• 1.

    Koch Hein EC, et al. Immune checkpoint inhibitors in advanced cutaneous squamous cell carcinoma: Real-world experience from a Canadian comprehensive cancer centre. Cancers 2023; 15:4312. doi: 10.3390/cancers15174312

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  • 2.

    Carroll RP, et al. Immune checkpoint inhibitors in kidney transplant recipients: A multicentre, single-arm, phase 1 study. Lancet Oncol 2022; 23:10781086. doi: 10.1016/S1470-2045(22)00368-0

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  • 3.

    Barnett R, et al. Preserved renal-allograft function and the PD-1 pathway inhibitor nivolumab. N Engl J Med 2017; 376:191192. doi: 10.1056/NEJMc1614298

  • 4.

    Schenk KM, et al. Nivolumab + tacrolimus + prednisone ± ipilimumab for kidney transplant recipients with advanced cutaneous cancers. J Clin Oncol 2024; 42:10111020. doi: 10.1200/JCO.23.01497

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  • 5.

    Hanna GJ, et al. Cemiplimab for kidney transplant recipients with advanced cutaneous squamous cell carcinoma. J Clin Oncol 2024; 42:10211030. doi: 10.1200/JCO.23.01498

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mTOR Inhibitors and Pulsed Steroid Regimen in Kidney Transplant Recipients Undergoing Immune Checkpoint Inhibitor Therapy for Advanced Cutaneous Malignancies: The Key Toward Maximizing Efficacy and Mitigating Rejection

Rose Mary Attieh Rose Mary Attieh, MD, is the Galdi Fellow in Onco-Nephrology and Glomerular Diseases at Northwell Health, and Kenar D. Jhaveri, MD, FASN, is professor of medicine and an attending nephrologist at Northwell Health in New Hyde Park, NY, and is editor-in-chief of Kidney News. Hani M. Wadei, MD, FASN, is a transplant nephrology specialist and professor of medicine at the Mayo Clinic, Jacksonville, FL.

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Kenar D. Jhaveri Rose Mary Attieh, MD, is the Galdi Fellow in Onco-Nephrology and Glomerular Diseases at Northwell Health, and Kenar D. Jhaveri, MD, FASN, is professor of medicine and an attending nephrologist at Northwell Health in New Hyde Park, NY, and is editor-in-chief of Kidney News. Hani M. Wadei, MD, FASN, is a transplant nephrology specialist and professor of medicine at the Mayo Clinic, Jacksonville, FL.

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Hani M. Wadei Rose Mary Attieh, MD, is the Galdi Fellow in Onco-Nephrology and Glomerular Diseases at Northwell Health, and Kenar D. Jhaveri, MD, FASN, is professor of medicine and an attending nephrologist at Northwell Health in New Hyde Park, NY, and is editor-in-chief of Kidney News. Hani M. Wadei, MD, FASN, is a transplant nephrology specialist and professor of medicine at the Mayo Clinic, Jacksonville, FL.

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Immune checkpoint inhibitors (ICIs) have revolutionized treatment of patients with advanced cutaneous malignancies (1). By stimulating T cell-mediated antitumor responses, ICIs offer new hope for a durable response and improved survival in these patients who previously had a poor prognosis. Kidney transplant recipients (KTRs) are particularly susceptible to cutaneous malignancies due to their immunocompromised state. In fact, the risk of non-melanoma skin cancer is 65- to 250-fold higher among KTRs compared with the general population, and this risk continues to increase with time following transplantation. Unfortunately, KTRs have traditionally been excluded from clinical trials involving ICIs due to concerns over lack of efficacy and fear of precipitating allograft rejection when graft-specific memory T cells are reactivated.

Various modifications to immunosuppression (IS) regimens have been proposed in an effort to enhance antitumor response and mitigate rejection risk among KTRs receiving ICIs. Although some experts have suggested maintaining baseline IS without modification (2), others have recommended converting the calcineurin inhibitor (CNI) to a mammalian target of rapamycin (mTOR) inhibitor along with a dynamic mini-steroid pulse (3). Unfortunately, robust evidence guiding the management of KTRs with advanced cutaneous malignancies treated with ICIs is still lacking.

