Immunotherapy in organ-transplanted cancer patients: efficacy and risk of organ rejection.

Abstract

Organ-transplanted patients have a significantly higher risk of developing solid tumors [1.Engels E.A. Pfeiffer R.M. Fraumeni J.F. et al.Spectrum of cancer risk among US solid organ transplant recipients.JAMA. 2011; 306: 1891-1901Crossref PubMed Scopus (885) Google Scholar]. These patients are systematically excluded from clinical trials, so their available therapeutic options are very limited. With the incorporation of immunotherapy to cancer treatment in recent years, mostly anti-programmed death 1 (PD1)/PD1 ligand (PDL1) and anticytotoxic T-lymphocyte-associated protein 4 (CTLA-4) drugs, further concerns arise for this special population: transplant-related immunosuppression could diminish immunotherapy efficacy, and immune system enhancement caused by checkpoint inhibitors could potentially lead to graft rejection. We carried out a comprehensive review of published reports from 2014 to 2018 involving immunotherapy treatments in organ-transplanted solid-cancer patients. We found 34 clinical reports, women being 29.4% of all cases. Median age was 62 years (range 14–75). Renal allograft was the most frequent transplant (61.7%), followed by liver (26.4%), and heart (11.7%). The most frequent malignancies reported in organ-transplanted immunosuppressed patients were skin tumors—melanoma and squamous cell carcinoma—(76.4%). Lung (8.8%), liver (8.8%), intestinal cancer (3%), and urothelial carcinoma (3%) were also reported (Table 1). Median time from organ transplant to immunotherapy was 12 years (range 16 months to 30 years). A total of 6 patients received ipilimumab monotherapy, 12 nivolumab monotherapy, and 8 pembrolizumab monotherapy. One patient had treatment with ipilimumab and nivolumab combination, one patient received pembrolizumab plus chemotherapy and 6 patients received sequential treatment: first ipilimumab and then nivolumab [2.Bour-Jordan H. Esensten J.H. Martinez-Llordella M. et al.Intrinsic and extrinsic control of peripheral T-cell tolerance by costimulatory molecules of the CD28/B7 family.Immunol Rev. 2011; 241: 180-205Crossref PubMed Scopus (282) Google Scholar] or pembrolizumab [3.Riella L.V. Paterson A.M. Sharpe A.H. Chandraker A. Role of the PD‐1 pathway in the immune response.Am J Transplant. 2012; 12: 2575-2587Crossref PubMed Scopus (251) Google Scholar] upon progression. One patient (3%) achieved complete response, 3 (8.8%) stable disease, 13 (38.2%) partial response, and 10 (29.4%) progressive disease as best response. Outcomes and risk of rejection by immunotherapy or immunosuppressive regimens are summarized in Table 2. Tumor response was not available in six patients (17.6%). A total of 13 cases of allograft rejection after starting immunotherapy were reported, 11 (85%) of these being related with an anti-PD1 monotherapy blockade. Only one allograft rejection was related with anti-CTLA-4 treatment. Median time to rejection after anti-PD1 therapy was 28 days (range 5–120 days). Median time from transplant to immunotherapy in patients without organ rejection was 11 years whereas median time from transplant to immunotherapy in patients with organ rejection was 13 years. Of note, from the six patients who received anti-PD1 treatment after progression to anti-CTLA-4 and the one patient who received ipilimumab plus nivolumab, 43% (3/7) preserved allograft function during anti-CTLA-4 treatment but subsequentially presented allograft rejection during