Chimeric antigen receptor (CAR)-T-cell therapy has sparked a wave of optimism in hematological malignancies, reflected by the successful results of early clinical trials involving patients with pre-B-cell acute lymphoblastic leukemia, B-cell lymphomas and multiple myeloma. CAR-T-cell therapy is considered to be a novel immunotherapy treatment that has the potential for curing certain hematological cancers. However, as use of CAR-T-cell therapy has grown, new challenges have surfaced. These challenges include the process of manufacturing the CAR-T cells, the mechanisms of resistance that underlie disease relapse, adverse effects and cost. This review describes the published results of clinical trials and expected developments to overcome CAR-T resistance.
SiegelRL, MillerKD, JemalA. Cancer statistics, 2020. CA Cancer J Clin2020;70:7–30.doi:10.3322/caac.21590
2.
ParkJH, BrentjensRJ. Adoptive immunotherapy for B-cell malignancies with autologous chimeric antigen receptor modified tumor targeted T cells. Discov Med2010;9:277–88.
3.
EshharZ, WaksT, GrossG, . Specific activation and targeting of cytotoxic lymphocytes through chimeric single chains consisting of antibody-binding domains and the gamma or zeta subunits of the immunoglobulin and T-cell receptors. Proc Natl Acad Sci U S A1993;90:720–4.doi:10.1073/pnas.90.2.720
4.
MiloneMC, FishJD, CarpenitoC, . Chimeric receptors containing CD137 signal transduction domains mediate enhanced survival of T cells and increased antileukemic efficacy in vivo. Mol Ther2009;17:1453–64.doi:10.1038/mt.2009.83
5.
CarpenterRO, EvbuomwanMO, PittalugaS, . B-Cell maturation antigen is a promising target for adoptive T-cell therapy of multiple myeloma. Clin Cancer Res2013;19:2048–60.doi:10.1158/1078-0432.CCR-12-2422
6.
HudecekM, IzsvákZ, JohnenS, . Going non-viral: the sleeping Beauty transposon system breaks on through to the clinical side. Crit Rev Biochem Mol Biol2017;52:355–80.doi:10.1080/10409238.2017.1304354
7.
GarfallAL, MausMV, HwangW-T, . Chimeric antigen receptor T cells against CD19 for multiple myeloma. N Engl J Med2015;373:1040–7.doi:10.1056/NEJMoa1504542
8.
O'ConnorBP, RamanVS, EricksonLD, . Bcma is essential for the survival of long-lived bone marrow plasma cells. J Exp Med2004;199:91–8.doi:10.1084/jem.20031330
9.
XuS, LamKP. B-Cell maturation protein, which binds the tumor necrosis factor family members BAFF and April, is dispensable for humoral immune responses. Mol Cell Biol2001;21:4067–74.doi:10.1128/MCB.21.12.4067-4074.2001
10.
NovakAJ, DarceJR, ArendtBK, . Expression of BCMA, TACI, and BAFF-R in multiple myeloma: a mechanism for growth and survival. Blood2004;103:689–94.doi:10.1182/blood-2003-06-2043
11.
BellucciR, AlyeaEP, ChiarettiS, . Graft-versus-tumor response in patients with multiple myeloma is associated with antibody response to BCMA, a plasma-cell membrane receptor. Blood2005;105:3945–50.doi:10.1182/blood-2004-11-4463
12.
ShahUA, SmithEL, MyelomaM. Multiple myeloma, targeting B-cell maturation antigen with chimeric antigen receptor T-cells. Cancer J2019;25:208–16.doi:10.1097/PPO.0000000000000379
13.
ChauhanD, SinghAV, BrahmandamM, . Functional interaction of plasmacytoid dendritic cells with multiple myeloma cells: a therapeutic target. Cancer Cell2009;16:309–23.doi:10.1016/j.ccr.2009.08.019
SanchezE, LiM, KittoA, . Serum B-cell maturation antigen is elevated in multiple myeloma and correlates with disease status and survival. Br J Haematol2012;158:727–38.doi:10.1111/j.1365-2141.2012.09241.x
16.
