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Antitumor activity of nivolumab on hemodialysis after renal allograft rejection

Antitumor activity of nivolumab on hemodialysis after renal allograft rejection Background: Nivolumab (Opdivo™) is a novel IgG4 subclass programmed death-1 (PD-1) inhibiting antibody that has demonstrated breakthrough-designation anti-tumor activity. To date, clinical trials of nivolumab and other checkpoint inhibitors have generally excluded patients with solid organ transplantation and patients with concurrent immunosuppression. However, organ transplant recipients are at high-risk of development of malignancy as a result of suppressed immune surveillance of cancer. Case presentation: We illustrate the outcomes of a 63 year-old type I diabetic female patient who developed pulmonary metastatic, BRAF wild-type cutaneous melanoma 10 years after renal transplantation. After downward titration of the patient’s immunosuppressive medications and extensive multidisciplinary review, she was treated with nivolumab in the first-line setting. Within 1 week of administration, the patient experienced acute renal allograft rejection, renal failure and concurrent diabetic ketoacidosis due to steroid therapy. Allograft function did not return, but patient made a full clinical recovery after being placed on hemodialysis. Subsequently, the patient had clinical disease progression off therapy and required re-challenge with nivolumab on hemodialysis, resulting in ongoing clinical and radiographic response. Conclusions: This case illustrates multiple practical challenges and dangers of administering anti-PD1 immune checkpoint inhibitors to patients with solid-organ transplantation including need for titration of immunosuppressive medications, risks of allograft rejection, and treatment during hemodialysis. Keywords: Melanoma, Acute allograft rejection, Organ transplant, Hemodialysis, Anti-PD-1 therapy, Nivolumab Background Immune checkpoint inhibition with anti-cytotoxic T- Novel cancer immunotherapies targeting programmed- lymphocyte-associated protein-4 (CTLA-4) antibodies death-1 (PD-1) and its ligand (PD-L1) have demonstrated have previously been reported as successfully and safely remarkable anti-cancer activity and survival benefit lead- administered with low dose-immunosuppression in ing to regulatory approvals in metastatic melanoma, non- liver transplant [4, 5] and renal transplant patients [6]. small cell lung cancer, and renal cell carcinoma [1, 2]. Recent literature has seen an emerging trend of anti- Clinical trials of nivolumab (Opdivo™), an IgG4 subclass PD-1 medications being linked to rejection in trans- PD-1-inhibiting antibody, and other similar immune plant patients [7–10]. Herein we report acaseof acute checkpoint inhibitors have generally excluded patients renal allograft rejection seven days after administration with solid organ transplantation and patients with concur- of first dose of nivolumab in the setting of concomitant rent immunosuppression. However, organ transplant re- radiological response of the metastatic melanoma. cipients are a high-risk cohort for developing metastatic cancer as a result of suppressed immune surveillance [3]. Case presentation A 63 year-old female with longstanding type-1 diabetes * Correspondence: mong@toh.ca mellitus and hypertension developed chronic renal fail- Department of Medicine, The Ottawa Hospital, 501 Smyth Road, Ottawa, ON ure in 2002 and underwent a pre-emptive renal allograft K1H 8L6, Canada 2 transplant from her donor husband in 2004 without The Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, ON K1H 8L6, Canada requiring prior dialysis. Both the donor and recipient © 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Ong et al. Journal for ImmunoTherapy of Cancer (2016) 4:64 Page 2 of 5 were cytomegalovirus-negative. She received basiliximab intensely hypermetabolic (SUV max 9.9) left hilar lymph 20 mg prior to her transplant surgery and another node enlarging to 16 mm, along with non-FDG avid 20 mg on day 4 post-transplant. Following transplant- pulmonary nodules. An endobronchial ultrasound-guided ation she was immunosuppressed with mycophenolate biopsy of the hilar lymph node (station 11 L) demon- mofetil, prednisone and tacrolimus. She had longstand- strated atypical cells reactive for S100/melanA, confirming ing stable kidney function following transplantation with metastatic melanoma. Her case was discussed at the a baseline GFR of 84 mL/min and a creatinine of 80 multidisciplinary tumor board and renal transplantation micromol/L. Her past medical history was remarkable team, and a recommendation for anti-PD-1 treatment was for iatrogenic hypothyroidism following parathyroidec- made, based on available safety data and high risk of tomy for primary hyperparathyroidism, and she had no cancer-related mortality. Full discussion with patient and prior history of malignancy. her husband regarding the risks and benefits of treatment In April 2015, after ten years of immunosupression, she were had and the patient wished to proceed with treat- developed an irregular hyperpigmented and evolving ment including unknown risks of allograft rejection. lesion on her left upper back which was resected in May Immunosuppressive medications were titrated off and she 2015. The biopsy of the left scapular site revealed a super- was left on 10 mg of prednisone daily, with no deterior- ficial