Combination checkpoint blockade for metastatic cutaneous malignancies in kidney transplant recipients

Megan H Trager, Shana M Coley, Geoffrey Dube, Shaheer Khan, Matthew Ingham, Faramarz H Samie, Larisa J Geskin, Diana McDonnell, Daniel Brouder, Yvonne Saenger, Richard Carvajal, Megan H Trager, Shana M Coley, Geoffrey Dube, Shaheer Khan, Matthew Ingham, Faramarz H Samie, Larisa J Geskin, Diana McDonnell, Daniel Brouder, Yvonne Saenger, Richard Carvajal

Abstract

Background: Immune checkpoint blockade has emerged as a highly effective treatment for patients with metastatic melanoma and cutaneous squamous cell carcinoma. Nivolumab blocks the interactions between programmed cell death protein 1 and programmed death ligand 1 allowing for activation of a latent immune response against the malignancy. Ipilimumab binds to and blocks cytotoxic T-lymphocyte-associated protein 4, alleviating the negative regulation of T-cell activation that is mediated by that checkpoint. Combination therapy with nivolumab and ipilimumab is associated with longer overall survival at 5 years compared with nivolumab monotherapy. Solid organ transplant recipients have a significantly higher risk of malignancies compared with the general population. There is limited data surrounding the efficacy of combination immunotherapy in solid organ transplant recipients, as these patients were excluded from seminal trials due to risk of organ rejection.

Case presentations: Here we present four cases of combination immunotherapy in kidney transplant recipients. Three patients had metastatic melanoma, and one patient had metastatic cutaneous squamous cell carcinoma. Two patients had radiographic responses from immunotherapy, one patient had stable disease, and one patient had disease progression. Only one patient had biopsy-proven rejection. At last follow-up, three patients had functioning grafts, though one required hemodialysis after treatment, and one patient succumbed to disease, but graft function remained intact throughout her course.

Conclusions: These cases describe the use of ipilimumab and nivolumab combination immunotherapy for cutaneous malignancies in kidney transplant recipients. They highlight the potential to preserve kidney graft function while effectively treating the disease.

Trial registration number: NCT03816332.

Keywords: immunotherapy; melanoma; transplantation immunology.

Conflict of interest statement

Competing interests: RC is a consultant for Astra Zeneca, BMS, Castle Biosciences, Foundation Medicine, Immunocore, Incyte, Merck, Novartis, Roche, Compugen, I-Mab, PureTech Health, Sanofi Genzyme, and Sorrento Therapeutics. He is on advisory boards for Aura Biosciences, Chimeron, and Rgenix.

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1
Figure 1
Radiographic improvement in disease. (A) Case 1: baseline chest CT in July 2019 at initiation of ipilimumab and nivolumab showing lung metastases; left axillary lesion (red arrow) was further examined with ultrasound and found to be a benign seroma or hematoma post left axillary biopsy. (B) CT in October 2019 after two doses of ipilimumab and nivolumab showing improvement in the lung metastases. (C) Case 3: baseline CT in August 2019 (at initiation of ipilimumab and nivolumab). (D) Case 3: October 2019 (after three treatments with ipilimumab and nivolumab). (E) Case 3: February 2019 (4 months after last dose ipilimumab). The CT scan shows significant reduction in lung metastases at the end of treatment with continual improvement 4 months after completing treatment with immunotherapy. Arrows track the metastases in each of the scans.
Figure 2
Figure 2
eGFR values over time after treatment with immunotherapy. Y label max is 60, indicates eGFR >60. (A) Case 1: metastatic melanoma diagnosed in July 2019. (B) Case 2: primary melanoma diagnosed in February 2018. (C) Case 3: metastatic cutaneous squamous cell carcinoma diagnosed in January 2019. (D) Case 4. primary melanoma diagnosed in December 2017. metastatic melanoma diagnosed in August 2019.
Figure 3
Figure 3
Kidney allograft biopsy in case 4, after treatment with combination immunotherapy and decreased immunosuppression, showing moderate interstitial inflammation, severe lymphocytic tubulitis, peritubular capillaritis and diffuse C4d positivity, consistent with mixed acute T-cell mediated and antibody-mediated rejection. (A) Periodic acid Schiff stain. (B and C) Jones methenamine silver stain. (D) C4d indirect immunofluorescence stain.

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