Adoptive cell therapies represent a new frontier in the quest for potent, personalized therapies for malignant disease with fewer of the widespread adverse events associated with standard chemotherapy. Adoptive cell therapies involve the identification, isolation, and expansion (with or without genetic manipulation) and then transfer of T cells with specific antitumor activity into patients with malignant disease to activate an effective antitumor immune response. These therapies include the tumor infiltrating lymphocytes, T-cell receptors, and chimeric antigen receptor T cells. These therapies are associated with unique, potentially devastating but usually reversible toxicities related to supraphysiologic cytokine activation, including cytokine release syndrome, chimeric antigen receptor T-cell-related encephalopathy syndrome, and hemophagocytic lymphohistiocytosis; tumor lysis syndrome is uncommon but can occur in patients with large disease burdens. Prompt, vigilant, and aggressive supportive care with a multidisciplinary approach is imperative to treat the toxicities associated with the adoptive cell therapies. From a renal standpoint, adoptive cell therapy has been associated with varying degrees of acute kidney injury, ranging from mild increases in creatinine to renal failure requiring renal replacement therapy. Renal injury may be related to significant intravascular volume shifts in the setting of cytokine-related vasodilation. This review aims to familiarize nephrologists with these relatively new therapies and their associated toxicities.
KalosMJuneCH.Adoptive T cell transfer for cancer immunotherapy in the era of synthetic biology. Immunity2013; 39(1): 49–60.
2.
ColeyWB.The treatment of malignant tumors by repeated inoculations of erysipelas: with a report of ten original cases. Am J Med Sci1893; 105: 487–511.
3.
BillinghamREBrentLMedawarPB.Quantitative studies on tissue transplantation immunity. II. The origin, strength and duration of actively and adoptively acquired immunity. Proc R Soc Lond B Biol Sci1954; 143(910): 58–80.
4.
RosenbergSARestifoNPYangJC, et al. Adoptive cell transfer: a clinical path to effective cancer immunotherapy. Nat Rev Cancer2008; 8(4): 299–308.
5.
JiangTZhouCRenS.Role of IL-2 in cancer immunotherapy. Oncoimmunology2016; 5: e1163462.
6.
GaoCManjiliMHSubjeckJR, et al. Therapeutic cancer vaccines: past, present and future. Adv Cancer Res2013; 119: 421–475.
7.
SchmidtsAMausMV.Making CAR T cells a solid option for solid tumors. Front Immunol2018; 9: 2593.
8.
FreyN.Cytokine release syndrome: who is at risk and how to treat. Best Pract Res Clin Haematol2017; 30(4): 336–340.
9.
BalkwillFRCapassoMHagemannT.The tumor microenvironment at a glance. J Cell Sci2012; 125(Pt. 23): 5591–5596.
10.
BelliCTrapaniDVialeG, et al. Targeting the microenvironment in solid tumors. Cancer Treat Rev2018; 65: 22–32.
11.
ChenFZhuangXLinL, et al. New horizons in tumor microenvironment biology: challenges and opportunities. BMC Med2015; 13: 45.
12.
MarkovOVMironovaNLVlasovVV, et al. Molecular and cellular mechanisms of antitumor immune response activation by dendritic cells. Acta Nat2016; 8(3): 17–30.
13.
BurnetFM.Immunological aspects of malignant disease. Lancet1967; 1: 1171–1174.
ChenDSMellmanI.Oncology meets immunology: the cancer-immunity cycle. Immunity2013; 39(1): 1–10.
16.
ParishCR.Cancer immunotherapy: the past, the present and the future. Immunol Cell Biol2003; 81: 106–113.
17.
MorganDARuscettiFWGalloR.Selective in vitro growth of T lymphocytes from normal human bone marrows. Science1976; 193(4257): 1007–1008.
18.
RosenbergSALotzeMT.Cancer immunotherapy using interleukin-2 and interleukin-2-activated lymphocytes. Annu Rev Immunol1986; 4: 681–709.
19.
DonohueJHRosensteinMChangAE, et al. The systemic administration of purified interleukin 2 enhances the ability of sensitized murine lymphocytes to cure a disseminated syngeneic lymphoma. J Immunol1984; 132(4): 2123–2128.
20.
RosenbergSARestifoNP.Adoptive cell transfer as personalized immunotherapy for human cancer. Science2015; 348(6230): 62–68.
21.
RosenbergSAYangJCSherryRM, et al. Durable complete responses in heavily pretreated patients with metastatic melanoma using T cell transfer immunotherapy. Clin Cancer Res2011; 17(13): 4550–4557.
22.