spreading invasive melanoma with a maximum ation in renal function prior to nivolumab administration. Breslow thickness of 2.59 mm, Clark level of IV, with, The patient received her first treatment of nivolumab mitoses of 5/mm . No ulceration was identified, but (anti-PD-1 treatment for metastatic melanoma, single th tumor infiltrating lymphocytes and tumor regression were intravenous dose of 324 mg) on January 7 , 2016. She present. Peripheral margins were uninvolved, but deep reported no subjective toxicities within the first week of margin was involved by a satellite nodule and microsatelli- treatment, but on day 8 the patient developed lethargy, tosis was also present. Wide-local excision and bilateral abdominal pain, nausea, vomiting and loose stools (4 axillary lymph node biopsies were performed July 2015, as times per day), malaise, anorexia and fatigue. Physical lymphoscintigraphy had identified drainage of each of the examination demonstrated signs of uremia and concur- lesion to the contralateral axilla when injected with tech- rent tenderness in the lower abdomen at the site of allo- netium 99 sulfur colloid. Three right axillary lymph nodes graft implantation without peritoneal signs. Laboratory were removed and were negative for malignancy, but 1 left investigations showed a creatinine rise to 577 micromol/L axillary lymph node was removed and pathology revealed without any change in electrolytes. The ultrasound Dop- an 8.5 mm × 7.5 mm melanoma deposit with extranodal pler of her kidney showed markedly abnormal appearance extension. As a result, the patient required a wide local of the transplant kidney with findings suggestive of acute excision with a 2 cm margin and pathology demonstrated medical renal disease, poor perfusion and elevated resist- residual disease and microsatellites, with negative margins. ive indices concerning for transplant dysfunction. She A second lesion was excised at the time of surgery in the received a pulse of corticosteroids (methylprednisolone right scapula, again consistent with superficial spreading 500 mg IV × 1), and developed diabetic ketoacidosis invasive melanoma, Breslow thickness 1 mm, Clark level requiring insulin infusion and initiation of hemodialysis. II, without ulceration, no mitoses and clear margins She had a second pulse of steroids with close endocrino- (pT1a). Completion lymph-node dissection August 2015 logic monitoring and insulin sliding scale, after which retrieved 22 lymph nodes, all of which were negative for prednisone was tapered down. Renal allograft function did melanoma, with final American Joint Committee on not return and she was discharged home on hemodialysis. Cancer (AJCC) pathological staging of pT3aN2c. Nivolumab was withheld and the patient was observed. Staging CT in July 2015 showed a non-specific Restaging CT thorax on February 2016 demonstrated 6.5 mm non-calcified right lower lobe (RLL) lung nod- a partial resolution of bilateral pulmonary nodules, ule, not previously present. BRAF mutation test of the hilar lymph nodes and mediastinal lymph nodes but with real-time PCR assay using the Qiagen BRAF RGQ right lower pleural thickening was noted. However, the kit was BRAF wild-type. The patient was not offered ad- patient had subsequent clinical deterioration 6 weeks juvant radiotherapy and declined high-dose adjuvant later in March 2016 with dyspnea, cough and hypoxia interferon. with CT thorax showing significant progression of lung Follow-up CT imaging in October 2015 demonstrated parenchymal disease and multiple new lung nodules. increase in size of the RLL lung nodule and the appear- Infection was ruled out by bronchoscopic examination, ance of at least eight new subcentimeter bilateral pulmon- and empiric treatment with piperacillin/tazobactam. After ary nodules, along with increased mediastinal and left careful consideration and multidisciplinary review, the hilar lymphadenopathy (12 mm). The patient was asymp- patient was re-administered nivolumab starting April tomatic. A follow-up 2-deoxy-2[F-18] fluoro-D-glucose 2016, with both ongoing clinical and radiographic (FDG) PET-CT scan in December 2015 demonstrated an response. Restaging 12-week CT thorax June 2016 on Ong et al. Journal for ImmunoTherapy of Cancer (2016) 4:64 Page 3 of 5 nivolumab shows almost total resolution of previously Moreover, a longer waiting period prior to nivolumab ad- noted multiple bilateral pulmonary nodules and consoli- ministration may have ruled out rejection due to titration dations (Fig. 1), but some slight increase in size of medias- of immunosuppressive medications, however, the patient’s tinal and hilar lymph nodes not meeting criteria for aggressive course of disease suggested a faster timeline for progression by immune-related response criteria (irRC) in treatment and there was the option for hemodialysis as solid tumors [11]. At the time of publication the patient rescue. A less aggressive reduction in immunosuppression has an ongoing (8-month) response in lung metasta- would be warranted with other transplants (e.g. heart, liver ses and stable mediastinal/hilar lymph nodes, but slight etc.) since transplant failure would inevitably lead to growth of a single axillary lymph node. patient death. The product monograph for nivolumab does not suggest an adjustment of nivolumab on hemodialysis Conclusions [12–14], and in our patient this was safely and effectively In this case