A Pilot Study of Checkpoint Inhibitors in Solid Organ Transplant Recipients with Metastatic Cutaneous Squamous Cell Carcinoma

Significance 

Post-transplant malignancy is a significant adverse event in solid organ transplant recipients, and the risk of developing cancer has been reported to be between 2- and 4-fold. This risk is largely attributed to the state of immune tolerance induced by the immunosuppressive drugs taken by patients to maintain graft viability. Increased rates of malignancies, such as skin cancer; Hodgkin and non-Hodgkin lymphoma; Kaposi sarcoma; and liver, lung, and thyroid cancers have been reported for this population. Immune checkpoint inhibitors (ICIs) have successfully been applied in the treatment of several types of cancers, though solid organ transplant recipients have always been excluded in its clinical trials because of the increased risk of severe and irreversible allograft rejection.

Cutaneous squamous cell carcinoma is the most prevalent post-transplant malignancy in solid organ transplant recipients. This patient population have high tumor burdens as a result of UV-induced carcinogenesis that stems from exposure to the sun. Initial management of cutaneous squamous cell carcinoma involves minimization of immunosuppression, adjuvant radiation therapy, or surgical therapy. Traditionally, treatment for metastatic cutaneous cell carcinoma involved more toxic therapies like chemotherapy and epidermal growth factor receptor targeted therapy, which had less durable response rates.

Immunosuppressive medications act in direct opposition to PD-1 immunotherapies, which are used to enhance the cell-mediated immune response to cancer antigens. Therefore, in the clinical trials these drugs were investigated in, solid organ transplant recipients were excluded; thus, safety and efficacy has not been studied in this population. Given the paucity of data, there remains a significant amount of uncertainty regarding the use of immunotherapies in this group of patients.

In light of these insufficiencies, University of Michigan researchers Dr. Irene Tsung, Dr. Francis Worden, and Dr. Robert Fontana reported their preliminary experience of the safety and efficacy of immune checkpoint inhibitors in solid organ transplant recipients with advanced head and neck cutaneous squamous cell carcinoma who failed attempts at immunosuppression minimization and surgical, radiation and other systemic therapies. Their research work is published in the journal, The Oncologist.

The research team identified solid organ transplant recipients at the University of Michigan. The recipients included those who had undergone various transplant surgeries including heart, kidney, liver, and lung transplants. The researchers then retrospectively reviewed patients’ clinical and demographic features, immunosuppression, treatment efficacy, immune checkpoint inhibitor regimen, and other severe events. Seven solid organ transplant recipients, who had previously undergone locoregional surgery and adjuvant radiation therapy, were all diagnosed with neck and head cutaneous squamous cell carcinoma. The seven recipients consisted of four kidney, two liver and one lung solid organ transplant recipients. The patients were treated with cemiplimab or pembrolizumab after calcineurin inhibitors were minimized.

The researchers recorded an overall tumor response of 57.1% during the 7.1 months median follow-up. This response rate corresponded to three partial responders and one complete responder. At a median of 135 days after starting immune checkpoint inhibitor, four patients died. Two of them died from tumor progression and the other two from other causes. When it came to adverse events, one lung transplant recipient developed acute pneumonitis that was managed by high doses of steroids, while one renal transplant recipient developed progressive renal injury and eventually died of unrelated causes. The authors observed that the three patients who administered prophylactic prednisone responded well to cemiplimab, reported preserved allograft function and had no severe events.

The findings of the study suggest that minimization of calcineurin inhibitors as well as the conversion of calcineurin inhibitor to mammalian target of rapamycin inhibitors together with a well-thought-out use of prophylactic steroid could allow for the safe use immune checkpoint inhibitors in solid organ transplant recipients with advanced cutaneous squamous cell carcinoma. Although short term efficacy are quite promising, prospective studies with additional follow-up and standardization protocols for prophylactic steroids are still needed.

About the author

Dr. Irene Tsung graduated from Case Western Reserve University with BS/MS degrees in Biomedical Engineering. She then obtained her medical degree from Indiana University School of Medicine and completed an internal medicine residency at the University of Michigan. She is currently a fellow at the University of Michigan Hematology/Oncology Fellowship Training Program.

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Reference

Irene Tsung, Francis P. Worden, and Robert J. Fontana. A Pilot Study of Checkpoint Inhibitors in Solid Organ Transplant Recipients with Metastatic Cutaneous Squamous Cell Carcinoma. The Oncologist 2021, issue 26, pages 133–138.

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