The immune checkpoint proteins, including the B7/CD28 receptor superfamily, have become increasingly important targets for pharmacologic blockade. Several classes of new agents have impressive clinical activity, and their eventual approval for treatment of lung cancer seems likely.
Methods:
This article discusses the current development of these agents, including the CTLA-4, PD-1, and PD-L1 inhibitory pathways, killer immunoglobulin receptor (KIR) inhibition, and other checkpoint proteins.
Results:
Ipilimumab in combination with chemotherapy has exhibited encouraging results in small-cell and non–small-cell lung cancer alike. Reported phase I trials of the monoclonal antibodies nivolumab, MK-3475, MEDI4736, and MPDL3280A are demonstrating durable overall radiological response rates in the 20% to 25% range in lung cancer. This exceptional activity includes squamous lung cancers, a population historically bereft of significant therapeutic advances. Retrospective examination of tumor PD-L1 expression suggests that PD-L1 may eventually be evaluable as a predictive biomarker. Dual checkpoint blockade strategies, such as those combining anti-CTLA-4, anti-LAG-3, or anti-KIR, are being tested to increase the proportion and durability of tumor responses. Examination of acquired immune resistance and post-immunotherapy relapse strategies are underway.
Conclusions:
These emerging antibodies hold great potential for the systemic control of epithelial cancers such as lung cancer.
References
1.
MatsushitaH., VeselyM.D., KoboldtD.C.. Cancer exome analysis reveals a T-cell-dependent mechanism of cancer immunoediting.Nature.2012; 482(7385): 400–404.
2.
DerniameS., VignaudJ.M., FaureG.C.. Alteration of the immunological synapse in lung cancer: a microenvironmental approach.Clin Exp Immunol.2008; 154(1): 48–55.
3.
KidaH., IharaS., KumanogohA.. Involvement of STAT3 in immune evasion during lung tumorigenesis.Oncoimmunology.2013; 2(1): e22653.
4.
SchneiderT., HoffmannH., DienemannH.. Non-small cell lung cancer induces an immunosuppressive phenotype of dendritic cells in tumor microenvironment by upregulating B7–H3.J Thorac Oncol.2011; 6(7): 1162–1168.
5.
SterlacciW., WolfD., SavicS.. High transforming growth factor-β expression represents an important prognostic parameter for surgically resected non-small cell lung cancer.Hum Pathol.2012; 43(3): 339–349.
6.
SalmonH., DonnadieuE.. Within tumors, interactions between T cells and tumor cells are impeded by the extracellular matrix.Oncoimmunology.2012; 1(6): 992–994.
7.
SalmonH., FranciszkiewiczK., DamotteD.. Matrix architecture defines the preferential localization and migration of T cells into the stroma of human lung tumors.J Clin Invest.2012; 122(3): 899–910.
8.
RamnathN., TanD., LiQ.. Is downregulation of MHC class I antigen expression in human non-small cell lung cancer associated with prolonged survival?Cancer Immunol Immunother.2006; 55(8): 891–899.
9.
LinA., ZhuC.C., ChenH.X.. Clinical relevance and functional implications for human leucocyte antigen-g expression in non-small-cell lung cancer.J Cell Mol Med.2010; 14(9): 2318–2329.
10.
HanagiriT., ShigematsuY., KurodaK.. Prognostic implications of human leukocyte antigen class I expression in patients who underwent surgical resection for non–small-cell lung cancer.J Surg Res.2013; 181(2): e57–e63.
11.
WooE.Y., YehH., ChuC.S.. Cutting edge: regulatory T cells from lung cancer patients directly inhibit autologous T cell proliferation.J Immunol.2002; 168(9): 4272–4276.
12.
Dieu-NosjeanM.C., AntoineM., DanelC.. Long-term survival for patients with non–small-cell lung cancer with intratumoral lymphoid structures.J Clin Oncol.2008; 26(27): 4410–4417.
13.
