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7th International Conference on New Trends in Immunosuppression and Immunotherapy

Berlin, Germany / February 16-19, 2006

“Cancer is now a leading cause of death in organ transplantation, having passed even cardiac death at some centres,” according to Dr. Josep Campistol, Provincial Hospital Clinic, Barcelona, Spain. “After 10 to 30 years, 80% of patients will develop a malignancy. About 75% of those will be skin cancer, but 40% of transplanted individuals will eventually develop an organ cancer that will often be the cause of death in otherwise successfully treated cases.”

Dr. Campistol noted that calcineurin inhibitors (CNIs), in particular, have an unmistakable oncogenic effect that appears to be related to the intensity of immunosuppression. The incidence of cancer is significantly greater and time to development of malignancy is significantly shorter when patients are treated with more intense CNI immunosuppression, he explained, adding that CNI use has been shown to lead especially to lung metastasis and larger organ tumours. Moreover, it is believed that CNI immunosuppressive agents may activate cancer-causing oncoviruses.

As suggested by Dr. Campistol, the new family of mTOR inhibitors are not only powerful immunosuppressive agents in their own right, but also possess significant anti-tumour and anti-cell cycle proliferative effects that are independent of their immunosuppressive properties. When it binds to mTOR, sirolimus blocks one of the main pathways used by oncogenes that are commonly implicated in human cancer. “The mTOR inhibitors block tumour activity in two ways; one by blocking tumour growth and the second by blocking angiogenesis,” Dr. Campistol explained. “Angiogenesis plays a strategic role in the development and growth of tumours and propagation of metastasis.”

Kidney Transplant Results

Dr. Campistol’s initial observation that replacing cyclosporine (CsA) with sirolimus could lead to comprehensive regression of established Kaposi’s sarcoma in transplant patients has been confirmed in an Italian trial. Fifteen cadaveric kidney recipients were switched from CsA and mycophenalate mofetil (MMF) plus prednisone to sirolimus and prednisone when Kaposi’s sarcoma was diagnosed. He reported that the skin lesions began disappearing within one month and had completely vanished in all patients by month 3 following the initiation of sirolimus. All biopsy specimens taken at six months were histologically negative for Kaposi’s sarcoma.

To investigate the impact on graft survival and function of withdrawing CsA from a sirolimus-containing regimen, more than 500 renal transplant patients were assigned to triple-agent therapy with sirolimus, CsA and steroids, with CsA treatment being withdrawn from half of the patients after three months. The other half were maintained on sirolimus plus a steroid.

Dr. Campistol reported, “Graft survival and renal function at three and four years’ follow-up were significantly superior in patients who were removed from CNI treatment at three months, and they had a better histologic profile. The incidence of any type of malignancy at five years was significantly lower in the patients no longer taking CsA.”

He added, “For skin cancer, the difference between the treatment arms was very great and statistically significant both by on-therapy and intention-to-treat [ITT] analysis. The incidence of organ cancer in the ITT analysis at five years was significantly lower in patients not taking CsA than those on triple therapy, and this included lung, bladder, kidney, gastrointestinal and other cancers. Of the seven cancer-related deaths in the study, five occurred in the triple-therapy group and two in the cohort receiving sirolimus plus steroid.”

Mechanisms for Change

Dr. Edward Geissler, University of Regensburg, Germany, pointed out that transforming growth factor-beta (TGF-ß), which affects tumour growth and has been reported to actually render tumour cells more invasive, is increased by CNIs, as is vascular endothelial growth factor (VEGF), which he indicated is probably the most important growth factor for the formation of the blood vessels tumours need to expand and grow. The activities of mTOR inhibitors, on the other hand, are mediated through the inhibition of those intracellular signalling pathways that are vital for cancer cell growth, metastasis and tumour angiogenesis. “If we block mTOR, we may block the ability of cancer cells to function, grow and expand,” he told delegates. “To test that premise, we implanted colon adenocarcinomas into mice and observed that the tumours became substantially inhibited in sirolimus-treated animals compared with the large and well-vascularized ones in saline controls.”

Dr. Geissler reported that the area of vascularization in sirolimus-treated animals was much smaller and the developing blood vessels did not interconnect well or function effectively enough to provide blood needed for the tumours to expand, whereas the rapid formation of vessels in a number of the animals given CsA was even more prolific than in those who remained untreated with any active compound. He said sirolimus limits angiogenesis by inhibiting the production, transcription and signalling capacity of VEGF, and this has been observed in many models, including human renal-cell carcinoma and adenocarcinoma at his institution. Moreover, he added that the anti-tumour effect of mTOR inhibition in organ transplant recipients is not lost even in the presence of a CNI.

“If we use an mTOR inhibitor, perhaps we can counterbalance the malignant effects of immunosuppression in organ transplant patients by decreasing angiogenesis, inhibiting tumour growth and metastasis of tumour cells,” he concluded. “These new immunosuppressive agents may even exert a favourable effect on viral replication, which would be important because the tumours associated with transplantation are often initiated by viruses.”

Post-transplant Organ Function

“Nephrotoxicity accompanies the continuous use of CNI drugs in virtually all treated kidney transplant patients and we are stuck with the inexorable decline of renal function with time,” remarked Dr. Stuart M. Flechner, Cleveland Clinic Lerner College of Medicine Transplant Center, Ohio. “Results deteriorate quite briskly after the first year, with a large amount of graft loss by five years and 10-year numbers that are no better than over past decades, showing a decline in renal function accompanied by features of CNI nephrotoxicity.”

In a prospective, randomized trial to explore the outcome of CNI-free immunosuppression in low- to moderate-risk renal transplant recipients, his group used basiliximab induction followed by MMF, steroids and either sirolimus or CsA. Dr. Flechner reported that the rates of delayed graft function of cadaveric donor recipients and acute rejection were no higher in the CNI-free population as long as patients were treated with antibodies. Beginning at three months, there was a significant 15% to 20% difference in serum creatinine in favour of CNI-free treatment.

A substudy of the same patient group demonstrated that more than 70% of CNI-free patient biopsies were Banff 0, in contrast to only 20% of those on CNI. There was also a difference in measured glomerular filtration rates (GFRs) of up to 20% and no significant difference in protein excretion. Regarding patient survival, there has been no penalty for being CNI-free at five years, but there was a 7% difference in graft survival. Censoring out those who died with graft function, the difference in graft survival at five years was 20%.

“CNI-free immunosuppression with antibody induction can be done safely, with comparable five-year outcomes in low- to moderate-risk patients,” Dr. Flechner concluded. “The CNI-free combination results in better renal function at all time points, preserved graft histology at two years, and I believe the implication from the preserved histology is improved GFR.”