RajeN, BerdejaJ, LinY, . Anti-BCMA CAR T-cell therapy bb2121 in relapsed or refractory multiple myeloma. N Engl J Med2019;380:1726–37.doi:10.1056/NEJMoa1817226
17.
MiharaK, BhattacharyyaJ, KitanakaA, . T-Cell immunotherapy with a chimeric receptor against CD38 is effective in eliminating myeloma cells. Leukemia2012;26:365–7.doi:10.1038/leu.2011.205
18.
DrentE, ThemeliM, PoelsR, . A rational strategy for reducing on-target Off-Tumor effects of CD38-Chimeric antigen receptors by affinity optimization. Mol Ther2017;25:1946–58.doi:10.1016/j.ymthe.2017.04.024
GuoB, ChenM, HanQ, . CD138-directed adoptive immunotherapy of chimeric antigen receptor (CAR)-modified T cells for multiple myeloma. J Cell Immunother2016;2:28–35.doi:10.1016/j.jocit.2014.11.001
21.
RamosCA, SavoldoB, TorranoV, . Clinical responses with T lymphocytes targeting malignancy-associated κ light chains. J Clin Invest2016;126:2588–96.doi:10.1172/JCI86000
22.
ChuJ, HeS, DengY, . Genetic modification of T cells redirected toward CS1 enhances eradication of myeloma cells. Clin Cancer Res2014;20:3989–4000.doi:10.1158/1078-0432.CCR-13-2510
23.
SmithEL, HarringtonK, StaehrM, . Gprc5D is a target for the immunotherapy of multiple myeloma with rationally designed CAR T cells. Sci Transl Med2019;11:eaau7746.doi:10.1126/scitranslmed.aau7746
24.
FernándezL, FernándezA, MironesI, . GMP-Compliant manufacturing of NKG2D CAR memory T cells using CliniMACS Prodigy. Front Immunol2019;10:2361.doi:10.3389/fimmu.2019.02361
25.
SpearP, WuM-R, SentmanM-L, . Nkg2D ligands as therapeutic targets. Cancer Immun2013;13:8.
26.
LeeDW, GardnerR, PorterDL, . Current concepts in the diagnosis and management of cytokine release syndrome. Blood2014;124:188–95.doi:10.1182/blood-2014-05-552729
HayKA, HanafiL-A, LiD, . Kinetics and biomarkers of severe cytokine release syndrome after CD19 chimeric antigen receptor-modified T-cell therapy. Blood2017;130:2295–306.doi:10.1182/blood-2017-06-793141
29.
LeeDW, SantomassoBD, LockeFL, . ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol Blood Marrow Transplant2019;25:625–38.doi:10.1016/j.bbmt.2018.12.758
30.
TeacheyDT, LaceySF, ShawPA, . Identification of predictive biomarkers for cytokine release syndrome after chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia. Cancer Discov2016;6:664–79.doi:10.1158/2159-8290.CD-16-0040
31.
MaudeSL, FreyN, ShawPA, . Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med2014;371:1507–17.doi:10.1056/NEJMoa1407222
32.
YangS, ChenL, XuJ, . Dynamic analysis of cytokine profile for cytokine release syndrome in multiple myeloma patients after CAR-T cell therapy. Blood2019;134:5617.doi:10.1182/blood-2019-131799
33.
BrentjensRJ, DavilaML, RiviereI, . CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci Transl Med2013;5:177ra38.doi:10.1126/scitranslmed.3005930
34.
LeRQ, LiL, YuanW, . Fda approval summary: tocilizumab for treatment of chimeric antigen receptor T cell-induced severe or life-threatening cytokine release syndrome. Oncologist2018;23:943–7.doi:10.1634/theoncologist.2018-0028
35.
KalosM, LevineBL, PorterDL, . T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med2011;3:73-95.doi:10.1126/scitranslmed.3002842
36.
KochenderferJN, DudleyME, FeldmanSA, . 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;119:2709–20.doi:10.1182/blood-2011-10-384388
37.
RieglerLL, JonesGP, LeeDW. Current approaches in the grading and management of cytokine release syndrome after chimeric antigen receptor T-cell therapy. Ther Clin Risk Manag2019;15:323–35.doi:10.2147/TCRM.S150524
38.