LesokhinA.M., HohlT.M., KitanoS.. Monocytic CCR2+ myeloid-derived suppressor cells promote immune escape by limiting activated CD8 T-cell infiltration into the tumor microenvironment.Cancer Res.2012; 72(4): 876–886.
14.
NagarajS., YounJ.I., GabrilovichD.I.. Reciprocal relationship between myeloid-derived suppressor cells and t cells.J Immunol.2013; 191(1): 17–23.
15.
KellyR.J., GiacconeG.. Lung cancer vaccines.Cancer J.2011; 17(5): 302–308.
16.
ErfaniN., MehrabadiS.M., GhayumiM.A.. Increase of regulatory T cells in metastatic stage and CTLA-4 over expression in lymphocytes of patients with non-small cell lung cancer (NSCLC).Lung Cancer.2012; 77(2): 306–311.
17.
LiL., ChaoQ.G., PingL.Z.. The prevalence of FOXP3+ regulatory T-cells in peripheral blood of patients with NSCLC.Cancer Biother Radiopharm.2009; 24(3): 357–367.
18.
ZatloukalP., HeoD.S., ParkK.. Randomized phase II clinical trial comparing tremelimumab (CP-675,206) with best supportive care (BSC) following first-line platinum-based therapy in patients (pts) with advanced non-small cell lung cancer (NSCLC).J Clin Oncol.2009; 27 (15S): 8071. Abstract.
19.
CalabròL, MorraA., FonsattiE.. Tremelimumab for patients with chemotherapy-resistant advanced malignant mesothelioma: an open-label, single-arm, phase 2 trial.Lancet Oncol.2013; 14(11): 1104–1111.
20.
LynchT.J., BondarenkoI., LuftA.. Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non–small-cell lung cancer: results from a randomized, double-blind, multicenter phase II study.J Clin Oncol.2012; 30(17): 2046–2054.
21.
OxnardG.R., MorrisM.J., HodiF.S.. When progressive disease does not mean treatment failure: reconsidering the criteria for progression.J Natl Cancer Inst.2012; 104(20): 1534–1541.
22.
WolchokJ.D., HoosA., O'DayS.. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria.Clin Cancer Res.2009; 15(23): 7412–7420.
23.
GoodP.I., HardinJ.W.. Common Errors in Statistics (and How to Avoid Them).Hoboken, NJ: John Wiley & Sons;2012.
24.
DrilonA., RekhtmanN., LadanyiM.. Squamous-cell carcinomas of the lung: emerging biology, controversies, and the promise of targeted therapy.Lancet Oncol.2012; 13(10): e418–e426.
25.
NokiharaH.. Phase 1 study of ipilimumab in combination with paclitaxel/carboplatin in patients with non-small cell lung cancer. Presented at: IASLC 15th World Conference on Lung Cancer; October 2013; Sydney, Australia; P2.11-040.
26.
GenovaC., RijavecE., BarlettaG.. Ipilimumab (MDX-010) in the treatment of non-small cell lung cancer.Expert Opin Biol Ther.2012; 12(7): 939–948.
27.
ReckM., BondarenkoI., LuftA.. Ipilimumab in combination with paclitaxel and carboplatin as first-line therapy in extensive-disease small-cell lung cancer: results from a randomized, double-blind, multicenter phase 2 trial.Ann Oncol.2013; 24(1): 75–83.
28.
LiuH., ZhangT., YeJ.. Tumor-infiltrating lymphocytes predict response to chemotherapy in patients with advance non-small cell lung cancer.Cancer Immunol Immunother.2012; 61(10): 1849–1856.
29.
ReckM.. What future opportunities may immuno-oncology provide for improving the treatment of patients with lung cancer?Ann Oncol.2012; 23(Suppl 8): viii28–viii34.
30.
AgataY., KawasakiA., NishimuraH.. Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes.Int Immunol.1996; 8(5): 765–772.
31.
SauceD., AlmeidaJ.R., LarsenM.. PD-1 expression on human CD8 T cells depends on both state of differentiation and activation status.AIDS.2007; 21(15): 2005–2013.
32.