anti-PD1 treatment. Interestingly, these patients started anti-PD1 treatment soon after progression to ipilimumab (2–4 weeks), whereas those patients who received sequential treatment with a wash-out period of at least 4 months maintained allograft function.Table 1Population characteristics and graft outcomeAgeSexTransplant typeTumor typeImmunotherapy (IT)Time from transplant to IT (years)Immunosuppressive regimen before ITBest responseGraft outcomeOutcome of the rejection Rejection treatmentGraft outcomeTime from IT to rejection (days)References67MaleLiverMelanomaIpilimumab8Rapamycin 1 mg dailyPRNo rejectionMorales et al. [5.Morales R.E. Shoushtari A.N. Walsh M.M. et al.Safety and efficacy of ipilimumab to treat advanced melanoma in the setting of liver transplantation.J Immunother Cancer. 2015; 3: 22Crossref PubMed Scopus (68) Google Scholar]59FemaleLiverMelanomaIpilimumab8Tacrolimus 1mg twice dailySDNo rejectionRanganath and Panella [6.Ranganath H.A. Panella T.J. Administration of ipilimumab to a liver transplant recipient with unresectable metastatic melanoma.J Immunother. 2015; 38: 211Crossref PubMed Scopus (59) Google Scholar]72MaleKidneyMelanomaIpilimumab11Prednisone 5 mg dailyPRNo rejectionLipson et al. [7.Lipson E.J. Bodell M.A. Kraus E.S. Sharfman W.H. Successful administration of ipilimumab to two kidney transplantation patients with metastatic melanoma.J Clin Oncol. 2014; 32: e69-e71Crossref PubMed Scopus (101) Google Scholar]58MaleKidneyMelanomaIpilimumab8Prednisone 5 mg dailyPRNo rejectionLipson et al. [7.Lipson E.J. Bodell M.A. Kraus E.S. Sharfman W.H. Successful administration of ipilimumab to two kidney transplantation patients with metastatic melanoma.J Clin Oncol. 2014; 32: e69-e71Crossref PubMed Scopus (101) Google Scholar]40MaleKidneyMelanomaIpilimumab16TacrolimusPDAcute rejectionMethylprednisoloneGraft recovered42Jose et al. [8.Jose A. Yiannoullou P. Bhutani S. et al.Renal allograft failure after ipilimumab therapy for metastatic melanoma: a case report and review of the literature.Transplant Proc. 2016; 48: 3137-3141Crossref PubMed Scopus (35) Google Scholar]69FemaleHeartMelanomaIpilimumab15MMF and tacrolimusSDNo rejectionGastman and Ernstoff [9.Gastman B.R. Ernstoff M.S. Tolerability of immune checkpoint inhibition cancer therapy in a cardiac transplant patient.Ann Oncol. 2016; 27: 2304-2305Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar]68MaleKidneyCutaneous SCCIpilimumab and nivolumab4MMF and sirolimusPRAcute rejectionMethylprednisolone and hemodialysisGraft failure8Miller et al. [10.Miller D.M. Faulkner-Jones B.E. Stone J.R. Drews R.E. Complete pathologic response of metastatic cutaneous squamous cell carcinoma and allograft rejection after treatment with combination immune checkpoint blockade.JAAD Case Rep. 2017; 3: 412-415Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar]77MaleKidneyMelanomaIpilimumab then nivolumab8Prednisone 5 mg daily and tacrolimus 2 mg b.i.d.PDNo rejectionLivingstone et al. [11.Livingstone E. Schilling B. Franklin C. et al.Checkpoint inhibitors in chronic kidney failure and an organ transplant recipient.Eur J Cancer. 2016; 67: 66-72Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar]48MaleKidneyMelanomaIpilimumab then nivolumab15Prednisone 5 mg dailyPRAcute and chronic rejectionHigh-dose steroids and hemodialysisGraft failure28Spain et al. [12.Spain L. Higgins R. Gopalakrishnan K. et al.Acute renal allograft rejection after immune checkpoint inhibitor therapy for metastatic melanoma acute renal allograft rejection after immune checkpoint inhibitor therapy for metastatic melanoma.Ann Oncol. 