Abstract 3719: Systemic and subcutaneous modeling of A20 murine B cell lymphoma in mice: A comparative assessment
Authors: Barnes Sheri R. , Urs Sumithra , Draper David , Wise Scott , Franklin Maryland Rosenfeld 
Published: August 2019

To advance immuno-oncology drug development, there is a need for well-characterized syngeneic tumor models. In addition to subcutaneous modeling, orthotopic models are equally important for preclinical development as they are posited to have improved clinical translatability compared to subcutaneous implantation. To this end, we have generated both subcutaneous and systemic A20 murine B cell lymphoma models.

Specific to orthotopic modeling, a luciferase-enabled A20 model (A20-luc) was created to monitor tumor progression by bioluminescence imaging. Systemic parental A20 or A20-luc models show slight differences in median survival (34.5 days and 39 days, respectively) but similar take rates and clinical manifestations, including abdominal distension and metastatic foci in the liver. These data suggest that parental A20 and A20-luc behave similarly in systemic disease.

To understand how checkpoint blockade and costimulatory agonists act on A20, anti-mPD-1, anti-mPD-L1, anti-mCD137, and anti-mGITR were evaluated for efficacy against both established subcutaneous and systemic A20 models. Our data indicate that neither anti-mPD-1 nor anti-mGITR demonstrate antitumor activity in either model. Anti-mPD-L1 is inactive in systemic disease but shows some efficacy on A20 subcutaneous tumors with delayed growth observed in 40% of mice. Contrastingly, the costimulatory agonist anti-mCD137 elicits a stronger response, with 50% of established subcutaneous A20 tumors having delayed growth including two complete responses and one tumor free survivor. Similarly, in systemic A20 disease, 50% of animals treated with anti-mCD137 exhibited a profound decrease in luciferase signal. While modestly responsive, both A20 and A20-luc show promise for use in combination strategies.

To determine whether this modest activity is due to an infiltration of immunosuppressive cells into the tumor, the composition of immune cells in established subcutaneous A20 tumors was evaluated. Despite modest activity, 50% of total CD45+ infiltrate were T cells and NK cells, 7% were MDSCs and macrophages, and the remaining were dendritic in nature. As high T cell infiltrate is more common in tumors responsive to immunotherapy, these infiltrated T cells are hypothesized to lack signals required for activation or are reactive to non-tumor-associated antigen. Similar assays with metastatic foci resulting from systemic disease are planned.

Both subcutaneous and orthotopic A20 models exhibit favorable characteristics for evaluation of investigational agents. Response to immunotherapy is minimal to moderate in both models but are generally aligned. The high infiltrate of T cells in the subcutaneous model have potential for exploitation of this model in development of agents targeting T cells. Taken together, our results indicate that A20 is a favorable syngeneic tumor model for both subcutaneous and orthotopic applications.

Citation Format: Sheri R. Barnes, Sumithra Urs, David Draper, Scott Wise, Maryland Rosenfeld Franklin. Systemic and subcutaneous modeling of A20 murine B cell lymphoma in mice: A comparative assessment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3719.