Ultrasound detection of non‐Hodgkin's lymphoma in three cynomolgus monkeys after renal transplantation and cyclosporine immunosuppression

Abstract

Ultrasound provides a rapid, non-invasive means of early detection of NHL in animal transplantation models prior to the onset of clinical symptoms of disease.

Immunosuppression by the JAK3 Inhibitor CP-690,550 Delays Rejection and Significantly Prolongs Kidney Allograft Survival in Nonhuman Primates

“…In addition to the absence of obvious neurotoxicity or nephrotoxicity, no cancers were observed in animals dosed with CP-690,550. Although the follow-up was limited to a maximum of 3 months, posttransplant lymphoproliferative disease has been reported as early as 36 days after renal transplantation in NHPs treated with cyclosporine (41)(42)(43). Although JAK3 blockade was potent enough to control organ allograft rejection, we did not observe overt bacterial infections in this population of wildcaught animals housed in standard, nonsterile conditions.…”

Combined Use of the JAK3 Inhibitor CP-690,550 with Mycophenolate Mofetil to Prevent Kidney Allograft Rejection in Nonhuman Primates

“…The tumoral proliferation was found at the routine necropsy check-up and appeared isolated and restricted to a single mesenteric lymph node. NHPs, and particularly cynomolgus monkeys, may be prone to develop lymphomas (44,45) as early as 36 days after renal transplantation upon treatment with cyclosporine (46). Despite the fact that there were no such findings in our previous series of 18 NHP transplant recipients immunosuppressed with CP-690,550 as monotherapy, the current finding obviously warrants caution in the clinical development of this immunosuppressive combination regimen.…”

Carcinogenicity Assessments of Biotechnology-Derived Pharmaceuticals

“…It is interesting to note that for cyclosporine, a drug of choice for transplantation that is also used in the treatment of psoriasis, malignancy risk was also identified in monkey studies. Following pharmacologic cyclosporine immunosuppression and cardiac or renal transplantation in cynomolgus monkeys, lymphomas have been reported in as little as thirty-six days in association with Epstein-Barr Virus (EBV) seropositivity (Gaschen and Schuurman 2001). The contrasting results obtained in monkeys infected with viruses associated with lymphoma following exposure to cyclosporine, or immunosuppressive biotherapeutics (alefacept and abatacept) illustrates that although viral transformation is a known mechanism by which immunosuppressive agents can underlie carcinogenicity, demonstration of the associated risk in monkeys infected with viruses linked to cancer is difficult.…”

“…Neoplasia, presumably associated with viral recrudescence, has been observed in cynomolgus monkeys following administration of immunosuppressive agents such as cyclosporine (Gaschen and Schuurman 2001) and alefacept. However, the ability to detect neoplasia will depend heavily on the background of the specific primate colony, the nature of the immunosuppression, and specifics of the study design, such as study duration and number of animals, as illustrated by the lack of findings with known oncogenic immunosuppressive agents (Haustein et al, 2008; Lerche and Osborn 2003; Mahalingam et al 2007; Sasseville and Diters 2008; Wachtman and Mansfield 2008).…”