2016; 27: 1135-1137Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar]62MaleHeartMelanomaIpilimumab then pembrolizumab12TacrolimusPDNo rejectionQin and Salama [13.Qin R. Salama A.K. Report of ipilimumab in a heart transplant patient with metastatic melanoma on tacrolimus.Melanoma Manag. 2015; 2: 311-314Crossref PubMed Google Scholar]68MaleKidneyMelanomaIpilimumab then pembrolizumab15Cyclosporine and prednisoneNRAcute mixed cellular rejectionMethylprednisolone and tacrolimusGraft failure21Alhamad et al. [14.Alhamad T. Venkatachalam K. Linette G.P. Brennan D.C. 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Use of the PD-1 pathway inhibitor nivolumab in a renal transplant patient with malignancy.Am J Transplant. 2016; 16: 2496-2497Crossref PubMed Scopus (59) Google Scholar]63MaleKidneyMelanomaNivolumab12MMF, prednisone and tacrolimusPRAcute rejectionMethylprednisolone and hemodialysisGraft failure8Ong et al. [18.Ong M. Ibrahim A.M. Bourassa-Blanchette S. et al.Antitumor activity of nivolumab on hemodialysis after renal allograft rejection.J Immunother Cancer. 2016; 4: 1-5Crossref Scopus (54) Google Scholar]49MaleHeartCutaneous SCCNivolumab19Tacrolimus, sirolimus and prednisoneNRAcute cellular rejectionMethylprednisolone sirolimus and tacrolimusGraft recovered5Owonikoko et al. [19.Owonikoko T.K. Kumar M. Yang S. et al.Cardiac allograft rejection as a complication of PD-1 checkpoint blockade for cancer immunotherapy: a case report.Cancer Immunol Immunother. 2017; 66: 45-50Crossref PubMed Scopus (38) Google Scholar]60FemaleKidneyMelanomaNivolumab13Cyclosporine, prednisone and MMFPDNo rejectionWinkler et al. [20.Winkler J.K. Gutzmer R. Bender C. et al.Safe administration of an anti-PD-1 antibody to kidney-transplant patients: 2 clinical cases and review of the literature.J Immunother. 2017; 40: 341-344Crossref PubMed Scopus (25) Google Scholar]69FemaleKidneyCutaneous SCCNivolumab14Sirolimus and 5 mg of prednisone dailyPRNo rejectionKittai et al. [21.Kittai A.S. Oldham H. Cetnar J. Taylor M. Immune checkpoint inhibitors in organ transplant patients.J Neurosurg Anesthesiol. 2017; 40: 1Crossref Scopus (72) Google Scholar]72FemaleHeartNSCLC SCCNivolumab10Cyclosporine and MMFSDNo rejectionKittai et al. [21.Kittai A.S. Oldham H. Cetnar J. Taylor M. Immune checkpoint inhibitors in organ transplant patients.J Neurosurg Anesthesiol. 2017; 40: 1Crossref Scopus (72) Google Scholar]54MaleLiverNSCLC SCCNivolumab13Tacrolimus, prednisone and MMFPDNo rejectionBiondani et al. [22.Biondani P. De Martin E. Samuel D. Safety of an anti-PD-1 immune checkpoint inhibitor in a liver transplant recipient.Ann Oncol. 2018; 29: 286-287Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar]41MaleLiverHCCNivolumab16 monthsTacrolimus 1 mg dailyPRNo rejectionMunker and De Toni [23.Munker S. De Toni E.N. Use of checkpoint inhibitors in liver transplant recipients.United Eur Gastroenterol J. 2018; 6: 970-973Crossref PubMed Scopus (46) Google Scholar]20MaleLiverHCCNivolumab4Sirolimus 2 mg dailyNRAcute and chronic T-cell and antibody-mediated rejectionHigh-dose steroids and intravenous immunoglobulin17Friend et al. [24.Friend Venick B.D. McDiarmid R.S.S.V. et al.Fatal orthotopic liver transplant organ rejection induced by a checkpoint inhibitor in two patients with refractory, metastatic hepatocellular carcinoma.Pediatr Blood Cancer. 