LockeFL, NeelapuSS, BartlettNL, . Preliminary Results of Prophylactic Tocilizumab after Axicabtageneciloleucel (axi-cel; KTE-C19) Treatment for Patients with Refractory, Aggressive Non-Hodgkin Lymphoma (NHL). Blood2017;130:1547.
39.
GustJ, HayKA, HanafiL-A, . Endothelial activation and blood-brain barrier disruption in neurotoxicity after adoptive immunotherapy with CD19 CAR-T cells. Cancer Discov2017;7:1404–19.doi:10.1158/2159-8290.CD-17-0698
40.
SantomassoB, BachierC, WestinJ, . The other side of car T-cell therapy: cytokine release syndrome, neurologic toxicity, and financial burden. Am Soc Clin Oncol Educ Book2019;39:433–44.doi:10.1200/EDBK_238691
41.
SternerRM, SakemuraR, CoxMJ, . Gm-Csf inhibition reduces cytokine release syndrome and neuroinflammation but enhances CAR-T cell function in xenografts. Blood2019;133:697–709.doi:10.1182/blood-2018-10-881722
42.
NeelapuSS. Managing the toxicities of car T-cell therapy. Hematol Oncol2019;37:48–52.doi:10.1002/hon.2595
43.
ShahNN, FryTJ. Mechanisms of resistance to CAR T cell therapy. Nat Rev Clin Oncol2019;16:372–85.doi:10.1038/s41571-019-0184-6
44.
TurtleCJ, HanafiL-A, BergerC, . CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients. J Clin Invest2016;126:2123–38.doi:10.1172/JCI85309
45.
WherryEJ, KurachiM. Molecular and cellular insights into T cell exhaustion. Nat Rev Immunol2015;15:486–99.doi:10.1038/nri3862
46.
SiegelAM, HeimallJ, FreemanAF, . A critical role for STAT3 transcription factor signaling in the development and maintenance of human T cell memory. Immunity2011;35:806–18.doi:10.1016/j.immuni.2011.09.016
47.
GajewskiTF, LouahedJ, BrichardVG. Gene signature in melanoma associated with clinical activity: a potential clue to unlock cancer immunotherapy. Cancer J2010;16:399–403.doi:10.1097/PPO.0b013e3181eacbd8
48.
JoyceJA, FearonDT. T cell exclusion, immune privilege, and the tumor microenvironment. Science2015;348:74–80.doi:10.1126/science.aaa6204
49.
GreenDJ, PontM, SatherBD, . Fully human BCMA targeted chimeric antigen receptor T cells administered in a defined composition demonstrate potency at low doses in advanced stage high risk multiple myeloma. Blood2018;132:1011.doi:10.1182/blood-2018-99-117729
50.
MajznerRG, MackallCL. Tumor antigen escape from CAR T-cell therapy. Cancer Discov2018;8:1219–26.doi:10.1158/2159-8290.CD-18-0442
51.
RosenthalJ, NaqviAS, LuoM, . Heterogeneity of surface CD19 and CD22 expression in B lymphoblastic leukemia. Am J Hematol2018;93:E352–5.doi:10.1002/ajh.25235
52.
OrlandoEJ, HanX, TribouleyC, . Genetic mechanisms of target antigen loss in CAR19 therapy of acute lymphoblastic leukemia. Nat Med2018;24:1504–6.doi:10.1038/s41591-018-0146-z
53.
SotilloE, BarrettDM, BlackKL, . Convergence of acquired mutations and alternative splicing of CD19 enables resistance to CART-19 immunotherapy. Cancer Discov2015;5:1282–95.doi:10.1158/2159-8290.CD-15-1020
HamiehM, DobrinA, CabrioluA, . Car T cell trogocytosis and cooperative killing regulate tumour antigen escape. Nature2019;568:112–6.doi:10.1038/s41586-019-1054-1
56.
ChenKH, WadaM, PinzKG, . A compound chimeric antigen receptor strategy for targeting multiple myeloma. Leukemia2018;32:402–12.doi:10.1038/leu.2017.302
57.
ZahE, LinM-Y, Silva-BenedictA, . T cells expressing CD19/CD20 bispecific chimeric antigen receptors prevent antigen escape by malignant B cells. Cancer Immunol Res2016;4:498–508.doi:10.1158/2326-6066.CIR-15-0231
58.