LiangS.C., LatchmanY.E., BuhlmannJ.E.. Regulation of PD-1, PD-L1, and PD-L2 expression during normal and autoimmune responses.Eur J Immunol.2003; 33(10): 2706–2716.
33.
WangS., BajorathJ., FliesD.B.. Molecular modeling and functional mapping of B7–H1 and B7–DC uncouple costimulatory function from PD-1 interaction.J Exp Med.2003; 197(9): 1083–1091.
34.
PfistershammerK., KlauserC., PicklW.F.. No evidence for dualism in function and receptors: PD-L2/B7-DC is an inhibitory regulator of human T cell activation.Eur J Immunol.2006; 36(5): 1104–1113.
35.
KonishiJ., YamazakiK., AzumaM.. B7-H1 expression on non-small cell lung cancer cells and its relationship with tumor-infiltrating lymphocytes and their PD-1 expression.Clin Cancer Res.2004; 10(15): 5094–5100.
36.
MuC.Y., HuangJ.A., ChenY.. High expression of PD-L1 in lung cancer may contribute to poor prognosis and tumor cells immune escape through suppressing tumor infiltrating dendritic cells maturation.Med Oncol.2011; 28(3): 682–688.
37.
HiraharaK., GhoreschiK., YangX.P.. Interleukin-27 priming of T cells controls IL-17 production in trans via induction of the ligand PD-L1.Immunity.2012; 36(6): 1017–1030.
38.
WölfleS.J., StrebovskyJ., BartzH.. PD-L1 expression on tolerogenic APCs is controlled by STAT-3.Eur J Immunol.2011; 41(2): 413–424.
39.
SasakiH., SuzukiA., ShitaraM.. PD-L1 gene expression in Japanese lung cancer patients.Biomed Rep.2013; 1(1): 93–96.
40.
ChenC., ShenY., QuQ.X.. Induced expression of B7–H3 on the lung cancer cells and macrophages suppresses T-cell mediating anti-tumor immune response.Exp Cell Res.2013; 319(1): 96–102.
41.
ZhangG., XuY., LuX.. Diagnosis value of serum B7–H3 expression in non-small cell lung cancer.Lung Cancer.2009; 66(2): 245–249.
42.
SunY., WangY., ZhaoJ.. B7–H3 and B7–H4 expression in non-small-cell lung cancer.Lung Cancer.2006; 53(2): 143–151.
43.
ZhouY.H., ChenY.J., MaZ.Y.. 4IgB7-H3 is the major isoform expressed on immunocytes as well as malignant cells.Tissue Antigens.2007; 70(2): 96–104.
44.
ZhangY., HuangS., GongD.. Programmed death-1 upregulation is correlated with dysfunction of tumor-infiltrating CD8+ T lymphocytes in human non-small cell lung cancer.Cell Mol Immunol.2010; 7(5): 389–395.
45.
BrahmerJ.. Nivolumab (anti-PD-1; BMS-936558; ONO-4538) in patients with non-small cell lung cancer (NSCLC): overall survival and long-term safety in a phase 1 trial. Presented at: IASLC 15th World Conference on Lung Cancer; October 2013; Sydney, Australia. MO18.03.
46.
RizviN.. A phase I study of nivolumab (anti-PD-1; BMS-936558, ONO-4538) plus platinum-based doublet chemotherapy (PT-doublet) in chemotherapy-naive non-small cell lung cancer (NSCLC) patients (pts).J Clin Oncol.2013; 31(suppl; abstr 8072).
47.
WolchokJ.D., KlugerH., CallahanM.K.. Nivolumab plus ipilimumab in advanced melanoma.N Engl J Med.2013; 369: 122–133.
48.
LipsonE.J., SharfmanW.H., DrakeC.G.. Durable cancer regression off-treatment and effective reinduction therapy with an anti-PD-1 antibody.Clin Cancer Res.2013; 19(2): 462–468.
49.