2017; 64: 1-4Crossref Scopus (63) Google Scholar]14MaleLiverHCCNivolumab3Tacrolimus 4 mg twice dailyNRAcute T-cell and antibody-mediated rejectionHigh-dose steroidsGraft failure7Friend et al. [24.Friend Venick B.D. McDiarmid R.S.S.V. et al.Fatal orthotopic liver transplant organ rejection induced by a checkpoint inhibitor in two patients with refractory, metastatic hepatocellular carcinoma.Pediatr Blood Cancer. 2017; 64: 1-4Crossref Scopus (63) Google Scholar]57FemaleKidneyCutaneous SCCPembrolizumab25Prednisone 5 mg dailyPRAcute and chronic cell-mediated rejectionHigh-dose steroids and hemodialysisGraft failure60Lipson et al. [4.Lipson E.J. Bagnasco S.M. Moore Jr, J. et al.Tumor regression and allograft rejection after administration of anti-PD-1 HHS public access.N Engl J Med. 2016; 374: 896-898Crossref PubMed Scopus (168) Google Scholar]55MaleKidneyMelanomaPembrolizumab30CyclosporinePDNo rejectionWinkler et al. [20.Winkler J.K. Gutzmer R. Bender C. et al.Safe administration of an anti-PD-1 antibody to kidney-transplant patients: 2 clinical cases and review of the literature.J Immunother. 2017; 40: 341-344Crossref PubMed Scopus (25) Google Scholar]35MaleLiverMelanomaPembrolizumab20TacrolimusCRNo rejectionSchvartsman et al. [25.Schvartsman G. Perez K. Sood G. et al.Immune checkpoint inhibitor therapy in a liver transplant recipient with melanoma.Ann Intern Med. 2017; 167: 361Crossref PubMed Scopus (24) Google Scholar]58MaleKidneyMelanomaPembrolizumab13Tacrolimus 1.5 mg twice daily and MMF 500 mg twice dailyPDAcute rejectionNRGraft failure42Kwatra et al. [26.Kwatra V. Karanth N.V. Priyadarshana, Charakidis K.M. Pembrolizumab for metastatic melanoma in a renal allograft recipient with subsequent graft rejection and treatment response failure: a case report.J Med Case Rep. 2017; 11: 73Crossref PubMed Scopus (35) Google Scholar]61FemaleKidneyUrothelial carcinomaPembrolizumab +BVZ+ CDDP+GEM8Tacrolimus and mycophenolatePRNo rejectionWu et al. [27.Wu C.-K. Juang G.-D. Lai H-C. Tumor regression and preservation of graft function after combination with anti-PD-1 immunotherapy without immunosuppressant titration.Ann Oncol. 2017; 28: 2895-2896Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar]65MaleKidneyMelanomaPembrolizumab then IpilimumabNRPrednisone, MMF and everolimusPDNo rejectionTio et al. [28.Tio M. Rai R. Ezeoke O.M. et al.Anti-PD-1/PD-L1 immunotherapy in patients with solid organ transplant, HIV or hepatitis B/C infection.Eur J Cancer. 2018; 104: 137-144Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar]70MaleKidneyMelanomaPembrolizumabNRTacrolimus and prednisonePDNo rejectionTio et al. [28.Tio M. Rai R. Ezeoke O.M. et al.Anti-PD-1/PD-L1 immunotherapy in patients with solid organ transplant, HIV or hepatitis B/C infection.Eur J Cancer. 2018; 104: 137-144Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar]75MaleKidneyMelanomaPembrolizumabNRPrednisonePRNo rejectionTio et al. [28.Tio M. Rai R. Ezeoke O.M. et al.Anti-PD-1/PD-L1 immunotherapy in patients with solid organ transplant, HIV or hepatitis B/C infection.Eur J Cancer. 2018; 104: 137-144Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar]65MaleKidneyMelanomaPembrolizumabNRPrednisone, MMF and tacrolimusPDNo rejectionTio et al. [28.Tio M. Rai R. Ezeoke O.M. et al.Anti-PD-1/PD-L1 immunotherapy in patients with solid organ transplant, HIV or hepatitis B/C infection.Eur J Cancer. 2018; 104: 137-144Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar]48MaleKidneyMelanomaNivolumabNRPrednisone and tacrolimusPRAcute rejectionMethylprednisolone and dialysisGraft failureNRTio et al. [28.Tio M. Rai R. Ezeoke O.M. et al.Anti-PD-1/PD-L1 immunotherapy in patients with solid organ transplant, HIV or hepatitis B/C infection.Eur J Cancer. 