Review
Immune checkpoint inhibitor therapy in solid organ transplant recipients: A patient-centered systematic review

https://doi.org/10.1016/j.jaad.2019.07.005Get rights and content

Background

The use of immunotherapies in the treatment of metastatic cancers has significantly advanced oncology. However, due to safety concerns, solid organ transplant recipients (SOTRs) are routinely excluded from immunotherapy trials; thus, there is limited data for these agents in this population.

Methods

A systematic review was performed to evaluate the safety and efficacy of immunotherapies in SOTRs with metastatic cancers. Fisher's exact test and Kruskal-Wallis test were used for analysis.

Results

In total, 37% of patients experienced organ rejection, and 14% died as a result of graft rejection. Nivolumab was associated with the highest rejection rate (52.2%), followed by pembrolizumab (26.7%) and ipilimumab (25%; P = .1774). The highest rejection rate was seen in patients with kidney transplants (40.1%), then liver (35%) and heart (20%) transplants (P = .775), and 64% of patients succumbed to the progression of malignancy. For all cases, rates of progression or death secondary to disease were highest for ipilimumab (75%), followed by nivolumab (43%) and pembrolizumab (40%; P = .1892). The overall response rate was highest for pembrolizumab (40%), followed by nivolumab (30%) and ipilimumab (25%; P = .7929).

Limitations

The small sample size.

Conclusion

Physicians must be cautious when administering immunotherapy to SOTRs. However, rejection is not the most common cause for death in this population.

Section snippets

Methods

This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement.13 A PubMed and Embase database search was performed for articles published up to January 6, 2019, without date restrictions. Search terms included “PD-1 inhibitor,” “immune checkpoint inhibitor,” “CTLA-4 inhibitor,” “ipilimumab transplant,” “nivolumab transplant,” and “pembrolizumab transplant.” Articles were screened by evaluating title and abstract for

Results

In total, 13 SOTRs, from 2 retrospective studies, and 44 SOTRs, from 34 case reports or series, who were treated with immunotherapies for various metastatic cancers were identified for inclusion. The detailed outcomes and demographics of each patient are reported in Table I.14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 In all reported cases, the use of ipilimumab, nivolumab, or pembrolizumab alone

Discussion

SOTRs require close monitoring and augmentation of immunosuppression in order to maintain graft function and prevent graft loss. Immunosuppressive medications act in direct opposition to PD-1 and CTLA-4 immunotherapies, which are used to enhance the cell-mediated immune response to cancer antigens. In mouse and human participant studies, the PD-1–PD-L1 interaction has been shown to be important in graft tolerance and counter-regulation of rejection.50, 51, 52 Furthermore, knockout of CTLA-4 in

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      In patients who relapse after transplantation, the dose of immunosuppressants is usually reduced before starting ICIs treatment to avoid potential interference of immunosuppressants with the antitumor effects of ICIs. It has been reported that replacing tacrolimus with mTOR inhibitors, such as rapamycin in combination with lowdose glucocorticoids during PD-1 inhibitor therapy, can reduce the risk of rejection [48–50]. Previous clinical studies have shown that compared to recipients using calcineurin inhibitors, recipients using mTOR inhibitors have a significantly lower rate of postoperative tumor recurrence, and systemic therapy with mTOR inhibitor combined with sorafenib in patients with HCC recurrence after liver transplantation can achieve a certain degree of survival benefit [51,52].

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    Funding sources: None.

    Conflicts of interest: Dr Zeitouni is a speaker for Genentech, Sanofi, and Biofrontera and has received research grants from Biofrontera and SunPharma. She is also on the advisory board for Sanofi and a consultant for InMed Pharmaceuticals. Dr Fisher, Ms Fan, and Dr Samie have no conflicts of interest to disclose.

    Reprints not available from the authors.

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