AntoniaS.. Association of tumor PD-L1 expression and immune biomarkers with clinical activity in patients with non-small cell lung cancer treated with nivolumab. Presented at: IASLC 15th World Conference on Lung Cancer; October 2013; Sydney, Australia. P2.11-035.
50.
GettingerS.H.. Efficacy of nivolumab in patients with previously traeted advanced non-small cell lung cancer: subpopulation response analysis in a phase I trial. Presented at: IASLC 15th World Conference on Lung Cancer; October 2013; Sydney, Australia. P2.11-038.
51.
PatnaikA., KangS.P., TolcherA.W.. Phase I study of MK-3475 (anti-PD-1 monoclonal antibody) in patients with advanced solid tumors.J Clin Oncol.2012; 30(suppl): 2512. Abstract.
52.
HamidO., RobertC., DaudA.. Safety and tumor responses with lambrolizumab (anti–PD-1) in melanoma.N Engl J Med.2013; 369(2): 134–144.
53.
GaronE.. Preliminary clinical safety and activity of MK-3475 monotherapy for the treatment of previously treated patients with non-small cell lung cancer. Presented at: IASLC 15th World Conference on Lung Cancer; October 2013; Sydney, Australia. MO18.02.
54.
BeckA., WurchT., ReichertJ.M.. 6th Annual European Antibody CongressMAbs.20113(2): 111–132.
55.
MkrtichyanM., NajjarY.G., RaulfsE.C.. Anti-PD-1 synergizes with cyclophosphamide to induce potent anti-tumor vaccine effects through novel mechanisms.Eur J Immunol.2011; 41(10): 2977–2986.
56.
BennettF., LuxenbergD., LingV.. Program death-1 engagement upon TCR activation has distinct effects on costimulation and cytokine-driven proliferation: attenuation of ICOS, IL-4, and IL-21, but not CD28, IL-7, and IL-15 responses.J Immunol.2003; 170(2): 711–718.
57.
BrahmerJ.R., TykodiS.S., ChowL.Q.. Safety and activity of anti–PD-L1 antibody in patients with advanced cancer.N Engl J Med.2012; 366(26): 2455–2465.
58.
HerbstR., GordonM.S., FineG.D.. A study of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic tumors.J Clin Oncol.2013; 31(suppl): 3000. Abstract.
59.
HornL.. An analysis of the relationship of clinical activity to baseline EGFR status, PD-L1 expression and prior treatment history in patients with non-small cell lung cancer (NSCLC) following PD-L1 blockade with MPD-L3280A (anti-PDL1). Presented at: IASLC 14th World Conference on Lung Cancer; July 2012; Amsterdam, the Netherlands. MO18.01.
60.
PowderlyJ.D., KoeppenH., HodiS.. Biomarkers and associations with the clinical activity of PD-L1 blockade in a MPDL3280A study.J Clin Oncol.2013; 31(suppl). Absract 3001.
61.
MühlbauerM., FleckM., SchützC.. PD-L1 is induced in hepatocytes by viral infection and by interferon-α and -γ and mediates T cell apoptosis.J Hepatol.2006; 45(4): 520–528.
62.
FreidinM.B., BhudiaN., LimE.. Impact of collection and storage of lung tumor tissue on whole genome expression profiling.J Mol Diagn.2012; 14(2): 140–148.
63.
KhleifS.. MEDI4736, an anti-PD-L1 antibody with modified Fc domain: preclinical evaluation and early clinical results from a phase 1 study in patients with advanced solid tumors. In: Proceedings from the European Cancer Congress 2013; September 27-October 1, 2013; Amsterdam, The Netherlands. Abstract 802.
64.
MkrtichyanM., NajjarY.G., RaulfsE.C.. B7-DC-Ig enhances vaccine effect by a novel mechanism dependent on PD-1 expression level on T cell subsets.J Immunol.2012; 189(5): 2338–2347.
65.
SmothersF., HoosA., LangermannS.. AMP-224, a fusion protein that targets PD-1.Ann Oncol.2013; 24(Suppl 1): i7.
66.