2018; 104: 137-144Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar]63FemaleLiverMelanomaPembrolizumabNRCyclosporineNRAcute rejectionMethylprednisolone, cyclosporine, tacrolimus and MMFGraft failure18Tio et al. [28.Tio M. Rai R. Ezeoke O.M. et al.Anti-PD-1/PD-L1 immunotherapy in patients with solid organ transplant, HIV or hepatitis B/C infection.Eur J Cancer. 2018; 104: 137-144Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar]HCC, hepatocellular carcinoma; PR, partial response; SD, stable disease; PD, progression disease; CR, complete response; NR, not reported. Open table in a new tab Table 2Clinical outcomes based on immunotherapy treatment and immunosuppressive drug regimenClinical outcomesPR n (%)aPartial response group includes one complete response with anti-PD1 treatment.SD n (%)PD n (%)NR n (%)Rejection n (%)Immunotherapy drug regimen Anti-PD1 (N=27)10 (40.7%)1 (3.7%)9 (33.3%)6 (22.2%)11 (40.7%) Anti-CTLA4 (N=6)3 (50%)2 (33.3%)1 (16.6%)01 (16.6%) Anti-PD1+anti-CTLA4 (N=1)1 (100%)0001 (100%) Total (N=34)14 (41%)3 (8.8%)10 (29.4%)6 (17.6%)13Immunosuppressive drug regimen Regimen monotherapy (N=16)91326 (37.5%)mTOR/calcineurin inhibitors (N =9)31223 (33.3%)Steroids (N =5)50002 (40%)Cyclosporine (N =2)00111 (50%) Regimen combination (N=18)62737 (38.8%)a Partial response group includes one complete response with anti-PD1 treatment. Open table in a new tab HCC, hepatocellular carcinoma; PR, partial response; SD, stable disease; PD, progression disease; CR, complete response; NR, not reported. Although both CTLA-4 and PD1 pathways inhibit T cells function, their mechanism of action is different: while CTLA-4 is crucial for the induction phase of immune tolerance [2.Bour-Jordan H. Esensten J.H. Martinez-Llordella M. et al.Intrinsic and extrinsic control of peripheral T-cell tolerance by costimulatory molecules of the CD28/B7 family.Immunol Rev. 2011; 241: 180-205Crossref PubMed Scopus (282) Google Scholar], PD1 is critical for the maintenance phase, regulatory T-cell (Treg) induction and allograft acceptance [4.Lipson E.J. Bagnasco S.M. Moore Jr, J. et al.Tumor regression and allograft rejection after administration of anti-PD-1 HHS public access.N Engl J Med. 2016; 374: 896-898Crossref PubMed Scopus (168) Google Scholar]. Anti-PD1 treatment also enhance effector T-cell activity by preventing PD1 from binding to PDL1 expressed on both tumor cells and immune cells. This blockade has been described to impair the forkhead box P3 (FOXP3) regulatory T-cell-mediated graft tolerance in kidney tubular cells [3.Riella L.V. Paterson A.M. Sharpe A.H. Chandraker A. Role of the PD‐1 pathway in the immune response.Am J Transplant. 2012; 12: 2575-2587Crossref PubMed Scopus (251) Google Scholar]. In conclusion, in the case reports available in the literature, immune checkpoint blockade in organ-transplanted cancer patients is an active treatment in spite of transplant-associated immunosuppression treatment. In addition, published clinical reports suggest that therapy with anti-PD1 drugs is associated with a higher risk of organ rejection in transplanted patients than anti-CTLA-4 drugs. This might be due to the central role of PD1 in the maintenance of adaptive tolerance to transplanted solid organs. Therefore, anti-CTLA-4 drugs—when available—could be a preferred therapeutic option in this special population.