GoffSLDudleyMCitrinDE, et al. A randomized, prospective evaluation comparing intensity of lymphodepletion prior to adoptive transfer of tumor infiltrating lymphocytes for patients with metastatic melanoma. J Clin Oncol2016; 34(Suppl.): 3006.
LizéeGOverwijkWWRadvanyiL, et al. Harnessing the power of the immune system to target cancer. Annu Rev Med2013; 64: 71–90.
25.
RosenbergSAYannelliJRYangJC, et al. Treatment of patients with metastatic melanoma with autologous tumor-infiltrating lymphocytes and interleukin 2. J Natl Cancer Inst1994; 86: 1159–1166.
26.
RadvanyiLGBernatchezCZhangM, et al. Specific lymphocyte subsets predict response to adoptive cell therapy using expanded autologous tumor-infiltrating lymphocytes in metastatic melanoma patients. Clin Cancer Res2012; 18: 6758–6770.
27.
BesserMJShapira-FrommerRTrevesAJ, et al. Clinical responses in a phase II study using adoptive transfer of short-term cultured tumor infiltration lymphocytes in metastatic melanoma patients. Clin Cancer Res2010; 16(9): 2646–2655.
28.
ClinicalTrials.gov. A phase II study using short-term cultured, autologous tumor-infiltrating lymphocytes following a lymphocyte depleting regimen in metastatic cancers plus the administration of pembrolizumabat time of progression (Clinical trial number NCT01174121), https://clinicaltrials.gov/ct2/show/NCT01174121
29.
RohaanMWvan den BergJHKvistborgP, et al. Adoptive transfer of tumor-infiltrating lymphocytes in melanoma: a viable treatment option. J Immunother Cancer2018; 6(1): 102.
30.
JuneCHRiddellSRSchumacherTN.Adoptive cellular therapy: a race to the finish line. Sci Transl Med2015; 7: 280–287.
31.
FesnakADJuneCHLevineBL.Engineered T cells: the promise and challenges of cancer immunotherapy. Nat Rev Cancer2016; 16(9): 566–581.
32.
RestifoNPDudleyMERosenbergSA.Adoptive immunotherapy for cancer: harnessing the T cell response. Nat Rev Immunol2012; 12(4): 269–281.
33.
PingYLiuCZhangY.T-cell receptor-engineered T cells for cancer treatment: current status and future directions. Protein Cell2018; 9(3): 254–266.
34.
SharpeMMountN.Genetically modified T cells in cancer therapy: opportunities and challenges. Dis Model Mech2015; 8(4): 337–350.
35.
MorganRADudleyMEWunderlichJR, et al. Cancer regression in patients after transfer of genetically engineered lymphocytes. Science2006; 314(5796): 126–129.
36.
JohnsonLAMorganRADudleyME, et al. Gene therapy with human and mouse T-cell receptors mediates cancer regression and targets normal tissues expressing cognate antigen. Blood2009; 114(3): 535–546.
37.
ChodonTComin-AnduixBChmielowskiB, et al. Adoptive transfer of MART-1 T-cell receptor transgenic lymphocytes and dendritic cell vaccination in patients with metastatic melanoma. Clin Cancer Res2014; 20(9): 2457–2465.
38.
RapoportAPStadtmauerEABinder-SchollGK, et al. NY-ESO-1-specific TCR-engineered T cells mediate sustained antigen-specific antitumor effects in myeloma. Nat Med2015; 21(8): 914–921.
39.
RobbinsPFMorganRAFeldmanSA, et al. Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1. J Clin Oncol2011; 29(7): 917–924.
40.
RobbinsPFKassimSHTranTL, et al. A pilot trial using lymphocytes genetically engineered with an NY-ESO-1-reactive T-cell receptor: long term follow-up and correlates with response. Clin Cancer Res2015; 21(5): 1019–1027.
CurranKJPegramHJBrentjensRJ.Chimeric antigen receptors for T cell immunotherapy: current understanding and future directions. J Gene Med2012; 14(6): 405–415.
44.
MiliotouANPapadopoulouLC.CAR T-cell therapy: a new era in cancer immunotherapy. Curr Pharm Biotechnol2018; 19(1): 5–18.
45.
MaudeSLTeacheyDTPorterDL, et al. CD19-targeted chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia. Blood2015; 125(26): 4017–4023.
46.
LittmanDHexnerE.Cancer immunotherapy with chimeric antigen receptor (CAR) T cells. J Onco Nephrol2017; 1(3): 151–155.
47.
BrentjensRJRiviereIParkJH, et al. Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias. Blood2011; 118(18): 4817–4828.
48.
