Xenotransplantation of genetically modified pig organs offers great potential to address the shortage of human organs for allotransplantation. Persistence of hyperacute rejection in Gal KO pigs due to elicited non Gal antibody response required further genetic modifications of donor pigs and better control of the B cell response to xeno antigens. We report significant prolongation of graft survival of 8 months when peri-transplant B-cell depletion was added to an established anti CD154 and MMF based immunosuppressive regimen. Specifically Galactosyl transferase “knock-out” and human CD46 transgenic (GTKO.CD46Tg) pig cardiac xenografts were heterotopically transplanted into specific pathogen free (SPF) baboons. The B cell numbers and non Gal antibody production remained suppressed for over 2 months after only 4 doses of induction treatment with an anti CD20 antibody. Continuous evaluation of the transplanted hearts and recipients by telemetry provided accurate assessment of graft function and aided post operative care, allowing prevention of several major complications. The significant difference in graft survival with the addition of anti CD20 antibody identifies a critical role for B cells in the mechanisms of delayed xenograft rejection and represents a significant advance toward clinical application.

Epithelioid hemangioendothelioma (EHE) is a genetically homogenous vascular sarcoma that is a paradigm for TAZ dysregulation in cancer. EHE harbors a WWTR1(TAZ)-CAMTA1 gene fusion in >90% of cases, 45% of which have no other genetic alterations. In this study, we used a first of its kind approach to target the Wwtr1-Camta1 gene fusion to the Wwtr1 locus, to develop a conditional EHE mouse model whereby Wwtr1-Camta1 is controlled by the endogenous transcriptional regulators upon Cre activation. These mice develop EHE tumors that are indistinguishable from human EHE clinically, histologically, immunohistochemically, and genetically. Overall, these results demonstrate unequivocally that TAZ-CAMTA1 is sufficient to drive EHE formation with exquisite specificity, as no other tumor types were observed. Furthermore, we fully credential this unique EHE mouse model as a valid preclinical model for understanding the role of TAZ dysregulation in cancer formation and for testing therapies directed at TAZ-CAMTA1, TAZ, and YAP/TAZ signaling.