LocatelliF, SchrappeM, BernardoME, . How I treat relapsed childhood acute lymphoblastic leukemia. Blood2012;120:2807–16.doi:10.1182/blood-2012-02-265884
59.
GruppSA, KalosM, BarrettD, . Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med2013;368:1509–18.doi:10.1056/NEJMoa1215134
60.
MaudeSL, LaetschTW, BuechnerJ, . Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med2018;378:439–48.doi:10.1056/NEJMoa1709866
LeeDW, KochenderferJN, Stetler-StevensonM, . T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet2015;385:517–28.doi:10.1016/S0140-6736(14)61403-3
63.
SehnLH, GascoyneRD. Diffuse large B-cell lymphoma: optimizing outcome in the context of clinical and biologic heterogeneity. Blood2015;125:22–32.doi:10.1182/blood-2014-05-577189
64.
GisselbrechtC, GlassB, MounierN, . Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol2010;28:4184–90.doi:10.1200/JCO.2010.28.1618
65.
CoiffierB, ThieblemontC, Van Den NesteE, . Long-Term outcome of patients in the LNH-98.5 trial, the first randomized study comparing rituximab-CHOP to standard CHOP chemotherapy in DLBCL patients: a study by the Groupe d'Etudes des Lymphomes de l'Adulte. Blood2010;116:2040–5.doi:10.1182/blood-2010-03-276246
66.
CrumpM, NeelapuSS, FarooqU, . Outcomes in refractory diffuse large B-cell lymphoma: results from the International SCHOLAR-1 study. Blood2017;130:1800–8.doi:10.1182/blood-2017-03-769620
67.
SehnLH, AssoulineSE, StewartDA, . A phase 1 study of obinutuzumab induction followed by 2 years of maintenance in patients with relapsed CD20-positive B-cell malignancies. Blood2012;119:5118–25.doi:10.1182/blood-2012-02-408773
68.
Van Den NesteE, SchmitzN, MounierN, . Outcome of patients with relapsed diffuse large B-cell lymphoma who fail second-line salvage regimens in the International coral study. Bone Marrow Transplant2016;51:51–7.doi:10.1038/bmt.2015.213
69.
CrumpM, KuruvillaJ, CoubanS, . Randomized comparison of gemcitabine, dexamethasone, and cisplatin versus dexamethasone, cytarabine, and cisplatin chemotherapy before autologous stem-cell transplantation for relapsed and refractory aggressive lymphomas: NCIC-CTG LY.12. J Clin Oncol2014;32:3490–6.doi:10.1200/JCO.2013.53.9593
70.
SchusterSJ, BishopMR, TamCS, . Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med2019;380:45–56.doi:10.1056/NEJMoa1804980
71.
NeelapuSS, LockeFL, BartlettNL, . Axicabtagene Ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med2017;377:2531–44.doi:10.1056/NEJMoa1707447
AbramsonJS, GordonLI, PalombaML, . Updated safety and long term clinical outcomes in TRANSCEND NHL 001, pivotal trial of lisocabtagene maraleucel (JCAR017) in R/R aggressive NHL. JCO2018;36:7505.doi:10.1200/JCO.2018.36.15_suppl.7505
75.
HallekM. On the architecture of translational research designed to control chronic lymphocytic leukemia. Hematology Am Soc Hematol Educ Program2018;2018:1–8.doi:10.1182/asheducation-2018.1.1
76.
ByrdJC, BrownJR, O'BrienS, O'BrienS, . Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med2014;371:213–23.doi:10.1056/NEJMoa1400376
77.
ByrdJC, HarringtonB, O'BrienS, O'BrienS, . Acalabrutinib (ACP-196) in relapsed chronic lymphocytic leukemia. N Engl J Med2016;374:323–32.doi:10.1056/NEJMoa1509981
78.
WendtnerC-M. Ibrutinib: the home run for cure in CLL?Blood2019;133:2003–4.doi:10.1182/blood-2019-03-901090
79.