BrudnoJNSomervilleRPTShiV, et al. Allogeneic T cells that express an anti-CD19 chimeric antigen receptor induce remissions of B-cell malignancies that progress after allogeneic hematopoietic stem-cell transplantation without causing graft-versus-host disease. J Clin Oncol2016; 34(10): 1112–1121.
49.
BrentjensRJDavilaMLRivièreI, et al. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci Transl Med2013; 5(177): 177ra38.
50.
DavilaMLRivièreIWangX, et al. Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci Transl Med2014; 6(224): 224ra25.
51.
LeeDWKochenderferJNStetler-StevensonM, et al. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukemia in children and young adults: a phase 1 dose-escalation trial. Lancet2015; 385: 517–528.
52.
KochenderferJNDudleyMEKassimSH, et al. Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor. J Clin Oncol2015; 33: 540–549.
53.
MaudeSLFreyNShawPA, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med2014; 371: 1507–1517.
54.
PorterDLLevineBLKalosM, et al. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med2011; 365: 725–733.
55.
BeattyGLO’HaraM.Chimeric antigen receptor-modified T cells for the treatment of solid tumors: defining the challenges and next steps. Pharmacol Ther2016; 166: 30–39.
56.
GruppSAKalosMBarrettD, et al. Chimeric antigen receptor–modified T cells for acute lymphoid leukemia. N Engl J Med2013; 368(16): 1509–1518.
KostiPMaherJArnoldJN.Perspectives on chimeric antigen receptor T-cell immunotherapy for solid tumors. Front Immunol2018; 9: 1104.
59.
AdusumilliPSCherkasskyLVillena-VargasJ, et al. Regional delivery of mesothelin-targeted CAR T cell therapy generates potent and long-lasting CD4-dependent tumor immunity. Sci Transl Med2014; 6(261): 261ra151.
60.
ChoiBDSuryadevaraCMGedeonPC, et al. Intracerebral delivery of a third generation EGFRvIII-specific chimeric antigen receptor is efficacious against human glioma. J Clin Neurosci2014; 21(1): 189–190.
61.
PricemanSJTilakawardaneDJeangB, et al. Regional delivery of chimeric antigen receptor-engineered T cells effectively targets HER2+ breast cancer metastasis to the brain. Clin Cancer Res2018; 24(1): 95–105.
62.
AvanziMPYekuOLiX, et al. Engineered tumor-targeted T cells mediate enhanced anti-tumor efficacy both directly and through activation of the endogenous immune system. Cell Rep2018; 23(7): 2130–2141.
63.
MorganMASchambachA.Engineered CAR-T cells for improved function against solid tumors. Front Immunol2018; 9: 2493.
64.
HuBRenJLuoY, et al. Augmentation of antitumor immunity by human and mouse CAR T cells secreting IL-18. Cell Rep2017; 20(13): 3025–3033.
65.
LeeDWGardnerRPorterDL, et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood2014; 124(2): 188–195.
66.
ShiraliACPerazellaMAGettingerS.Association of acute interstitial nephritis with programmed cell death 1 inhibitor therapy in lung cancer patients. Am J Kidney Dis2016; 68(2): 287–291.
67.
TopalianSLHodiFSBrahmerJR, et al. Safety, activity and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med2012; 366: 2443–2454.
68.
MorganRAChinnasamyNAbate-DagaD, et al. Cancer regression and neurological toxicity following anti-MAGE-A3 TCR gene therapy. J Immunother2013; 36(2): 133–151.
69.
PorterDFreyNWoodPA, et al. Grading of cytokine release syndrome associated with the CAR T cell therapy tisagenlecleucel. J Hematol Oncol2018; 11: 35.
ChatenoudLFerranCLegendreC, et al. In vivo cell activation following OKT3 administration: systemic cytokine release and modulation by corticosteroids. Transplantation1990; 49(4): 697–702.
72.
PihuschRHollerEMühlbayerD, et al. The impact of antithymocyte globulin on short-term toxicity after allogeneic stem cell transplantation. Bone Marrow Transplant2002; 30(6): 347–354.
73.
SuntharalingamGPerryMRWardS, et al. Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N Engl J Med2006; 355(10): 1018–1028.
74.
WinklerUJensenMManzkeO, et al. Cytokine-release syndrome in patients with B-cell chronic lymphocytic leukemia and high lymphocyte counts after treatment with an anti-CD20 monoclonal antibody (rituximab, IDEC-C2B8). Blood1999; 94(7): 2217–2224.
75.
WingMGMoreauTGreenwoodJ, et al. Mechanism of first-dose cytokine-release syndrome by CAMPATH 1-H: involvement of CD16 (FcgammaRIII) and CD11a/CD18 (LFA-1) on NK cells. J Clin Invest1996; 98(12): 2819–2826.
