Adoptive therapy with chimeric antigen receptor (CAR) redirected T cells achieved lasting remissions in hematologic malignancies, even in terminal stages of the disease. Exploring CAR T cell therapy in the treatment of solid tumors has just begun, balancing efficacy versus toxicity in early phase trials. In contrast to leukemia/lymphoma, solid tumors display a tremendously variable biology demanding different strategies to make a T cell attack successful in the long term. This article summarizes current developments, discusses the hurdles, and considers some modifications to improve the CAR T cell therapy in the treatment of solid tumors.
Get full access to this article
View all access options for this article.
References
1.
DudleyME, WunderlichJR, RobbinsPF, et al.Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science, 2002; 298:850–854.
2.
DudleyME, GrossCA, SomervilleRPT, et al.Randomized selection design trial evaluating CD8+-enriched versus unselected tumor-infiltrating lymphocytes for adoptive cell therapy for patients with melanoma. J Clin Oncol, 2013; 31:2152–2159.
3.
HinrichsCS, RosenbergSA. Exploiting the curative potential of adoptive T-cell therapy for cancer. Immunol Rev, 2014; 257:56–71.
4.
MorganRA, DudleyME, WunderlichJR, et al.Cancer regression in patients after transfer of genetically engineered lymphocytes. Science, 2006; 314:126–129.
5.
GrossG, WaksT, EshharZ. Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity. Proc Natl Acad Sci U S A, 1989; 86:10024–10028.
6.
EshharZ, WaksT, GrossG, et al.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 A, 1993; 90:720–724.
7.
FinneyHM, LawsonAD, BebbingtonCR, et al.Chimeric receptors providing both primary and costimulatory signaling in T cells from a single gene product. J Immunol, 1998; 161:2791–2797.
8.
HombachA, WieczarkowieczA, MarquardtT, et al.Tumor-specific T cell activation by recombinant immunoreceptors: CD3 zeta signaling and CD28 costimulation are simultaneously required for efficient IL-2 secretion and can be integrated into one combined CD28/CD3 zeta signaling receptor molecule. J Immunol, 2001; 167:6123–6131.
9.
HombachAA, AbkenH. Costimulation by chimeric antigen receptors revisited the T cell antitumor response benefits from combined CD28-OX40 signalling. Int J Cancer, 2011; 129:2935–2944.
10.
KawalekarOU, O'ConnorRS, FraiettaJA, et al.Distinct signaling of coreceptors regulates specific metabolism pathways and impacts memory development in CAR T cells. Immunity, 2016; 44:380–390.
11.
HombachAA, ChmielewskiM, RapplG, et al.Adoptive immunotherapy with redirected T cells produces CCR7– cells that are trapped in the periphery and benefit from combined CD28-OX40 costimulation. Hum Gene Ther, 2013; 24:259–269.
KershawMH, WestwoodJA, ParkerLL, et al.A Phase I study on adoptive immunotherapy using gene-modified T cells for ovarian cancer. Clin Cancer Res, 2006; 12:6106–6115.
14.
LamersCHJ, SleijferS, VultoAG, et al.Treatment of metastatic renal cell carcinoma with autologous T-lymphocytes genetically retargeted against carbonic anhydrase IX: first clinical experience. J Clin Oncol, 2006; 24:e20–22.
15.
ParkJR, DigiustoDL, SlovakM, et al.Adoptive transfer of chimeric antigen receptor re-directed cytolytic T lymphocyte clones in patients with neuroblastoma. Mol Ther, 2007; 15:825–833.
16.
PuleMA, SavoldoB, MyersGD, et al.Virus-specific T cells engineered to coexpress tumor-specific receptors: persistence and antitumor activity in individuals with neuroblastoma. Nat Med, 2008; 14:1264–1270.
17.
BeattyGL, HaasAR, MausMV, et al.Mesothelin-specific chimeric antigen receptor mRNA-engineered T cells induce anti-tumor activity in solid malignancies. Cancer Immunol Res, 2014; 2:112–120.
18.
ZhangC, WangZ, YangZ, et al.Phase I escalating-dose trial of CAR-T therapy targeting CEA(+) metastatic colorectal cancers. Mol Ther, 2017; 25:1248–1258.