report, we add to the expanding literature administered while on hemodialysis. demonstrating that treatment with an anti-PD-1 antibody This case study and similar reports [7–10] demon- may be associated with transplant allograft rejection. At strate the importance of post-marketing studies in popu- the time of this adverse event there had not been any lations excluded by pivotal and early-phase clinical trials; previously documented cases of allograft rejection with in this case, solid organ transplant recipients (SOTRs). anti-PD1 agents, and several reports of safe administration Potential challenges and risks of immune-checkpoint of anti-CTLA-4 [4–6]. We had originally planned for inhibition for SOTRs include 1) strong potential for allograft extraction after the patient’s condition stabilized organ transplant rejection, at least with anti-PD-1/PD-L1 on hemodialysis; however, melanoma disease progression treatment as this case has demonstrated [4]; 2) potential ultimately required more urgent systemic treatment and for reduced anti-tumor activity of immune checkpoint we monitored the patient closely after resumption of inhibition, especially after titration of potent immunosup- nivolumab. The result was an objective response to treat- pressive medications that can reduce T-cell function; 3) ment to nivolumab which is ongoing. The timing of allo- complicated medical management of addressing organ graft rejection in reference to first-dose administration of failure (e.g. hemodialysis) and co-morbidities that led to nivolumab implies causality, especially in light of the organ failure (e.g. diabetes); 4) evolving treatment land- chronicity of the allograft (>10 years) and suggests T-cell- scape with multiple immune checkpoints that differ in mediated rejection [7]. mechanism and tolerability (i.e. CTLA-4 versus PD-1) We decided to stop all immunosuppression except pred- [7, 10, 15]. This case also raises the question of whether nisone (10 mg daily) prior to nivolumab administration. patients should be considered for the rather radical Although a more conservative reduction in immunosup- approach of allograft removal in order to become eli- pression may have prevented the transplant from failing, gible for treatment with anti-PD-1 agents. Although we were concerned of the effect of immunosuppressive phase III clinical studies have demonstrated that anti- medications on the anti-tumor effect of nivolumab. PD-1 agents such as nivolumab and pembrolizumab Fig. 1 Radiographic response to nivolumab on hemodialysis; CT chest exams performed at baseline and 12 weeks after re-initiation of therapy demonstrates resolution of lung nodules (indicated by the yellow arrows). The hilar lymph node indicated by the red arrow is stable Ong et al. Journal for ImmunoTherapy of Cancer (2016) 4:64 Page 4 of 5 have superior efficacy over ipilimumab in metastatic emerging as immunosuppressive agents for SOTRs [23, melanoma [16], individual case reports suggest that 24]. Therefore, graft rejection may have been predictable anti-CTLA-4 agents may be preferred for use in SOTRs in this case. due to the non-peripheral tissue-specific mechanism of While patients are now living longer and better with the CTLA-4 receptor compared to PD-1, which would organ transplants, their immunosuppressive environ- be less likely to be associated with acute rejection of ment is allowing the development of an increasing bur- the allograft. den of transplant-related malignancies. The development It is also important to note that allograft rejection of novel immunosuppressive drugs that reduce risk of occurred with both nivolumab and pembrolizumab [7] malignancy, as well as surveillance and monitoring strat- which is expected as the two anti-PD-1 antibodies egies should be considered for the management of can- possess similar therapeutic mechanisms. We suggest that cer in SOTRs. One emerging and promising area is the the characterization of PD-L1 expression on renal allo- use of mTOR inhibitors for immunosuppression com- grafts prior to administering an anti-PD-1 agent may pared to calcineurin inhibitor-based regimens which allow the stratification of patients at high risk of rejec- have shown to decrease risk of malignancy [25]. Further tion upon treatment. To date, no studies have character- studies to prevent and manage malignancies in this ized PD-L1 expression on a series of renal transplants complicated situation are required. correlating expression levels with rejection following Abbrevations anti-PD-1 therapy. It has however been demonstrated CTLA-4: Anti-cytotoxic T-lymphocyte-associated protein-4; that PD-1 expressing T-cell subsets are indicators of risk FDG: Fluorodeoxyglucose; GFR: Glomerular filtration rate; IgG- of rejection of renal transplants [17]. 