76.
AligSKDreylingMSeppiB, et al. Severe cytokine release syndrome after the first dose of Brentuximab Vedotin in a patient with relapsed systemic anaplastic large cell lymphoma (sALCL): a case report and review of literature. Eur J Haematol2015; 94(6): 554–557.
77.
RotzSJLeinoDSzaboS, et al. Severe cytokine release syndrome in a patient receiving PD-1-directed therapy. Pediatr Blood Cancer2017; 64(12): e26642.
78.
BonifantCLJacksonHJBrentjensRJ, et al. Toxicity and management in CAR T-cell therapy. Mol Ther Oncolytics2016; 3: 16011.
79.
HayKAHanafiLLiD, et al. Kinetics and biomarkers of severe cytokine release syndrome after CD19 chimeric antigen receptor-modified T-cell therapy. Blood2017; 130(21): 2295–2306.
80.
MaudeSLLaetschTWBuechnerJ, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med2018; 378(5): 439–448.
81.
SchusterSJSvobodaJChongEA, et al. Chimeric antigen receptor T cells in refractory B-cell lymphomas. N Engl J Med2017; 377(26): 2545–2554.
82.
ParkJHRivièreIGonenM, et al. Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia. N Engl J Med2018; 378(5): 449–459.
83.
BrudnoJNKochenderferJN.Toxicities of chimeric antigen receptor T cells: recognition and management. Blood2016; 127(26): 3321–3330.
84.
TeacheyDTLaceySFShawPA, et al. Identification of predictive biomarkers for cytokine release syndrome after chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia. Cancer Discov2016; 6(6): 664–679.
85.
FitzgeraldJCWeissSLMaudeSL, et al. Cytokine release syndrome after chimeric antigen receptor T cell therapy for acute lymphoblastic leukemia. Crit Care Med2017; 45(2): e124–e131.
86.
SchellerJGrötzingerJRose-JohnS.Updating interleukin-6 classic- and trans-signaling. Signal Trans2006; 6: 240–259.
87.
SchellerJChalarisASchmidt-ArrasD, et al. The pro- and anti-inflammatory properties of the cytokine interleukin–6. Biochim Biophys Acta2011; 1813(5): 878–888.
88.
TurtleCJHanafiLABergerC, et al. CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients. J Clin Invest2016; 126(6): 2123–2138.
89.
FreyNVHexnerEGillS, et al. Optimizing CAR T cell therapy for adult patients with relapsed or refractory acute lymphoblastic leukemia. J Clin Oncol2017; 2016: 7002.
90.
KalosMLevineBLPorterDL, et al. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med2011; 3(95): 95ra73.
91.
SavoldoBRamosCALiuE, et al. CD28 costimulation improves expansion and persistence of chimeric antigen receptor-modified T cells in lymphoma patients. J Clin Invest2011; 121(5): 1822–1826.
92.
Van der StegenSJCHamiehMSadelainM.The pharmacology of second-generation chimeric antigen receptors. Nat Rev Drug Discov2015; 14(7): 499–509.
93.
PorterDLHwangWFreyNV, et al. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci Transl Med2015; 7(303): 303ra139.
94.
KochenderferJNDudleyMEFeldmanSA, et al. B-cell depletion and remissions of malignancy along with cytokine-associated toxicity in a clinical trial of anti-CD19 chimeric-antigen-receptor-transduced T cells. Blood2012; 119(12): 2709–2720.
NeelapuSSTummalaSKebriaeiP, et al. Chimeric antigen receptor T—cell therapy—assessment and management of toxicities. Nat Rev Clin Oncol2018; 15(1): 47–62.
99.
NeelapuSSLockeFLBartlettNL, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med2017; 377(26): 2531–2544.
100.
AliSAShiVMaricI, et al. T cells expressing an anti-B-cell maturation antigen chimeric antigen receptor cause remissions of multiple myeloma. Blood2016; 128(13): 1688–1700.
101.
KochenderferJNSomervilleRPTLuT, et al. Lymphoma remissions caused by anti-CD19 chimeric antigen receptor T cells are associated with high serum interleukin-15 levels. J Clin Oncol2017; 35(16): 1803–1813.
102.
BrudnoJNMaricIHartmanSD, et al. T cells genetically modified to express an anti-B-cell maturation antigen chimeric antigen receptor cause remissions of poor prognosis relapsed multiple myeloma. J Clin Oncol2018; 36(22): 2267–2280.
103.
ParkJHRivièreISenechalB, et al. Baseline and early post-treatment clinical and laboratory factors associated with severe neurotoxicity following 19-28z CAR T cells in adult patients with B-ALL. J Clin Oncol2017; 35(Suppl.): 7024.
