Immune Checkpoint Inhibitors and the Risk of Allograft Rejection: A Comprehensive Analysis on an Emerging Issue
Open accessAbstract
Background: It is well known that the state of immune tolerance induced by broad immunosuppression to prevent allograft rejection leads to an increased risk of the development of cancer. One of the most promising new areas of cancer treatment has been the development of immune checkpoint inhibitors that target the cytotoxic T-lymphocyte-associated antigen 4 and programmed cell death protein 1/programmed death-ligand 1 (PD-L1) pathways. As a logical consequence, growing interest in these agents translated into their implementation in patients with transplant-related malignancies. Because of overlapping and perhaps mutually exclusive mechanisms of action of transplant immunosuppression and cancer immunomodulation, it is critical to examine these interactions. Materials and Methods: We carried out a systematic search for review articles and case reports published between July 2014 and November 2017 using three engines: Usearch, PubMed, and Up-to-date. Results: Overall, there were 20 cases with 12 allograft rejections. The rejection rate associated with nivolumab was 73% (8/11) and with pembrolizumab it was 100% (2/2). The use of ipilimumab did not lead to rejection in any instance (0/4, 0%). Of the two patients treated with the sequential use of ipilimumab/nivolumab, one lost his allograft, yielding a rejection rate of 50%. The sequential use of ipilimumab/pembrolizumab led to a rejection rate of 100% (1/1, 100%). Conclusion: The use of agents that act on the PD-L1 pathway are contraindicated in the face of solid organ allografts because of unacceptably high rates of irreversible allograft rejection. It appears that the use of ipilimumab may be tolerated as the mechanism is different from that of the PD-L1 agents. Implications for Practice: Transplant rejection is a complex process that puts stress on patients and their families and can lead to tragic results. Significant advancements in the field of immunosuppression have led to the engenderment of agents devised to extend the survival of transplant recipients. The advent of immunomodulators in cancer therapy has been paradigm-shifting; however, because of their mechanism of action, their use must be carefully considered in patients with allografts and concomitant cancer. It appears that ipilimumab can be administered safely in these patients but that agents acting on the programmed death-ligand 1 pathway are contraindicated because of high rates of irreversible rejection.
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Cancer immunotherapy results in organ rejection in the majority of patients with renal transplants who are candidates for ICIs.
“Cancer immunotherapy results in organ rejection in the majority of these patients, requiring more immunosuppression to prevent allograft rejection and graft loss7–9.”
From Targeting the mTOR pathway uncouples the efficacy and toxicity of PD-1 blockade in renal transplantation (2019) · cites this paper as [7]
Key recent reviews of all transplant cases treated with ICIs highlight the vast heterogeneity of immunosuppression regimens used and the void of translational data guiding treatment decisions.
“Key recent reviews of all the transplant cases treated with ICIs highlight the vast heterogeneity of the immunosuppression regimens used in this setting the void of any translational data guiding treatment decisions7–9.”
From Targeting the mTOR pathway uncouples the efficacy and toxicity of PD-1 blockade in renal transplantation (2019) · cites this paper as [7]
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Esfahani, K., Al-Aubodah, T.-A., Thebault, P., Lapointe, R., Hudson, M., Johnson, N. A., Baran, D., Bhulaiga, N., Takano, T., Cailhier, J.-F., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-12628-1 · Cited by 109 · see citing works
- Authors
- Aguirre, L. E., Guzman, M. E., Lopes, G., & Hurley, J.
- Affiliations
- University of Miami (US)
- Department of Hematology/Oncology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida, USA
- Corresponding author
- Hurley, Judith
- Venue
- The Oncologist
- Publisher
- Oxford University Press (OUP)
- Published
- 2018-11-09
- Volume
- 24
- Issue
- 3
- Pages
- 394-401
- ISSN
- 1083-7159 (ISSN-L)
- 1549-490X
- PMC
- PMC6519766
- OpenAlex
- W2899970113
- Cited by
- 68
- References
- 46
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 13 · 2023: 5 · 2022: 14 · 2021: 13 · 2020: 7 · 2019: 8
- FWCI
- 2.63
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- The Oncologist (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Surgery › Transplantation: Methods and Outcomes
- Health Sciences › Medicine › Transplantation › Renal Transplantation Outcomes and Treatments
- Keywords
- immune checkpoint inhibitors, allograft rejection, CTLA-4, nivolumab, pembrolizumab, ipilimumab, immunosuppression, solid organ transplantation, cancer immunotherapy, drug interactions, immune tolerance, sequential immunotherapy
- MeSH terms
- Antibodies, Monoclonal, Graft Rejection, Humans, Male, Middle Aged, Programmed Cell Death 1 Receptor, Allografts
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