4: Immunoglobulin G-4; irRC: Immune-related response criteria; IV: Intravenous; PCR: Polymerase chain reaction; PD-1: Programmed death Approximately half of all SOTRs will develop a skin receptor-1; PD-L1: Programmed death receptor-1 ligand; PET-CT: Positron malignancy, with squamous cell and basal cell carcinomas emission tomography-computed tomography; RLL: Right lower lobe; accounting for 90 % [18]. SOTRs have a 2.4 increased risk SOTR: Solid organ transplant recipient; SUV: Standardized uptake value of developing melanoma [19], and a retrospective review by Brewer et al. demonstrated that SOTRs with thick Authors’ contributions MO participated in the elaboration, writing and reviewing of this case report melanomas (Clark level III or IV or a Breslow thickness of as well as SB, AMI, CC and GK. The conclusion section was written by MO 1.5-3.0 mm) had a significantly poorer melanoma cause- and AMI. TF has shared his ideas about the patient’s case and his specific survival rate [20]. The introduction of effective understanding of immunology has been solicited. MO is the guarantor of this manuscript. All authors read and approved the manuscript. This therapies such as nivolumab in patients with prior solid manuscript has not previously been published and is not currently under organ transplants will have to take into consideration the consideration for publication in any other journal. risk of promoting foreign antibody from the graft leading to rejection, versus the benefit of treating their melanoma, Competing interests MO has been a consultant to and received honoraria from Bristol-Myers especially when the prognosis is compromised. We Squibb, Merck, AstraZeneca and Roche/Genentech. The other authors declare suggest that treating SOTRs with immune checkpoint that they have no competing interests. blockade could be more dangerous in non-renal trans- plant recipients (e.g. cardiac, pulmonary, and hepatic) Consent for publication where organ-replacement therapy equivalent to dialysis is Research Ethics Board approval was sought from The Ottawa Hospital Research Insitute and granted for case-publication. Patient consent for unavailable [21]. publication of this case was also sought and granted. Contact person: The exclusion of immunosuppressed patients or pa- Christine Banyard, Research Ethics Coordinator at the Ottawa Health tients with an existing autoimmune disorder in clinical Science Network Research Ethics Board – cbanyard@ohri.ca. trials investigating the safety of anti-PD-1/anti-PD-L1 Received: 3 August 2016 Accepted: 29 September 2016 agents has left us dependent on case report studies where to our knowledge, no group has been able to treat a melanoma (or other skin malignancy) with these anti- References bodies without causing acute graft rejection [7–10]. A 1. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N retrospective review of patients with advanced melan- Engl J Med. 2012;366:2443–54. doi:10.1056/NEJMoa1200690. oma and pre-existing autoimmune disorders has only 2. Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, et been conducted for patients who received ipilimumab al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373(19):1803–13. doi:10.1056/NEJMoa1510665. (anti-CTLA-4) and results showed generally exacerba- 3. Vajdic CM, van Leeuwen MT. Cancer incidence and risk factors after solid tions of their autoimmune symptoms that were manage- organ transplantation. Int J Cancer. 2009;125(8):1747–54. able [22]. Nonetheless, from murine transplant models, doi:10.1002/ijc.24439. 4. Morales RE, Shoushtari AN, Walsh MM, Grewal P, Lipson EJ, Carvajal RD. we have learned that the PD-1 pathway is critical for the Safety and efficacy of ipilimumab to treat advanced melanoma in the induction and maintenance of transplantation tolerance setting of liver transplantation. J Immunother Cancer. 2015;3(22). doi: 10. [15]. Furthermore, CTLA-4 and PD-1 agonists are 1186/s40425-015-0066-0. Ong et al. Journal for ImmunoTherapy of Cancer (2016) 4:64 Page 5 of 5 5. Ranganath HA, Panella TJ. Administration of ipilimumab to a liver transplant recipient with unresectable metastatic melanoma. J Immunother. 2015;38(5): 211. doi:10.1097/CJI.0000000000000077. 6. Lipson EJ, Bodell MA, Kraus ES, Sharfman WH. Successful administration of ipilimumab to two kidney transplantation patients with metastatic melanoma. J Clin Oncol. 2014;32(19):e69–71. doi:10.1200/JCO.2013.49.2314. 7. Lipson EJ, Bagnasco SM, Moore J, Jang S, Patel MJ, Zachary AA, et al. Tumor regression and allograft rejection after administration of anti-PD-1. N Engl J Med. 2016;374(9):896–8. doi:10.1056/NEJMc1509268. 8. Spain L, Higgins R, Gopalakrishnan K, Turajlic S, Gore M, Larkin J. Acute renal allograft rejection after immune checkpoint inhibitor therapy for metastatic melanoma. Ann Oncol. 2016;27(6):1135–7. doi:10.1093/annonc/mdw130. 9. Alhamad T, Venkatachalam K, Linette GP, Brennan DC. Checkpoint inhibitors in kidney transplant recipients and the potential risk of rejection. Am J Transplant. 2016;16(4):1332–3. doi:10.1111/ajt.13711. 10. Boils CL, Aljadir DN, Cantafio AW. Use of the PD-1 pathway inhibitor nivolumab in a renal transplant patient with malignancy. Am J Transplant. 2016. doi: 10.1111/ajt.13786. 11. Wolchok JD, Hoos A, O’Day S, Weber JS, Hamid O, Lebbe C, et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune- related response criteria. Clin Cancer Res. 2009;15(23):7412–20. doi:10.1158/ 1078-0432.CCR-09-1624. TM 12. Bristol-Myers Squibb Canada. OPDIVO (nivolumab) Product Monograph. Montreal, Canada: Bristol-Myers Squibb Canada. 2016:1–65. http://www.bmscanada.ca/static/products/en/pm_pdf/OPDIVO_EN_PM. pdf. Accessed 18 Jul 2016. 13. Janus N, Launay-Vacher V, Deray G, Islam MS, Thyss A, Thariat J. Management of targeted therapies in hemodialysis patients. Bull Cancer. 2012;99(3):381–8. doi:10.1684/bdc.2011.1484. 14. Jillella AP, Dainer PM, Kallab AM, Ustun C. Treatment of a patient with end- stage renal disease with Rituximab: pharmacokinetic evaluation suggests Rituxumab is not eliminated by hemodialysis. Am J Hematol. 