19.
KatzSC, BurgaRA, McCormackE, et al.Phase I hepatic immunotherapy for metastases study of intra-arterial chimeric antigen receptor-modified T-cell therapy for CEA+ liver metastases. Clin Cancer Res, 2015; 21:3149–3159.
20.
BrownCE, AlizadehD, StarrR, et al.Regression of glioblastoma after chimeric antigen receptor T-cell therapy. N Engl J Med, 2016; 375:2561–2569.
21.
MorganRA, YangJC, KitanoM, et al.Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. Mol Ther, 2010; 18:843–851.
22.
HombachA, HombachAA, AbkenH. Adoptive immunotherapy with genetically engineered T cells: modification of the IgG1 Fc “spacer” domain in the extracellular moiety of chimeric antigen receptors avoids “off-target” activation and unintended initiation of an innate immune response. Gene Ther, 2010; 17:1206–1213.
23.
LeeDW, GardnerR, PorterDL, et al.Current concepts in the diagnosis and management of cytokine release syndrome. Blood, 2014; 124:188–195.
24.
ChenF, TeacheyDT, PequignotE, et al.Measuring IL-6 and sIL-6R in serum from patients treated with tocilizumab and/or siltuximab following CAR T cell therapy. J Immunol Methods, 2016; 434:1–8.
25.
AhmedN, BrawleyVS, HegdeM, et al.Human epidermal growth factor receptor 2 (HER2)-specific chimeric antigen receptor-modified T cells for the immunotherapy of HER2-positive sarcoma. J Clin Oncol, 2015; 33:1688–1696.
26.
TeacheyDT, LaceySF, ShawPA, et al.Identification of predictive biomarkers for cytokine release syndrome after chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia. Cancer Discov, 2016; 6:664–679.
27.
BirkholzK, HombachA, KrugC, et al.Transfer of mRNA encoding recombinant immunoreceptors reprograms CD4+ and CD8+ T cells for use in the adoptive immunotherapy of cancer. Gene Ther, 2009; 16:596–604.
28.
MausMV, HaasAR, BeattyGL, et al.T cells expressing chimeric antigen receptors can cause anaphylaxis in humans. Cancer Immunol Res, 2013; 1:26–31.
29.
BrownCE, BadieB, BarishME, et al.Bioactivity and safety of IL13Rα2-redirected chimeric antigen receptor CD8+ T cells in patients with recurrent glioblastoma. Clin Cancer Res, 2015; 21:4062–4072.
30.
WuC-Y, RoybalKT, PuchnerEM, et al.Remote control of therapeutic T cells through a small molecule-gated chimeric receptor. Science, 2015; 350:aab4077.
31.
Di StasiA, De AngelisB, RooneyCM, et al.T lymphocytes coexpressing CCR4 and a chimeric antigen receptor targeting CD30 have improved homing and antitumor activity in a Hodgkin tumor model. Blood, 2009; 113:6392–6402.
32.
StraathofKC, PulèMA, YotndaP, et al.An inducible caspase 9 safety switch for T-cell therapy. Blood, 2005; 105:4247–4254.
33.
BuddeLE, BergerC, LinY, et al.Combining a CD20 chimeric antigen receptor and an inducible caspase 9 suicide switch to improve the efficacy and safety of T cell adoptive immunotherapy for lymphoma. PloS One, 2013; 8:e82742.
34.
PoseyAD, SchwabRD, BoesteanuAC, et al.Engineered CAR T cells targeting the cancer-associated Tn-glycoform of the membrane mucin MUC1 control adenocarcinoma. Immunity, 2016; 44:1444–1454.
35.
KakarlaS, ChowKKH, MataM, et al.Antitumor effects of chimeric receptor engineered human T cells directed to tumor stroma. Mol Ther, 2013; 21:1611–1620.
36.
ChinnasamyD, TranE, YuZ, et al.Simultaneous targeting of tumor antigens and the tumor vasculature using T lymphocyte transfer synergize to induce regression of established tumors in mice. Cancer Res, 2013; 73:3371–3380.
37.
ChmielewskiM, HahnO, RapplG, et al.T cells that target carcinoembryonic antigen eradicate orthotopic pancreatic carcinomas without inducing autoimmune colitis in mice. Gastroenterology, 2012; 143:1095–1107.e2.