104.
GauthierJTurtleCJ.Insights into cytokine release syndrome and neurotoxicity after CD19-specific CAR-T cell therapy. Curr Res Transl Med2018; 66(2): 50–52.
105.
TurtleCJHayKAHanafiLA, et al. Durable molecular remissions in chronic lymphocytic leukemia treated with CD19-specific chimeric antigen receptor-modified T cells after failure of ibrutinib. J Clin Oncol2017; 35(26): 3010–3020.
106.
SmolenJSBeaulieuARubbert-RothA, et al. Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial. Lancet2008; 371: 987–997.
107.
De BenedettiFBrunnerHIRupertoN, et al. Randomized trial of tocilizumab in systemic juvenile idiopathic arthritis. N Engl J Med2012; 367(25): 2385–2395.
DaneseSVermeireSHellsternP, et al. Randomised trial and open-label extension study of an anti-interleukin-6 antibody in Crohn’s disease (ANDANTE I and II). Gut2019; 68(1): 40–48.
110.
ChanKLadeSPrinceHM, et al. Update and new approaches in the treatment of Castleman’s disease. J Blood Med2016; 7: 145–158.
111.
RoddyJVHaverkosBMMcBrideA, et al. Tocilizumab for steroid refractory acute graft-versus-host disease. Leuk Lymphoma2016; 57: 81–85.
112.
LeRQLiLYuanW, et al. FDA approval summary: tocilizumab for treatment of chimeric antigen receptor T-cell-induced severe or life-threatening cytokine release syndrome. Oncologist2018; 23(8): 943–947.
113.
HuYWuZLuoY, et al. Potent anti-leukemia activities of chimeric antigen receptor-modified T cells against CD19 in Chinese patients with relapsed/refractory acute lymphocytic leukemia. Clin Cancer Res2017; 23(13): 3297–3306.
114.
Van RheeFFayadLVoorheesP, et al. Siltuximab, a novel anti-interleukin-6 monoclonal antibody, for Castleman’s disease. J Clin Oncol2010; 28(23): 3701–3708.
LeeDWWayneASHuynhV, et al. Updated results from ZUMA-4: a phase 1/2 study of KTE-C19 chimeric antigen receptor (CAR) T cell therapy in pediatric and adolescent patients with relapsed/refractory acute lymphoblastic leukemia (published as abstract only). Haematologica2017; 102: 346–347.
117.
ShahBHuynhVSenderLS, et al. High rates of minimal residual disease-negative (MRD-) complete responses (CR) in adult and pediatric patients with relapsed/refractory acute lymphoblastic leukemia (R/R ALL) treated with KTE-C19 (anti-CD19 chimeric antigen receptor [CAR] T cells): preliminary results of the ZUMA-3 and ZUMA-4 trials (conference abstract). Blood2016; 128(22): 92803.
118.
TeacheyDTBishopMRMaloneyDG, et al. Toxicity management after chimeric antigen receptor T cell therapy: one size does not fit “ALL.” Nat Rev Clin Oncol2018; 15: 218–219.
119.
TurtleCJHanafiLABergerC, et al. Immunotherapy of non-Hodgkin’s lymphoma with a defined ratio of CD8+ and CD4+ CD19-specific chimeric antigen receptor-modified T cells. Sci Transl Med2016; 8(355): 355ra116.
HuYSunJWuZ, et al. Predominant cerebral cytokine release syndrome in CD19-directed chimeric antigen receptor-modified T cell therapy. J Hematol Oncol2016; 9(1): 70.
122.
SadaatMJangS.Hemophagocytic lymphohistiocytosis with immunotherapy: brief review and case report. J Immunother Cancer2018; 6(1): 49.
123.
DaverNMcClainKAllenCE, et al. A consensus review on malignancy-associated hemophagocytic lymphohistiocytosis in adults. Cancer2017; 123(17): 3229–3240.
124.
SchramAMBerlinerN.How I treat hemophagocytic lymphohistiocytosis in the adult patient. Blood2015; 125(19): 2908–2914.
125.
AllenCEYuXKozinetzCA, et al. Highly elevated ferritin levels and the diagnosis of hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer2008; 50(6): 1227–1235.
HowardSCJonesDPPuiC.The tumor lysis syndrome. N Engl J Med2011; 364: 1844–1854.
128.
KochenderferJNDudleyMECarpenterRO, et al. Donor-derived CD19-targeted T cells cause regression of malignancy persisting after allogeneic hematopoietic stem cell transplantation. Blood2013; 122(25): 4129–4139.