2002;71(3): 219–22. doi:10.1002/ajh.10213. 15. Riella LV, Patterson AM, Sharpe AH, Chandraker A. Role of the PD-1 pathway in the immune response. Am J Transplant. 2012;12(10):2575–87. doi:10.1111/ j.1600-6143.2012.04224.x. 16. Robert C, Schachter J, Long GV, Arance A, Grob JJ, et al. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015;372:2521–32. doi:10.1056/NEJMoa1503093. 17. Pike R, Thomas N, Workman S, Ambrose L, Guzman D, et al. PD-1 expressing T cell subsets modify the rejection risk in renal transplant patients. Front Immunol. 2016;7:126. doi:10.3389/fimmu.2016.00126. 18. Euvrard S, Kanitakis J, Claudy A. Skin cancers after organ transplantation. N Engl J Med. 2003;348:1681–91. doi:10.1056/NEJMra022137. 19. Dahlke E, Murray CA, Kitchen J, Chan A-W. Systematic review of melanoma incidence and prognosis in solid organ transplant recipients. Transplant Res. 2014;3:10. doi:10.1186/2047-1440-3-10. 20. Brewer JD, Christenson LJ, Weaver AL, Dapprich DC, Weenig RH, Lim KK, et al. Malignant melanoma in solid transplant recipients. Arch Dertmatol. 2011; 147(7):790–6. doi:10.1001/archdermatol.2011.159. 21. Riella LV, Watanabe T, Sage PT, Yang J, Yeung M, Azzi J, et al. Essential role of PDL1 expression on nonhematopoietic donor cells in acquired tolerance to vascularized cardiac allografts. Am J Transplant. 2011;11(4):832–40. doi:10. 1111/j.1600-6143.2011.03451.x. 22. Johnson DB, Sullivan RJ, Ott PA, Carlino MS, Khushalani NI, Ye F, et al. Ipilimumab therapy in patients with advanced melanoma and preexisting autoimmune disorders. JAMA Oncol. 2016;2(2):234–40. doi:10.1001/ jamaoncol.2015.4368. Submit your next manuscript to BioMed Central 23. Vincenti F, Rostaing L, Grinyo J, Rice K, Steinberg S, et al. Belatacept and we will help you at every step: and long-term outcomes in kidney transplantation. N Engl J Med. 2016; 374:333–43. doi:10.1056/NEJMoa1506027. • We accept pre-submission inquiries 24. del Rio M-L, Buhler L, Gibbons C, Tian J, Rodriguez-Barbosa J-I. PD-1/PD-L1, � Our selector tool helps you to find the most relevant journal PD-1/PD-L2, and other co-inhibitory signaling pathways in transplantation. Transpl Int. 2008;21(11):1015–28. doi:10.1111/j.1432-2277.2008.00726.x. � We provide round the clock customer support 25. Geissler EK. Post-transplantation malignancies: here today, gone tomorrow? � Convenient online submission Nat Rev Clin Oncol. 2015;12(12):705–17. doi:10.1038/nrclinonc.2015.186. � Thorough peer review � Inclusion in PubMed and all major indexing services � Maximum visibility for your research Submit your manuscript at www.biomedcentral.com/submit http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal for ImmunoTherapy of Cancer Springer Journals

Antitumor activity of nivolumab on hemodialysis after renal allograft rejection

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Springer Journals
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Copyright © 2016 by The Author(s).
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Medicine & Public Health; Oncology; Immunology
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Abstract

Background: Nivolumab (Opdivo™) is a novel IgG4 subclass programmed death-1 (PD-1) inhibiting antibody that has demonstrated breakthrough-designation anti-tumor activity. To date, clinical trials of nivolumab and other checkpoint inhibitors have generally excluded patients with solid organ transplantation and patients with concurrent immunosuppression. However, organ transplant recipients are at high-risk of development of malignancy as a result of suppressed immune surveillance of cancer. Case presentation: We illustrate the outcomes of a 63 year-old type I diabetic female patient who developed pulmonary metastatic, BRAF wild-type cutaneous melanoma 10 years after renal transplantation. After downward titration of the patient’s immunosuppressive medications and extensive multidisciplinary review, she was treated with nivolumab in the first-line setting. Within 1 week of administration, the patient experienced acute renal allograft rejection, renal failure and concurrent diabetic ketoacidosis due to steroid therapy. Allograft function did not return, but patient made a full clinical recovery after being placed on hemodialysis. Subsequently, the patient had clinical disease progression off therapy and required re-challenge with nivolumab on hemodialysis, resulting in ongoing clinical and radiographic response. Conclusions: This case illustrates multiple practical challenges and dangers of administering anti-PD1 immune checkpoint inhibitors to patients with solid-organ transplantation including need for titration of immunosuppressive medications, risks of allograft rejection, and treatment during hemodialysis. Keywords: Melanoma, Acute allograft rejection, Organ transplant, Hemodialysis, Anti-PD-1 therapy, Nivolumab Background Immune checkpoint inhibition with anti-cytotoxic T- Novel cancer immunotherapies targeting programmed- lymphocyte-associated protein-4 (CTLA-4) antibodies death-1 (PD-1) and its ligand (PD-L1) have demonstrated have previously been reported as successfully and safely remarkable anti-cancer activity and survival benefit lead- administered with low dose-immunosuppression in ing to regulatory approvals in metastatic melanoma, non- liver transplant [4, 5] and renal transplant patients [6]. small cell lung cancer, and renal cell carcinoma [1, 2]. Recent literature has seen an emerging trend of