Background
Organ transplantation requires lifelong immunosuppression. A side effect is increased post-transplant de novo malignancy. During the last decades, the effectiveness of standard immunosuppressants in allograft transplantation has improved and so has the incidence of de novo cancer. A recent study of 905 recipients of transplanted hearts, lungs, or both has shown a 7.1 times increase in de novo cancers compared to the general population. Cancer-related death following transplantation is increasing and accounts for 13% of all deaths post transplant.
Regulatory T cells (T regs) maintain self-tolerance to autoantigens and are involved in the pathogenesis of various clinical conditions such as autoimmune diseases, chronic viral infections and cancer. Tregs appear more frequently in peripheral blood lymphocytes of cancer patients than healthy controls and interestingly, it seems that high levels of T-regs is a prerequisite for allograft tolerance following transplantation By manipulation of the interaction between CD4+ CD25+ T regs and dendritic cells, it may become possible to influence host offence and defence in cancer and organ transplantation. In these aspects it is of particular interest that immunosuppressive drugs used in transplantation have both an anti-rejection and anti-neoplastic activity. Rapamycin (Sirolimus, Rapamune®) is an established drug for prevention allograft rejection by blocking the intracellular pathway complex mTOR. It also appears that a Sirolimus based immunosuppression protocol has beneficial effects on tumor recurrence and survival with an acceptable rate of rejection and toxicity in liver transplanted HCC patients. Rapamycin is a potent VEGF antagonist showing significant anti angiogeneic effects in addition to a direct inhibitory effect on tumor growth and proliferation. The drug has shown clinical effect and objective x-ray responses and stabilization of disease in different types of cancer, such as advanced breast and renal cancer that has previously progressed on other treatments. Accordingly, rapamycin is an effective anticancer drug in addition to its immunosuppressive effects. This supports the use of the drug for patients transplanted for cancer and in patients with de novo post transplant malignancy.
In 2006 we acquired an ethical approval (S-05409 Regional Ethics Committee, Helse Sor-Ost) for a clinical pilot study (SECA-study) to investigate liver transplantation (Ltx) as treatment option for selected patients with non-resectable liver metastases after colo-rectal carcinoma (CRC), using the mTor inhibitor Rapamycin as standard immunosuppression from postoperative day 1. So far 13 patients have been transplanted in the study. All of the patients had advanced metastatic disease solely to the liver not eligible to resection at the time of Ltx. Twelve of the 13 patients (92%) are alive at 2-27 months follow-up. Health related quality of life (HRQOL) measured with EORTC QLQ-C29/30 is excellent. However, 7 of the 13 patients have experienced recurrence of the disease, five to the lungs, one to the ovary and one to regional lymph nodes. Four patients have been resected for recurrent disease, thus 9 patients are currently disease free. The burden of the surgery and convalescence thereafter is minimal compared to regular chemotherapy (the patients represent their own controls). Thus, it appears that the anti-neoplastic effect of the mTor inhibitor Rapamycin is not sufficient to prevent recurrence of cancer in these patients The study patients receive triple immunosuppressive therapy (IS) post transplant (Prednisolone®, Rapamune® and Cellcept®). The acute rejection rate of the study patients has been remarkable low <15% (in standard patients it is 30%). One possible explantation is that the T-cell profile in these cancer patients make them more tolerant to the allograft. If so, it could imply that the immunosuppressive load in these patients could be reduced further without developing allograft rejection. Furthermore, anti-cancer drugs are by definition cytotoxic in action, but their specific effects on Tcell populations are largely unknown. It would be of interest to explore if chemotheratutic agents may replace traditional IS post transplant. To elucidate these two hypotheses the following theories should explored:
• To characterize the temporal T-cell immunity of CRC patients, to establish if these patients have a higher tolerability for allografts and thus reduced need for traditional IS agents post transplantation.
• To characterize anti-cancer drugs influence on T-cell populations to examine their anti rejection potential in an allograft transplantation setting.
Regulatory T cells (T regs) maintain self-tolerance to autoantigens and are involved in the pathogenesis of various clinical conditions such as autoimmune diseases, chronic viral infections and cancer. Tregs appear more frequently in peripheral blood lymphocytes of cancer patients than healthy controls and interestingly, it seems that high levels of T-regs is a prerequisite for allograft tolerance following transplantation By manipulation of the interaction between CD4+ CD25+ T regs and dendritic cells, it may become possible to influence host offence and defence in cancer and organ transplantation. In these aspects it is of particular interest that immunosuppressive drugs used in transplantation have both an anti-rejection and anti-neoplastic activity. Rapamycin (Sirolimus, Rapamune®) is an established drug for prevention allograft rejection by blocking the intracellular pathway complex mTOR. It also appears that a Sirolimus based immunosuppression protocol has beneficial effects on tumor recurrence and survival with an acceptable rate of rejection and toxicity in liver transplanted HCC patients. Rapamycin is a potent VEGF antagonist showing significant anti angiogeneic effects in addition to a direct inhibitory effect on tumor growth and proliferation. The drug has shown clinical effect and objective x-ray responses and stabilization of disease in different types of cancer, such as advanced breast and renal cancer that has previously progressed on other treatments. Accordingly, rapamycin is an effective anticancer drug in addition to its immunosuppressive effects. This supports the use of the drug for patients transplanted for cancer and in patients with de novo post transplant malignancy.
In 2006 we acquired an ethical approval (S-05409 Regional Ethics Committee, Helse Sor-Ost) for a clinical pilot study (SECA-study) to investigate liver transplantation (Ltx) as treatment option for selected patients with non-resectable liver metastases after colo-rectal carcinoma (CRC), using the mTor inhibitor Rapamycin as standard immunosuppression from postoperative day 1. So far 13 patients have been transplanted in the study. All of the patients had advanced metastatic disease solely to the liver not eligible to resection at the time of Ltx. Twelve of the 13 patients (92%) are alive at 2-27 months follow-up. Health related quality of life (HRQOL) measured with EORTC QLQ-C29/30 is excellent. However, 7 of the 13 patients have experienced recurrence of the disease, five to the lungs, one to the ovary and one to regional lymph nodes. Four patients have been resected for recurrent disease, thus 9 patients are currently disease free. The burden of the surgery and convalescence thereafter is minimal compared to regular chemotherapy (the patients represent their own controls). Thus, it appears that the anti-neoplastic effect of the mTor inhibitor Rapamycin is not sufficient to prevent recurrence of cancer in these patients The study patients receive triple immunosuppressive therapy (IS) post transplant (Prednisolone®, Rapamune® and Cellcept®). The acute rejection rate of the study patients has been remarkable low <15% (in standard patients it is 30%). One possible explantation is that the T-cell profile in these cancer patients make them more tolerant to the allograft. If so, it could imply that the immunosuppressive load in these patients could be reduced further without developing allograft rejection. Furthermore, anti-cancer drugs are by definition cytotoxic in action, but their specific effects on Tcell populations are largely unknown. It would be of interest to explore if chemotheratutic agents may replace traditional IS post transplant. To elucidate these two hypotheses the following theories should explored:
• To characterize the temporal T-cell immunity of CRC patients, to establish if these patients have a higher tolerability for allografts and thus reduced need for traditional IS agents post transplantation.
• To characterize anti-cancer drugs influence on T-cell populations to examine their anti rejection potential in an allograft transplantation setting.
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