VitaleC, FalchiL, CicconeM, . Ofatumumab is safe and effective as front-line treatment in older patients with chronic lymphocytic leukemia and severe co-morbidities, including other malignancies. J Geriatr Oncol2020;11:19–23.doi:10.1016/j.jgo.2019.04.002
80.
PatelV, BalakrishnanK, BibikovaE, . Comparison of Acalabrutinib, a selective Bruton tyrosine kinase inhibitor, with ibrutinib in chronic lymphocytic leukemia cells. Clin Cancer Res2017;23:3734–43.doi:10.1158/1078-0432.CCR-16-1446
81.
SharmanJP, CoutreSE, FurmanRR, . Second Interim Analysis of a Phase 3 Study of Idelalisib (ZYDELIG®) Plus Rituximab (R) for Relapsed Chronic Lymphocytic Leukemia (CLL): Efficacy Analysis in Patient Subpopulations with Del(17p) and Other Adverse Prognostic Factors. Blood2014;124:330.doi:10.1182/blood. V124.21.330.330
82.
KaterAP, SeymourJF, HillmenP, . Fixed duration of Venetoclax-Rituximab in relapsed/refractory chronic lymphocytic leukemia eradicates minimal residual disease and prolongs survival: post-treatment follow-up of the MURANO phase III study. J Clin Oncol2019;37:269–77.doi:10.1200/JCO.18.01580
83.
SiddiqiT, SoumeraiJD, DorritieKA, . Rapid undetectable MRD (uMRD) responses in patients with relapsed/refractory (R/R) chronic lymphocytic Leukemia/Small lymphocytic lymphoma (CLL/SLL) treated with Lisocabtagene Maraleucel (liso-cel), a CD19-Directed CAR T cell product: updated results from Transcend CLL 004, a phase 1/2 study including patients with high-risk disease previously treated with ibrutinib. Blood2019;134:503.doi:10.1182/blood-2019-127603
84.
PorterDL, FreyNV, MelenhorstJJ, . Randomized, phase II dose optimization study of chimeric antigen receptor modified T cells directed against CD19 (CTL019) in patients with relapsed, refractory CLL. Blood2014;124:1982.doi:10.1182/blood. V124.21.1982.1982
85.
TimmersM, RoexG, WangY, . Chimeric antigen receptor-modified T cell therapy in multiple myeloma: beyond B cell maturation antigen. Front Immunol2019;10:1613.doi:10.3389/fimmu.2019.01613
86.
MoreauP, SonneveldP, BoccadoroM, . Chimeric antigen receptor T-cell therapy for multiple myeloma: a consensus statement from the European myeloma network. Haematologica2019;104:2358–60.doi:10.3324/haematol.2019.224204
87.
BrownCE, MackallCL. Car T cell therapy: inroads to response and resistance. Nat Rev Immunol2019;19:73–4.doi:10.1038/s41577-018-0119-y
PorterD, FreyN, WoodPA, . Grading of cytokine release syndrome associated with the CAR T cell therapy tisagenlecleucel. J Hematol Oncol2018;11:35.doi:10.1186/s13045-018-0571-y
90.
PorterD, FreyN, WoodPA, . Correction to: grading of cytokine release syndrome associated with the CAR T cell therapy tisagenlecleucel. J Hematol Oncol2018;11:81.doi:10.1186/s13045-018-0627-z
91.
ParkJH, RivièreI, GonenM, . Long-Term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia. N Engl J Med2018;378:449–59.doi:10.1056/NEJMoa1709919
92.
NeelapuSS, TummalaS, KebriaeiP, . Chimeric antigen receptor T-cell therapy - assessment and management of toxicities. Nat Rev Clin Oncol2018;15:47–62.doi:10.1038/nrclinonc.2017.148
93.
LockeFL, GhobadiA, JacobsonCA, . Long-Term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 trial. Lancet Oncol2019;20:31–42.doi:10.1016/S1470-2045(18)30864-7
94.
MadduriD, UsmaniSZ, JagannathS, . Results from CARTITUDE-1: a phase 1b/2 study of JNJ-4528, a CAR-T cell therapy directed against B-cell maturation antigen (BCMA), in patients with relapsed and/or refractory multiple myeloma (R/R Mm). Blood2019;134:577.doi:10.1182/blood-2019-121731