anti- Clinical trials of nivolumab (Opdivo™), an IgG4 subclass PD-1 medications being linked to rejection in trans- PD-1-inhibiting antibody, and other similar immune plant patients [7–10]. Herein we report acaseof acute checkpoint inhibitors have generally excluded patients renal allograft rejection seven days after administration with solid organ transplantation and patients with concur- of first dose of nivolumab in the setting of concomitant rent immunosuppression. However, organ transplant re- radiological response of the metastatic melanoma. cipients are a high-risk cohort for developing metastatic cancer as a result of suppressed immune surveillance [3]. Case presentation A 63 year-old female with longstanding type-1 diabetes * Correspondence: mong@toh.ca mellitus and hypertension developed chronic renal fail- Department of Medicine, The Ottawa Hospital, 501 Smyth Road, Ottawa, ON ure in 2002 and underwent a pre-emptive renal allograft K1H 8L6, Canada 2 transplant from her donor husband in 2004 without The Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, ON K1H 8L6, Canada requiring prior dialysis. Both the donor and recipient © 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Ong et al. Journal for ImmunoTherapy of Cancer (2016) 4:64 Page 2 of 5 were cytomegalovirus-negative. She received basiliximab intensely hypermetabolic (SUV max 9.9) left hilar lymph 20 mg prior to her transplant surgery and another node enlarging to 16 mm, along with non-FDG avid 20 mg on day 4 post-transplant. Following transplant- pulmonary nodules. An endobronchial ultrasound-guided ation she was immunosuppressed with mycophenolate biopsy of the hilar lymph node (station 11 L) demon- mofetil, prednisone and tacrolimus. She had longstand- strated atypical cells reactive for S100/melanA, confirming ing stable kidney function following transplantation with metastatic melanoma. Her case was discussed at the a baseline GFR of 84 mL/min and a creatinine of 80 multidisciplinary tumor board and renal transplantation micromol/L. Her past medical history was remarkable team, and a recommendation for anti-PD-1 treatment was for iatrogenic hypothyroidism following parathyroidec- made, based on available safety data and high risk of tomy for primary hyperparathyroidism, and she had no cancer-related mortality. Full discussion with patient and prior history of malignancy. her husband regarding the risks and benefits of treatment In April 2015, after ten years of immunosupression, she were had and the patient wished to proceed with treat- developed an irregular hyperpigmented and evolving ment including unknown risks of allograft rejection. lesion on her left upper back which was resected in May Immunosuppressive medications were titrated off and she 2015. The biopsy of the left scapular site revealed a super- was left on 10 mg of prednisone daily, with no deterior- ficial spreading invasive melanoma with a maximum ation in renal function prior to nivolumab administration. Breslow thickness of 2.59 mm, Clark level of IV, with, The patient received her first treatment of nivolumab mitoses of 5/mm . No ulceration was identified, but (anti-PD-1 treatment for metastatic melanoma, single th tumor infiltrating lymphocytes and tumor regression were intravenous dose of 324 mg) on January 7 , 2016. She present. Peripheral margins were uninvolved, but deep reported no subjective toxicities within the first week of margin was involved by a satellite nodule and microsatelli- treatment, but on day 8 the patient developed lethargy, tosis was also present. Wide-local excision and bilateral abdominal pain, nausea, vomiting and loose stools (4 axillary lymph node biopsies were performed July 2015, as times per day), malaise, anorexia and fatigue. Physical lymphoscintigraphy had identified drainage of each of the examination demonstrated signs of uremia and concur- lesion to the contralateral axilla when injected with tech- rent tenderness in the lower abdomen at the site of allo- netium 99 sulfur colloid. Three right axillary lymph nodes graft implantation without peritoneal signs. Laboratory were removed and were negative for malignancy, but 1 left investigations showed a creatinine rise to 577 micromol/L axillary lymph node was removed and pathology revealed without any change in electrolytes. The ultrasound Dop- an 8.5 mm × 7.5 mm melanoma deposit with extranodal pler of her kidney showed markedly abnormal appearance extension. As a result, the patient required a wide local of the transplant kidney with findings suggestive of acute excision with a 2 cm margin and pathology demonstrated medical renal disease, poor perfusion and elevated resist- residual disease and microsatellites, with negative margins. ive indices concerning for transplant dysfunction. She A second lesion was excised at the time of surgery in the received a pulse of corticosteroids (methylprednisolone right scapula, again consistent with superficial spreading 500 mg IV × 1), and developed diabetic ketoacidosis invasive melanoma, Breslow thickness 1 mm, Clark level requiring insulin infusion and initiation of hemodialysis. II, without ulceration, no mitoses and clear margins She had a second pulse of steroids with close endocrino- (pT1a). Completion lymph-node dissection August 2015 logic monitoring and insulin sliding scale, after which retrieved 22 lymph nodes, all of which were negative for prednisone was tapered down. Renal