RizviN.A., InfanteJ.R., GibneyG.T.. A phase I study of lirilumab (BMS-986015), an anti-KIR monoclonal antibody, administered with ipilimumab, an anti-CTLA-4 monoclonal antibody, in patients with select advanced solid tumors.J Clin Oncol.2013; 31(suppl): TPS3106. Abstract.
67.
JacobsR., HintzenG., KemperA.. CD56bright cells differ in their KIR repertoire and cytotoxic features from CD56dim NK cells.Eur J Immunol.2001; 31(10): 3121–3126.
68.
CarregaP., MorandiB., CostaR.. Natural killer cells infiltrating human nonsmall-cell lung cancer are enriched in CD56 bright CD16(–) cells and display an impaired capability to kill tumor cells.Cancer.2008; 112(4): 863–875.
69.
BjörklundA.T., SchafferM., FauriatC.. NK cells expressing inhibitory KIR for non–self-ligands remain tolerant in HLA-matched sibling stem cell transplantation.Blood.2010; 115(13): 2686–2694
70.
Al OmarS., MiddletonD., MarshallE.. Associations between genes for killer immunoglobulin-like receptors and their ligands in patients with solid tumors.Hum Immunol.2010; 71(10): 976–981.
71.
Al OmarS.Y., MarshallE., MiddletonD.. Increased numbers but functional defects of CD56+ CD3+ cells in lung cancer.Int Immunol.2012; 24(7): 409–415.
72.
Al OmarS.Y., MarshallE., MiddletonD.. Increased killer immunoglobulin-like receptor expression and functional defects in natural killer cells in lung cancer.Immunology.2011; 133(1): 94–104.
73.
DorothéeG., EchchakirH., ChansacB.L.M.. Functional and molecular characterization of a KIR3DL2/p140 expressing tumor-specific cytotoxic T lymphocyte clone infiltrating a human lung carcinoma.Oncogene.2003; 22(46): 7192–7198.
74.
WiśniewskiA., JankowskaR., Passowicz-MuszyńskaE.. KIR2DL2/S2 and HLA-C C1C1 genotype is associated with better response to treatment and prolonged survival of patients with non-small cell lung cancer in a Polish Caucasian population.Hum Immunol.2012; 73(9): 927–931.
75.
SanbornR.. A phase I dose-escalation and cohort expansion study of lirilumab (anti-KIR; BMS-986015) administered in combination with nivolumab (anti-PD-1; BMS-936558; ONO-4538) in patients (Pts) with advanced refractory solid tumors.J Clin Oncol.2013; 31(suppl): TPS3110. Abstract.
76.
SznolM., HodiF., MargolinK.. Phase I study of BMS-663513, a fully human anti-CD137 agonist monoclonal antibody, in patients (pts) with advanced cancer (CA).J Clin Oncol.2008; 26 (15S): 3007.
77.
MatsuzakiJ., GnjaticS., Mhawech-FaucegliaP.. Tumor-infiltrating NY-ESO-1-specific CD8+ T cells are negatively regulated by LAG-3 and PD-1 in human ovarian cancer.Proc Natl Acad Sci U S A.2010; 107(17): 7875–7880.
78.
OkazakiT., OkazakiI.M., WangJ.. PD-1 and LAG-3 inhibitory co-receptors act synergistically to prevent autoimmunity in mice.J Exp Med.2011; 208(2): 395–407.
79.
WooS.R., TurnisM.E., GoldbergM.V.. Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape.Cancer Res.2012; 72(4): 917–927.
GerberD.E., StopeckA.T., WongL.. Phase I safety and pharmacokinetic study of bavituximab, a chimeric phosphatidylserine-targeting monoclonal antibody, in patients with advanced solid tumors.Clin Cancer Res.2011; 17(21): 6888–6896.
82.
DigumartiR., SureshA., BhattacharyyaG.. Phase II study of bavituximab plus paclitaxel and carboplatin in untreated locally advanced or metastatic non-small cell lung cancer: interim results.J Clin Oncol.2010; 28 (15 suppl): 7589. Abstract.