38.
ParkhurstMR, YangJC, LanganRC, et al.T cells targeting carcinoembryonic antigen can mediate regression of metastatic colorectal cancer but induce severe transient colitis. Mol Ther, 2011; 19:620–626.
39.
HombachA, KochD, SircarR, et al.A chimeric receptor that selectively targets membrane-bound carcinoembryonic antigen (mCEA) in the presence of soluble CEA. Gene Ther, 1999; 6:300–304.
40.
LiuX, JiangS, FangC, et al.Affinity-tuned ErbB2 or EGFR chimeric antigen receptor T cells exhibit an increased therapeutic index against tumors in mice. Cancer Res, 2015; 75:3596–3607.
41.
CarusoHG, HurtonLV, NajjarA, et al.Tuning sensitivity of CAR to EGFR density limits recognition of normal tissue while maintaining potent antitumor activity. Cancer Res, 2015; 75:3505–3518.
42.
SmithTT, MoffettHF, StephanSB, et al.Biopolymers codelivering engineered T cells and STING agonists can eliminate heterogeneous tumors. J Clin Invest, 2017; 127:2176–2191.
43.
KershawMH, WangG, WestwoodJA, et al.Redirecting migration of T cells to chemokine secreted from tumors by genetic modification with CXCR2. Hum Gene Ther, 2002; 13:1971–1980.
44.
CraddockJA, LuA, BearA, et al.Enhanced tumor trafficking of GD2 chimeric antigen receptor T cells by expression of the chemokine receptor CCR2b. J Immunother, 2010; 33:780–788.
45.
MoonEK, CarpenitoC, SunJ, et al.Expression of a functional CCR2 receptor enhances tumor localization and tumor eradication by retargeted human T cells expressing a mesothelin-specific chimeric antibody receptor. Clin Cancer Res, 2011; 17:4719–4730.
46.
YasudaS, ShoM, YamatoI, et al.Simultaneous blockade of programmed death 1 and vascular endothelial growth factor receptor 2 (VEGFR2) induces synergistic anti-tumour effect in vivo. Clin Exp Immunol, 2013; 172:500–506.
47.
BuckanovichRJ, FacciabeneA, KimS, et al.Endothelin B receptor mediates the endothelial barrier to T cell homing to tumors and disables immune therapy. Nat Med, 2008; 14:28–36.
48.
ShrimaliRK, YuZ, TheoretMR, et al.Antiangiogenic agents can increase lymphocyte infiltration into tumor and enhance the effectiveness of adoptive immunotherapy of cancer. Cancer Res, 2010; 70:6171–6180.
49.
SallustoF, ImpellizzieriD, BassoC, et al.T-cell trafficking in the central nervous system. Immunol Rev, 2012; 248:216–227.
50.
SugermanPB, SavageNW, WalshLJ, et al.The pathogenesis of oral lichen planus. Crit Rev Oral Biol Med, 2002; 13:350–365.
51.
CaruanaI, SavoldoB, HoyosV, et al.Heparanase promotes tumor infiltration and antitumor activity of CAR-redirected T lymphocytes. Nat Med, 2015; 21:524–529.
52.
SchietingerA, PhilipM, KrisnawanVE, et al.Tumor-specific T cell dysfunction is a dynamic antigen-driven differentiation program initiated early during tumorigenesis. Immunity, 2016; 45:389–401.
53.
SenDR, KaminskiJ, BarnitzRA, et al.The epigenetic landscape of T cell exhaustion. Science, 2016; 354:1165–1169.
54.
OdorizziPM, PaukenKE, PaleyMA, et al.Genetic absence of PD-1 promotes accumulation of terminally differentiated exhausted CD8+ T cells. J Exp Med, 2015; 212:1125–1137.
55.
KoehlerH, KoflerD, HombachA, et al.CD28 costimulation overcomes transforming growth factor-beta-mediated repression of proliferation of redirected human CD4+ and CD8+ T cells in an antitumor cell attack. Cancer Res, 2007; 67:2265–2273.
56.