allograft function did melanoma, with final American Joint Committee on not return and she was discharged home on hemodialysis. Cancer (AJCC) pathological staging of pT3aN2c. Nivolumab was withheld and the patient was observed. Staging CT in July 2015 showed a non-specific Restaging CT thorax on February 2016 demonstrated 6.5 mm non-calcified right lower lobe (RLL) lung nod- a partial resolution of bilateral pulmonary nodules, ule, not previously present. BRAF mutation test of the hilar lymph nodes and mediastinal lymph nodes but with real-time PCR assay using the Qiagen BRAF RGQ right lower pleural thickening was noted. However, the kit was BRAF wild-type. The patient was not offered ad- patient had subsequent clinical deterioration 6 weeks juvant radiotherapy and declined high-dose adjuvant later in March 2016 with dyspnea, cough and hypoxia interferon. with CT thorax showing significant progression of lung Follow-up CT imaging in October 2015 demonstrated parenchymal disease and multiple new lung nodules. increase in size of the RLL lung nodule and the appear- Infection was ruled out by bronchoscopic examination, ance of at least eight new subcentimeter bilateral pulmon- and empiric treatment with piperacillin/tazobactam. After ary nodules, along with increased mediastinal and left careful consideration and multidisciplinary review, the hilar lymphadenopathy (12 mm). The patient was asymp- patient was re-administered nivolumab starting April tomatic. A follow-up 2-deoxy-2[F-18] fluoro-D-glucose 2016, with both ongoing clinical and radiographic (FDG) PET-CT scan in December 2015 demonstrated an response. Restaging 12-week CT thorax June 2016 on Ong et al. Journal for ImmunoTherapy of Cancer (2016) 4:64 Page 3 of 5 nivolumab shows almost total resolution of previously Moreover, a longer waiting period prior to nivolumab ad- noted multiple bilateral pulmonary nodules and consoli- ministration may have ruled out rejection due to titration dations (Fig. 1), but some slight increase in size of medias- of immunosuppressive medications, however, the patient’s tinal and hilar lymph nodes not meeting criteria for aggressive course of disease suggested a faster timeline for progression by immune-related response criteria (irRC) in treatment and there was the option for hemodialysis as solid tumors [11]. At the time of publication the patient rescue. A less aggressive reduction in immunosuppression has an ongoing (8-month) response in lung metasta- would be warranted with other transplants (e.g. heart, liver ses and stable mediastinal/hilar lymph nodes, but slight etc.) since transplant failure would inevitably lead to growth of a single axillary lymph node. patient death. The product monograph for nivolumab does not suggest an adjustment of nivolumab on hemodialysis Conclusions [12–14], and in our patient this was safely and effectively In this case report, we add to the expanding literature administered while on hemodialysis. demonstrating that treatment with an anti-PD-1 antibody This case study and similar reports [7–10] demon- may be associated with transplant allograft rejection. At strate the importance of post-marketing studies in popu- the time of this adverse event there had not been any lations excluded by pivotal and early-phase clinical trials; previously documented cases of allograft rejection with in this case, solid organ transplant recipients (SOTRs). anti-PD1 agents, and several reports of safe administration Potential challenges and risks of immune-checkpoint of anti-CTLA-4 [4–6]. We had originally planned for inhibition for SOTRs include 1) strong potential for allograft extraction after the patient’s condition stabilized organ transplant rejection, at least with anti-PD-1/PD-L1 on hemodialysis; however, melanoma disease progression treatment as this case has demonstrated [4]; 2) potential ultimately required more urgent systemic treatment and for reduced anti-tumor activity of immune checkpoint we monitored the patient closely after resumption of inhibition, especially after titration of potent immunosup- nivolumab. The result was an objective response to treat- pressive medications that can reduce T-cell function; 3) ment to nivolumab which is ongoing. The timing of allo- complicated medical management of addressing organ graft rejection in reference to first-dose administration of failure (e.g. hemodialysis) and co-morbidities that led to nivolumab implies causality, especially in light of the organ failure (e.g. diabetes); 4) evolving treatment land- chronicity of the allograft (>10 years) and suggests T-cell- scape with multiple immune checkpoints that differ in mediated rejection [7]. mechanism and tolerability (i.e. CTLA-4 versus PD-1) We decided to stop all immunosuppression except pred- [7, 10, 15]. This case also raises the question of whether nisone (10 mg daily) prior to nivolumab administration. patients should be considered for the rather radical Although a more conservative reduction in immunosup- approach of allograft removal in order to become eli- pression may have prevented the transplant from failing, gible for treatment with anti-PD-1 agents. Although we were concerned of the effect of immunosuppressive phase III clinical studies have demonstrated that anti- medications on the anti-tumor effect of nivolumab. PD-1 agents such as nivolumab and pembrolizumab Fig. 1 Radiographic response to nivolumab on hemodialysis; CT chest exams