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.

Brentuximab Vedotin is Efficacious as First Line Salvage Therapy in Patients with Relapsed/Refractory Hodgkin Lymphoma Prior to Autologous Hematopoietic Cell Transplantation

Picture1By Peter Martin, MD

Brentuximab vedotin (BV), is an antibody drug conjugate that selectively binds to a protein called CD30 on the surface of cells (e.g., Hodgkin lymphoma cells) and delivers a payload of toxin (monomethyl auristatin E) directly to that cell; i.e., a Trojan horse approach to cancer therapy. In 2011, the United States Food and Drug Administration (FDA) approved BV based on a phase II trial in which BV demonstrated an overall response rate (ORR) of 75% and complete response rate (CR) of 34% in patients with Hodgkin lymphoma that had relapsed following autologous hematopoietic cell transplantation (AHCT). Given the promising data, investigators at City of Hope and Weill Cornell Medical College-New York collaborated to evaluate the use of BV prior to AHCT. The standard approach for patients that relapse after first-line therapy includes cytotoxic chemotherapy followed by AHCT. However, this approach can be challenging for some patients and may be associated with some short-term and long-term toxicity. Use of BV prior to AHCT may cause patients some side effects and improve their quality of life prior to AHCT. Preliminary data from this trial were presented yesterday at the 56th Annual Meeting of the American Society of Hematology (ASH).

All patients had biopsy proven Hodgkin lymphoma that had relapsed following therapy with ABVD, BEACOPP, or a combination +/- radiation. Patients were treated with a standard dose of BV intravenously every 3 weeks for a maximum of 4 cycles. Over two-thirds of patients responded, including one third of patients that obtained a CR) and roughly half of the patients were able to proceed to AHCT without receiving additional chemotherapy. Treatments were well tolerated by all patients and no transfusions were required or neutropenic fevers developed.

The results from this trial suggest that BV may be an efficacious option as a first line salvage therapy. It is well tolerated and does not hinder stem cell collection or engraftment. Additional studies will be required to confirm these results. Moreover, this study may lay the groundwork for future studies with promising combinations.

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