Abstract 3482: Validation of novel therapeutic targets for T-cell non-Hodgkin lymphoma

Abstract

Abstract T-cell malignancies account for 10-15% of all human non-Hodgkin lymphomas (NHL). T-cell lymphomas are incurable, and the development of effective treatment strategies has been hindered by the relatively infrequency of these conditions. T-cell lymphomas occur spontaneously in dogs; they are morphologically similar to human T-cell lymphomas, resemble their biological behavior, and are relatively common (∼35% of all NHL), providing opportunities to improve our understanding of the pathogenesis of these tumors as well as to develop more effective therapies. Tumor-initiating cells (TICs) influence tumor progression and response to therapy in many cancers, so eliminating these cells may be necessary to achieve durable remissions. However, the existence of TICs and their potential significance have not been conclusively established in T-cell NHL. The objective of this study was to evaluate the existence of progenitor-like lymphoma cells (PLCs) in naturally occurring canine T-cell NHL. We identified a reproducible population of tumor-related PLCs in spontaneous T-cell malignancies. The cells expressed the hematopoietic progenitor antigen CD34 and tumor-specific T-cell receptor gene rearrangements. Somewhat unexpectedly, these cells also express B-cell surface proteins (CD20 and CD22), but not the major T-cell surface antigens (CD3 and CD5) that were expressed by the bulk of the tumor cells (BTCs). We have adapted a xenotransplantation assay for primary canine T-cell NHL using NOD/SCID/IL-2Rgammanull mice and genetically modifying the tumor cells to express luciferase as a means monitor tumor growth and distribution by in vivo imaging. This model allows us to expand and serially transplant primary canine T-cell NHL for more detailed studies, including limiting dilution assays and therapeutic targeting using anti-B-cell reagents. In summary, we propose a novel concept in which a small population of tumor cells with “B-cell progenitor” phenotypes may paradoxically contribute to the pathogenesis of T-cell lymphoma, potentially representing a novel therapeutic target. We already use dogs with naturally occurring disease in the pathway for therapy development, allowing us to expand these studies into clinical trials that can then be rapidly translated to benefit human patients (for example, by using approved agents such as anti-CD20 antibodies or CD22-targeted immunotoxins). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3482. doi:1538-7445.AM2012-3482