performed at baseline and 12 weeks after re-initiation of therapy demonstrates resolution of lung nodules (indicated by the yellow arrows). The hilar lymph node indicated by the red arrow is stable Ong et al. Journal for ImmunoTherapy of Cancer (2016) 4:64 Page 4 of 5 have superior efficacy over ipilimumab in metastatic emerging as immunosuppressive agents for SOTRs [23, melanoma [16], individual case reports suggest that 24]. Therefore, graft rejection may have been predictable anti-CTLA-4 agents may be preferred for use in SOTRs in this case. due to the non-peripheral tissue-specific mechanism of While patients are now living longer and better with the CTLA-4 receptor compared to PD-1, which would organ transplants, their immunosuppressive environ- be less likely to be associated with acute rejection of ment is allowing the development of an increasing bur- the allograft. den of transplant-related malignancies. The development It is also important to note that allograft rejection of novel immunosuppressive drugs that reduce risk of occurred with both nivolumab and pembrolizumab [7] malignancy, as well as surveillance and monitoring strat- which is expected as the two anti-PD-1 antibodies egies should be considered for the management of can- possess similar therapeutic mechanisms. We suggest that cer in SOTRs. One emerging and promising area is the the characterization of PD-L1 expression on renal allo- use of mTOR inhibitors for immunosuppression com- grafts prior to administering an anti-PD-1 agent may pared to calcineurin inhibitor-based regimens which allow the stratification of patients at high risk of rejec- have shown to decrease risk of malignancy [25]. Further tion upon treatment. To date, no studies have character- studies to prevent and manage malignancies in this ized PD-L1 expression on a series of renal transplants complicated situation are required. correlating expression levels with rejection following Abbrevations anti-PD-1 therapy. It has however been demonstrated CTLA-4: Anti-cytotoxic T-lymphocyte-associated protein-4; that PD-1 expressing T-cell subsets are indicators of risk FDG: Fluorodeoxyglucose; GFR: Glomerular filtration rate; IgG- of rejection of renal transplants [17]. 4: Immunoglobulin G-4; irRC: Immune-related response criteria; IV: Intravenous; PCR: Polymerase chain reaction; PD-1: Programmed death Approximately half of all SOTRs will develop a skin receptor-1; PD-L1: Programmed death receptor-1 ligand; PET-CT: Positron malignancy, with squamous cell and basal cell carcinomas emission tomography-computed tomography; RLL: Right lower lobe; accounting for 90 % [18]. SOTRs have a 2.4 increased risk SOTR: Solid organ transplant recipient; SUV: Standardized uptake value of developing melanoma [19], and a retrospective review by Brewer et al. demonstrated that SOTRs with thick Authors’ contributions MO participated in the elaboration, writing and reviewing of this case report melanomas (Clark level III or IV or a Breslow thickness of as well as SB, AMI, CC and GK. The conclusion section was written by MO 1.5-3.0 mm) had a significantly poorer melanoma cause- and AMI. TF has shared his ideas about the patient’s case and his specific survival rate [20]. The introduction of effective understanding of immunology has been solicited. MO is the guarantor of this manuscript. All authors read and approved the manuscript. This therapies such as nivolumab in patients with prior solid manuscript has not previously been published and is not currently under organ transplants will have to take into consideration the consideration for publication in any other journal. risk of promoting foreign antibody from the graft leading to rejection, versus the benefit of treating their melanoma, Competing interests MO has been a consultant to and received honoraria from Bristol-Myers especially when the prognosis is compromised. We Squibb, Merck, AstraZeneca and Roche/Genentech. The other authors declare suggest that treating SOTRs with immune checkpoint that they have no competing interests. blockade could be more dangerous in non-renal trans- plant recipients (e.g. cardiac, pulmonary, and hepatic) Consent for publication where organ-replacement therapy equivalent to dialysis is Research Ethics Board approval was sought from The Ottawa Hospital Research Insitute and granted for case-publication. Patient consent for unavailable [21]. publication of this case was also sought and granted. Contact person: The exclusion of immunosuppressed patients or pa- Christine Banyard, Research Ethics Coordinator at the Ottawa Health tients with an existing autoimmune disorder in clinical Science Network Research Ethics Board – cbanyard@ohri.ca. trials investigating the safety of anti-PD-1/anti-PD-L1 Received: 3 August 2016 Accepted: 29 September 2016 agents has left us dependent on case report studies where to our knowledge, no group has been able to treat a melanoma (or other skin malignancy) with these anti- References bodies without causing acute graft rejection [7–10]. A 1. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N retrospective review of patients with advanced melan- Engl J Med. 2012;366:2443–54. doi:10.1056/NEJMoa1200690. oma and pre-existing autoimmune disorders has only 2. 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Journal for ImmunoTherapy of Cancer – Springer Journals

Published: Oct 18, 2016

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