Establishment and application of a panel of PBMC-humanized mouse tumor models in cancer immunotherapy

Background: To meet the rapidly growing I/O market, the demands for fast, relevant and cost effective mouse tumor model systems are also increasing. We developed a panel of straightforward humanized tumor models, designated as MiXeno platform. Methods: CrownBio has established a sizable collection of MiXeno models where human PBMCs were reconstituted in the mouse system for the evaluation in vivo activity of immune checkpoint inhibitors or immune-modulators. These MiXeno models were characterized with tumor response to anti-PD-1 and anti-CTLA4 antibodies, and onset of possible graft versus host disease (GVHD) or graft versus tumor response (GVT) under different settings. To engage both host immune system and tumor antigens, we have developed some specific Mixeno tumor models by inoculating tumor cells over-expressing specific anti-tumor antigens (e.g. EGFR, CD47, Braf or PD-L1) into PBMC-humanized immunocompromised mice. Moreover, to improve capacity and consistency of MiXeno platform, we are conducting studies to characterize and validate commercialized frozen PBMCs for MiXeno model establishment. Results: Models with over-expression of a variety of tumor antigens (e.g. EGFR, CD47, Braf, PD-L1...) were used to develop specific Mixeno tumor models. Meanwhile, in order to overcome the limitation of PBMC shortage, commercialized PBMC has been purchase and implanted into several xenograft models, and exhibit consistent tumor growth with fresh PBMC, as well as human immune component reconstitution. Up to date, a variety of test articles of different categories, including checkpoint inhibitors, T cell modulators and bispecific T cell engagers (e.g. EpCam-CD3, CD47/CD3, BCMA/CD3) have been evaluated using this platform. Merchandized I/O drugs, such as Pembrolizumab, are being tested in commercialized PBMC implanted immunocompromised mice. Conclusions: MiXeno platform are valid model system for the human immuno-modulatory drugs including bispecific antibodies evaluation and will be optimized by introduction of specific Mixeno tumor models, commercial PBMC and B2M mice. Legal entity responsible for the study: CrownBio. Funding: CrownBio. Disclosure: L. Bourre, L. Zhang, S. Qi, H. Wu, L. Zhao, X. An, M. Qiao, Q. Shi, W. Yang: Employee: CrownBio. All other authors have declared no conflicts of interest.