KoflerDM, ChmielewskiM, RapplG, et al.CD28 costimulation impairs the efficacy of a redirected T-cell antitumor attack in the presence of regulatory T cells which can be overcome by preventing Lck activation. Mol Ther, 2011; 19:760–767.
57.
ZhangL, YuZ, MuranskiP, et al.Inhibition of TGF-β signaling in genetically engineered tumor antigen-reactive T cells significantly enhances tumor treatment efficacy. Gene Ther, 2013; 20:575–580.
58.
MohammedS, SukumaranS, BajgainP, et al.Improving chimeric antigen receptor-modified T cell function by reversing the immunosuppressive tumor microenvironment of pancreatic cancer. Mol Ther, 2017; 25:249–258.
59.
CherkasskyL, MorelloA, Villena-VargasJ, et al.Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition. J Clin Invest, 2016; 126:3130–3144.
60.
JohnLB, DevaudC, DuongCPM, et al.Anti-PD-1 antibody therapy potently enhances the eradication of established tumors by gene-modified T cells. Clin Cancer Res, 2013; 19:5636–5646.
61.
MoonEK, WangL-C, DolfiDV, et al.Multifactorial T-cell hypofunction that is reversible can limit the efficacy of chimeric antigen receptor-transduced human T cells in solid tumors. Clin Cancer Res, 2014; 20:4262–4273.
62.
ProsserME, BrownCE, ShamiAF, et al.Tumor PD-L1 co-stimulates primary human CD8(+) cytotoxic T cells modified to express a PD1:CD28 chimeric receptor. Mol Immunol, 2012; 51:263–272.
63.
LiuX, RanganathanR, JiangS, et al.A chimeric switch-receptor targeting PD1 augments the efficacy of second-generation CAR T cells in advanced solid tumors. Cancer Res, 2016; 76:1578–1590.
64.
KoboldS, SteffenJ, ChaloupkaM, et al.Selective bispecific T cell recruiting antibody and antitumor activity of adoptive T cell transfer. J Natl Cancer Inst, 2015; 107:364.
65.
MilanoG. Resistance to immunotherapy: clouds in a bright sky. Invest New Drugs, 2017Apr12 [Epub ahead of print]; DOI: 10.1007/s10637-017-0456-x.
66.
NinomiyaS, NaralaN, HuyeL, et al.Tumor indoleamine 2,3-dioxygenase (IDO) inhibits CD19-CAR T cells and is downregulated by lymphodepleting drugs. Blood, 2015; 125:3905–3916.
67.
NewickK, O'BrienS, SunJ, et al.Augmentation of CAR T-cell trafficking and antitumor efficacy by blocking protein kinase A localization. Cancer Immunol Res, 2016; 4:541–551.
68.
TextorA, ListopadJJ, WührmannLL, et al.Efficacy of CAR T-cell therapy in large tumors relies upon stromal targeting by IFNγ. Cancer Res, 2014; 74:6796–6805.
69.
LoA, WangL-CS, SchollerJ, et al.Tumor-promoting desmoplasia is disrupted by depleting FAP-expressing stromal cells. Cancer Res, 2015; 75:2800–2810.
70.
CurranKJ, SeinstraBA, NikhaminY, et al.Enhancing antitumor efficacy of chimeric antigen receptor T cells through constitutive CD40L expression. Mol Ther, 2015; 23:769–778.
71.
WooS-R, FuertesMB, CorralesL, et al.STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors. Immunity, 2014; 41:830–842.
72.
ChmielewskiM, HombachAA, AbkenH. Of CARs and TRUCKs: chimeric antigen receptor (CAR) T cells engineered with an inducible cytokine to modulate the tumor stroma. Immunol Rev, 2014; 257:83–90.
73.
ChmielewskiM, KopeckyC, HombachAA, et al.IL-12 release by engineered T cells expressing chimeric antigen receptors can effectively muster an antigen-independent macrophage response on tumor cells that have shut down tumor antigen expression. Cancer Res, 2011; 71:5697–5706.
74.
KoneruM, PurdonTJ, SpriggsD, et al.IL-12 secreting tumor-targeted chimeric antigen receptor T cells eradicate ovarian tumors in vivo. Oncoimmunology, 2015; 4:e994446.
75.
