Abstract A009: Establishment and application of a series of systemic bioluminescent hematologic cell line derived xenograft models
Authors: Song Yanrui , Nie Chenpan , Yang Tao , Yin Yinfei , Li Henry Qixiang , Ouyang Davy Xuesong 
Published: March 2020

Background: Hematologic malignancies, including leukemia, multiple myeloma and lymphoma, are at the forefront of immunotherapeutic innovations. Fueled by FDA approvals of two CD19 CAR-T therapies for relapsed/refractory B-cell precursor acute lymphoblastic leukemia (B-ALL) & diffuse large B-cell lymphoma (DLBCL) in the past 2 years, more than 500 of CAR-T, TCR-T and CAR-NK therapeutics are now in clinical testing. Majority of these cellular therapeutic trials target hematologic cancers, with CD19 as the dominant target, followed by BCMA, CD20, CD22, and CD33 etc. There are also a large numbers of bispecific T cell engagers, immune checkpoint inhibitors, and combinations of immunotherapeutics with radiotherapy, chemotherapy, targeted drugs at various stages of discovery and development. We need clinically relevant animal models to test the effectiveness of those treatments before entering clinic. Methods: Currently, most preclinical models of hematologic malignancies employ subcutaneous xenografts which rarely home to bone marrow or lymphoid organs, or metastasize to other tissues, thus unable to mimic the disseminated progression of disease. Several systemically engrafted xenograft models recapitulate patient disease progression much better, but the readout is often limited to single survival endpoint, which restricts our understanding of how tumors establish, progress and respond to treatment. In order to enable real-time monitoring of disease progression and response to various therapeutics, we have generated and characterized a series of firefly luciferase (Fluc) expressing hematologic xenograft models. Results: We have developed Fluc expressing DLBCL model Raji, as well as 4 derivatives from the parental line: Raji-PD-L1 (over-expressing human PD-L1), Raji-CD19KO (CD19 knockout), Raji-CD22KO (CD22 knockout), and Raji-CD19/22KO (CD19 & CD22 double knockout). We have also developed Fluc expressing multiple myeloma model MM.1S and three leukemia models Nalm6, MEC-1 and CCRF-CEM. These systemic CDX models have been successfully established in NPG/NOG mice via intravenous (i.v.) inoculation. Tumor progression was monitored by IVIS bioluminescent imaging twice per week with additional survival readout and endpoint ex vivo imaging of relevant tissues. Standard of care treatments were also tested in some models. Our data show that lenalidomide treatment leads to statistically significant anti-tumor response in MM.1S-Luc; while rituximab led to lower tumor burden in Raji-Luc, with no significant benefit on survival. We are continuing to characterize these models with immunotherapeutics and cellular therapies to determine opportunities for combination strategies. Conclusion: We have generated a series of systemic bioluminescent cell line xenograft models compatible with optical imaging to facilitate the drug discovery work for hematologic malignancies.

Citation Format: Yanrui Song, Chenpan Nie, Tao Yang, Yinfei Yin, Henry Qixiang Li, Davy Xuesong Ouyang. Establishment and application of a series of systemic bioluminescent hematologic cell line derived xenograft models [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A009. doi:10.1158/1535-7163.TARG-19-A009