylation of B-Cell Specific Enhancers
2963 – Mirna-181a expression Lead to Longer Animal Survival and Slower Tumor-Growth Rate in Diffuse Large B-Cell Lymphoma Xenograft Models
3021 – Characterization of DLBCL-Derived Exosomes and Investigation of Their Biological Properties
3091 – Unexpected and Serious Toxicity Observed with Combined Idelalisib, Lenalidomide and Rituximab in Relapsed/Refractory B Cell Lymphomas: Alliance A051201 and A051202
3547 – EBV Microrna Mir-BHRF1-2 Targets PRDM1/Blimp1: Potential Role in EBV Lymphomagenesis
4417 – A Phase 1 Study of the BET-Bromodomain Inhibitor OTX015 in Patients with Non-Leukemic Hematologic Malignancies

Hodgkin Lymphoma
501 – Results of a Phase II Trial of Brentuximab Vedotin As First Line Salvage Therapy in Relapsed/Refractory HL Prior to AHCT
4400 – Circulating Memory T Cells Isolated from Hodgkin Lymphoma Patients Display Evidence of Exhaustion and Chronic Activation

Mantle Cell Lymphoma
625 – Sustained Remission with the Combination Biologic Doublet of Lenalidomide Plus Rituximab As Initial Treatment for Mantle Cell Lymphoma: A Multi-Center Phase II Study Report
2250 – Acquired in Vitro Resistance to Ibrutinib Is Associated with Transcriptional Re-Programming and Sustained Survival Signaling in Waldenströms Macroglobulinemia and Mantle Cell Lymphoma, Independent of BTK Cys481Mutation
3047 – Poor Overall Survival of Patients with Ibrutinib-Resistant Mantle Cell Lymphoma
4453 – Single-Agent Ibrutinib Demonstrates Safety and Durability of Response at 2 Years Follow-up in Patients with Relapsed or Refractory Mantle Cell Lymphoma: Updated Results of an International, Multicenter, Open-Label Phase 2 Study
4461 – Safety Results from the United States Cohort of the Ibrutinib Early Access Treatment Protocol (EAP: MCL4001) in Patients with Relapsed or Refractory Mantle Cell Lymphoma
4471 – Efficacy and Safety of Single-Agent Ibrutinib in Patients with Mantle Cell Lymphoma Who Progressed after Bortezomib Therapy

Marginal Zone Lymphoma
705 – The Coding Genome of Nodal Marginal Zone Lymphoma Reveals Recurrent Molecular Alterations of PTPRD and Other Jak/Stat Signaling Genes

Non-Hodgkin Lymphoma
60 – Protein Arginine Methyltransferase 5 Directly Targets and Epigenetically Silences microRNAs miR33b and miR96 to Support Constitutive Cyclin D1 Activity in Non-Hodgkin’s Lymphoma
3063 – Durable Responses Following Treatment with the PI3K-Delta Inhibitor Idelalisib in Combination with Rituximab, Bendamustine, or Both, in Recurrent Indolent Non-Hodgkin Lymphoma: Phase I/II Results

T-cell Lymphoma
510 – Integrin αvβ3 Transduces Survival and Angiogenic Signals to T Cell Lymphomas and Is a Therapeutic Target
810 – Transcription Regulation Targeting in Peripheral T Cell Lymphomas Induces Apoptosis and Sensitization to BCL2 Inhibitors

Waldenstrom’s Macroglobulinemia
1689 – The Selective Bcl-2 Inhibitor ABT-199 Synergizes with BTK or Proteasome Inhibitors to Induce Potent Cell Death in Preclinical Models of Bortezomib or Ibrutinib-Resistant Waldenströms Macroglobulinemia
2250 – Acquired in Vitro Resistance to Ibrutinib Is Associated with Transcriptional Re-Programming and Sustained Survival Signaling in Waldenströms Macroglobulinemia and Mantle Cell Lymphoma, Independent of BTK Cys481Mutation
3115 – Therapeutic Sensitivity of CD20- Waldenströms Macroglobulinemia Cells Is Determined By Underlying Genomic and Epigenetic Events
3116 – Targeted Disruption of USP14 and UCHL5 with the Novel Deubiquitinase Enzyme (DUB) Inhibitor, VLX1570, Induces Immense Proteotoxicity and Cell Death in Malignant Plasma Cells
3551 – Methylation Patterns in Waldenströms Macroglobulinemia Cells That Are Inherently Resistant or Have Acquired Resistance to Bortezomib, Converge on the TP63 and Cepba Family of Transcription Factors