83.
DragnevK., AttiliS., GaguaR.. A randomized, open-label, phase 2 trial of paclitaxel/carboplatin with or without bavituximab in patients with previously untreated locally advanced or metastatic non-squamous non-small-cell lung cancer. Paper presented at: Multidisciplinary Symposium in Thoracic Oncology; September 6, 2012; Chicago, IL.
84.
StewartR.A., MulgrewK., WangS.. Blockade of PD-L1 mediated immunosuppression for cancer therapy-MEDI4736, monoclonal antibody discovery and preclinical development. Paper presented at; the 27th Annual Meeting of the Society for Immunotherapy of Cancer; October 26-28, 2012; North Bethesda, MD.
85.
ArmandP., NaglerA., WellerE.A.. Disabling immune tolerance by programmed death-1 blockade with pidilizumab after autologous hematopoietic stem-cell transplantation for diffuse large B-cell lymphoma: results of an international phase II trial.J Clin Oncol.2013 Oct 14. Epub ahead of print.
86.
WeinbergA.D., ThalhoferC., MorrisN.. Anti-OX40 (CD134) administration to nonhuman primates: immunostimulatory effects and toxicokinetic study.J Immunother.2006; 29(6): 575–585.
87.
van CruijsenH., RuizM.G., van der ValkP.. Tissue micro array analysis of ganglioside N-glycolyl GM3 expression and signal transducer and activator of transcription (STAT)-3 activation in relation to dendritic cell infiltration and microvessel density in non-small cell lung cancer.BMC Cancer.2009; 9(1): 180.
88.
BlancoR., RengifoC.E., CedeñoM.. Immunoreactivity of the 14F7 Mab (Raised against N-Glycolyl GM3 Ganglioside) as a positive prognostic factor in non-small-cell lung cancer.Patholog Res Int.2012; 2012: 235418.
89.
de LeonJ., FernándezA., MesaC.. Role of tumour-associated N-glycolylated variant of GM3 ganglioside in cancer progression: effect over CD4 expression on T cells.Cancer Immunol Immunother.2006; 55(4): 443–450.
90.
GomezD.E., VázquezA.M., AlonsoD.F.. Anti-idiotype antibodies in cancer treatment.Front Oncol.2012; 3: 37.
91.
ShawA.T., YeapB.Y., SolomonB.J.. Effect of crizotinib on overall survival in patients with advanced non-small-cell lung cancer harbouring ALK gene rearrangement: a retrospective analysis.Lancet Oncol.2011; 12(11): 1004–1012.
92.
PaezJ.G., JänneP.A., LeeJ.C.. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy.Science.2004; 304(5676): 1497–1500.
93.
SloanJ.A., CellaD., FrostM.H.. Assessing clinical significance in measuring oncology patient quality of life: introduction to the symposium, content overview, and definition of terms.Mayo Clin Proc.2002; 77(4): 367–370.
94.
MinaL.A., SledgeG.W.Jr. Rethinking the metastatic cascade as a therapeutic target.Nat Rev Clin Oncol.2011; 8(6): 325–332.
95.
SledgeG.W.Jr. The challenge and promise of the genomic era.J Clin Oncol.2012; 30(2): 203–209.
96.
OcañaA., AmirE., VeraF.. Addition of bevacizumab to chemotherapy for treatment of solid tumors: similar results but different conclusions.J Clin Oncol.2011; 29(3): 254–256.
97.
NiraulaS., SerugaB., OcanaA.. The price we pay for progress: a meta-analysis of harms of newly approved anticancer drugs.J Clin Oncol.2012; 30(24): 3012–3019.
98.
SullivanR., PeppercornJ., SikoraK.. Delivering affordable cancer care in high-income countries.Lancet Oncol.2011; 12(10): 933–980.
99.
RibasA., HerseyP., MiddletonM.R.. New challenges in endpoints for drug development in advanced melanoma.Clin Cancer Res.2012; 18(2): 336–341.