To address this critical unmet need, two trials were recently conducted and published this year in the Journal of Clinical Oncology (4, 5). The study by Schenk et al. (4) explored the safety and efficacy of low-dose tacrolimus plus prednisone in patients receiving nivolumab (NIVO) ± ipilimumab (IPI) in 8 KTRs, whereas the study by Hanna et al. (5) investigated the use of an mTOR inhibitor along with pulsed dose corticosteroids and cemiplimab in 12 KTRs. Table 1 illustrates key differences in study design, participant characteristics, and outcomes among the three main prospective clinical trials conducted to date in KTRs receiving ICI therapy.

Table 1

Comparison of main prospective clinical trials of ICI therapy among KTRs

Table 1

In summary, the trial conducted by Hanna et al. (5) demonstrated that the cancer response to cemiplimab among KTRs with cutaneous squamous cell carcinoma (SCC) maintained on an mTOR inhibitor with a pulsed prednisone regimen was satisfactory in both magnitude and duration. The tumor response was comparable to that observed among the general population with SCC treated with cemiplimab. In addition, there was no reported rejection among the patients. On the contrary, the study by Schenk et al. (4) showed that tacrolimus and prednisone not only proved ineffective in providing sufficient protection against rejection but also hindered the generation of an adequate antitumor response to NIVO and IPI. Elevated donor-derived cell-free DNA (dd-cfDNA) levels were proposed as an early marker of allograft rejection.

The investigators who conducted the two most recent trials are to be commended for their remarkable efforts. Despite their limitations, these trials mark one of the rare instances in which rigorously conducted prospective research has been undertaken in the field of transplant onconephrology. Nevertheless, caution is warranted when comparing these trials and generalizing their results to the broader KTR population undergoing ICI therapy. Patients in these trials had distinct types of cutaneous malignancies, were treated with different ICIs, and had failed previous lines of therapy (including immunotherapy with cetuximab). Moreover, the two trials had small sample sizes and lacked a control arm. Notably, neither of the two trials performed surveillance allograft biopsies. Although dd-cfDNA elevation preceded the rise in serum creatinine and treatment-related allograft loss, testing was not consistently performed in the trial by Hanna et al. (5), which reported no allograft rejection.

We eagerly anticipate the results of follow-up trials with larger numbers of KTRs to shed more light on the optimal IS regimen for these patients. We propose that future trials consider minimizing steroid exposure, for instance, by using the pulsed steroid regimen only with the initial dose of the ICI, when the risk of rejection is highest. This approach is likely to reduce the overall risk of hyperglycemia and infection and may also enhance the antitumor response. Further research is needed to determine the most effective IS regimen for KTRs with other malignancies and for recipients of non-renal allografts.

Footnotes

The authors report no conflicts of interest.

References

  • 1.

    Koch Hein EC, et al. Immune checkpoint inhibitors in advanced cutaneous squamous cell carcinoma: Real-world experience from a Canadian comprehensive cancer centre. Cancers 2023; 15:4312. doi: 10.3390/cancers15174312

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2.

    Carroll RP, et al. Immune checkpoint inhibitors in kidney transplant recipients: A multicentre, single-arm, phase 1 study. Lancet Oncol 2022; 23:10781086. doi: 10.1016/S1470-2045(22)00368-0

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3.

    Barnett R, et al. Preserved renal-allograft function and the PD-1 pathway inhibitor nivolumab. N Engl J Med 2017; 376:191192. doi: 10.1056/NEJMc1614298

  • 4.

    Schenk KM, et al. Nivolumab + tacrolimus + prednisone ± ipilimumab for kidney transplant recipients with advanced cutaneous cancers. J Clin Oncol 2024; 42:10111020. doi: 10.1200/JCO.23.01497

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5.

    Hanna GJ, et al. Cemiplimab for kidney transplant recipients with advanced cutaneous squamous cell carcinoma. J Clin Oncol 2024; 42:10211030. doi: 10.1200/JCO.23.01498

    • PubMed
    • Search Google Scholar
    • Export Citation
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