PorterDL, LevineBL, KalosM, et al.Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med, 2011; 365:725–733.
76.
MaudeSL, FreyN, ShawPA, et al.Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med, 2014; 371:1507–1517.
77.
DavilaML, RiviereI, WangX, et al.Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci Transl Med, 2014; 6:224ra25.
78.
BaiY, KanS, ZhouS, et al.Enhancement of the in vivo persistence and antitumor efficacy of CD19 chimeric antigen receptor T cells through the delivery of modified TERT mRNA. Cell Discov, 2015; 1:15040.
79.
Simon-KellerK, PaschenA, HombachAA, et al.Survivin blockade sensitizes rhabdomyosarcoma cells for lysis by fetal acetylcholine receptor-redirected T cells. Am J Pathol, 2013; 182:2121–2131.
80.
KlossCC, CondominesM, CartellieriM, et al.Combinatorial antigen recognition with balanced signaling promotes selective tumor eradication by engineered T cells. Nat Biotechnol, 2013; 31:71–75.
81.
MondinoA, VellaG, IcardiL. Targeting the tumor and its associated stroma: one and one can make three in adoptive T cell therapy of solid tumors. Cytokine Growth Factor Rev, 2017; 36:57–65
82.
RoybalKT, RuppLJ, MorsutL, et al.Precision tumor recognition by T cells with combinatorial antigen-sensing circuits. Cell, 2016; 164:770–779.
83.
QasimW, ZhanH, SamarasingheS, et al.Molecular remission of infant B-ALL after infusion of universal TALEN gene-edited CAR T cells. Sci Transl Med, 2017; 9.
84.
GattinoniL, FinkelsteinSE, KlebanoffCA, et al.Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+ T cells. J Exp Med, 2005; 202:907–912.
85.
KandalaftLE, PowellDJ, CoukosG. A Phase I clinical trial of adoptive transfer of folate receptor-alpha redirected autologous T cells for recurrent ovarian cancer. J Transl Med, 2012; 10:157.
86.
SampsonJH, ChoiBD, Sanchez-PerezL, et al.EGFRvIII mCAR-modified T-cell therapy cures mice with established intracerebral glioma and generates host immunity against tumor-antigen loss. Clin Cancer Res, 2014; 20:972–984.
87.
FengK-C, GuoY-L, LiuY, et al.Cocktail treatment with EGFR-specific and CD133-specific chimeric antigen receptor-modified T cells in a patient with advanced cholangiocarcinoma. J Hematol Oncol, 2017; 10:4.
88.
MorganRA, JohnsonLA, DavisJL, et al.Recognition of glioma stem cells by genetically modified T cells targeting EGFRvIII and development of adoptive cell therapy for glioma. Hum Gene Ther, 2012; 23:1043–1053.
89.
van SchalkwykMCI, PapaSE, JeannonJ-P, et al.Design of a Phase I clinical trial to evaluate intratumoral delivery of ErbB-targeted chimeric antigen receptor T-cells in locally advanced or recurrent head and neck cancer. Hum Gene Ther Clin Dev, 2013; 24:134–142.
90.
YouF, JiangL, ZhangB, et al.Phase 1 clinical trial demonstrated that MUC1 positive metastatic seminal vesicle cancer can be effectively eradicated by modified Anti-MUC1 chimeric antigen receptor transduced T cells. Sci China Life Sci, 2016; 59:386–397.
91.
KoneruM, O'CearbhaillR, PendharkarS, et al.A Phase I clinical trial of adoptive T cell therapy using IL-12 secreting MUC-16(ecto) directed chimeric antigen receptors for recurrent ovarian cancer. J Transl Med, 2015; 13:102.
92.
FengK, GuoY, DaiH, et al.Chimeric antigen receptor-modified T cells for the immunotherapy of patients with EGFR-expressing advanced relapsed/refractory non-small cell lung cancer. Sci China Life Sci, 2016; 59:468–479.
93.
AhmedN, BrawleyVS, HegdeM, et al.Human epidermal growth factor receptor 2 (HER2)–specific chimeric antigen receptor-modified T cells for the immunotherapy of HER2-positive sarcoma. J Clin Oncol, 2015; 33:1688–1696.
