Cancer recurrence remains a serious problem following liver transplantation in patients with a pretransplant hepatocellular carcinoma (HCC) diagnosis. While patients with limited tumors often have excellent outcomes after transplantation, HCC recurrence that occurs in approximately 1 out of 5 of these cases is largely untreatable. It is likely that standard immunosuppression required to protect against liver transplant rejection also directly contributes to the re-emergence of HCC by simultaneously interfering with immune responses against the cancer.1 Indeed, new immune therapies promoting immune HCC destruction are currently being tested in oncology and show at least some promise.2,3 Therefore, in liver transplant recipients with a history of HCC, special consideration should be taken for using drugs that minimize tumor-promoting immunosuppressive activities. For this purpose, mechanistic target of rapamycin (mTOR) inhibitors have shown promise against HCC in a prospective randomized trial but are not able to indefinitely prevent HCC recurrence.4 The question is whether other immunosuppressants may have advantageous properties that could reduce HCC recurrence on their own or perhaps be used in combination with mTOR inhibitors. In the current issue of Transplantation, Chen et al5 provide evidence that mycophenolic acid (MPA) and its prodrug, mycophenolate mofetil (MMF), inhibit HCC in in vitro experimental models and in patients.
In their publication, Chen et al5 consider the potential for the antiproliferative effects of MPA to be useful in the context of HCC tumor growth and development. The authors show that clinically relevant MPA concentrations substantially inhibit proliferation of different human HCC cell lines and development of colony forming units; in general, cell cycling was arrested by MPA at S-phase, involving a known basic mechanism that limits available guanine nucleotides, which lymphocytes are particularly sensitive to—hence the immunosuppressive effect. Furthermore, the formation of primary mouse liver tumor organoids was also markedly inhibited by MPA in vitro. Interestingly, these experimental antitumor effects were consistent with better survival and less cancer recurrence in a small cohort of HCC-related liver transplant recipients (years 1986–2007) receiving MMF. Overall, their study not only raises the possibility that MMF immunosuppression could be supportive in this patient population, but they also show that new inosine monophosphate dehydrogenase inhibitors (inhibiting guanine nucleotide pools) may possess even more potent antitumor activity without enhancing immunosuppressive properties.
While Chen et al5 provide intriguing data to support the idea that MMF treatment in HCC-related liver transplant patients could be advantageous, there are some aspects of the study, especially the clinical data, that require careful consideration. In particular, the very small cohort of liver transplant patients examined shows a favorable bias toward those patients receiving MMF. For example, the “MMF use” group (n = 12) had a vascular invasion rate of only 9%, while the “no MMF use” group (n = 32) had a rate over 3 times as high; vascular invasion is a well-known high-risk factor for HCC recurrence. Added to the concern about the tumor characteristics data, with only the proportion of patients with >2 tumors shown in the paper, the tumor sizes between groups could have varied widely between the two groups. In addition, alpha fetoprotein levels were generally lower in the “MMF use” group, which could also give an advantage to this patient subgroup with regard to reduced HCC recurrence. It should be noted as well that there was a higher than normally expected HCC recurrence rate (near 60%) and poorer than expected patient survival (40%) after approximately 4–5 years posttransplantation in the “no MMF use” group; recurrence and survival rates normally would be expected to be around 20% and above 60% at this time point, respectively, suggesting that there could have been significant bias in this group related to the limited single-center cohort available for analysis. Finally, it needs to be considered if there is actually an “antitumor” effect of MMF, or whether a reduced “protumor” effect of calcineurin inhibitors (likely given at low doses in these patients) is responsible for any observed differences. Nonetheless, since the HCC recurrence and survival differences between the “no MMF use” and “MMF use” were substantial, for now the results are intriguing and at this stage support their hypothesis and experimental data.
In the end, we do need to find better ways to decrease HCC recurrence in affected liver transplant patients but must be reminded that this is not easy to accomplish considering that we require immunosuppression to prevent graft rejection and at the same time want to promote effective immune responses against HCC. While the testing of new immunotherapies (eg, checkpoint inhibitors) shows potential in HCC oncology trials, and might be considered in the future for liver transplant HCC patients, evidence thus far suggests that checkpoint inhibitors carry a very high risk for eliciting organ transplant rejection.6-8 Therefore, manipulation of immunosuppression using drugs that may have both immunosuppressive and antitumor effects, like mTOR inhibitors and MMF, may actually provide the best possible solution. The article by Chen et al5 now opens the way for interrogating large HCC liver transplant data bases to see if their initial observation of a positive MMF effect can be confirmed. Another aspect that should be considered is dosing, because we published previously that maintaining a stable MPA level is critical to achieve an in vivo antitumor effect (on non-HCC xenogenic tumors).9 For the future, perhaps limiting the use of calcineurin inhibitors, which are associated with HCC recurrence,10 and optimizing the combination of mTOR inhibitors and MMF is a good option to reduce cancer recurrence without risking allograft rejection. Of course, the definitive test would be to assess this option in a prospective randomized trial—the study by Chen et al5 provides incentive to explore these new possibilities for liver transplant recipients with a history of HCC.
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