Lung cancer is the most common cause of cancer-related death in the United States, yet traditional chemotherapy fails to provide long-term benefit for many patients. New approaches are needed to improve overall survival beyond the current standard of care.
Methods
This review discusses recent clinical trials using immunotherapy techniques to treat both non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) and highlights ongoing immunotherapy research efforts at our center.
Results
For NSCLC, phase II clinical trials have examined allogeneic vaccines that target either mucin 1 (MUC1), epidermal growth factor or melanoma-associated antigen 3. These vaccines are now undergoing larger phase III trials. An autologous cellular therapy directed against transforming growth factor beta-2 and a recombinant protein with antitumor properties have also shown promise in prolonging survival in NSCLC in phase II trials. The monoclonal antibodies ipilimumab, BMS-936558 (anti–PD-1), and BMS936559 (anti–PD-L1) lead to enhanced T-cell–mediated antitumor effects and have produced objective responses in early-phase clinical trials. Studies for SCLC also exist, such as a novel vaccine therapy targeting p53.
Conclusions
Recent clinical trials in lung cancer demonstrate the potential of immunotherapeutics to increase overall survival in patients with lung cancer compared with the current standard of care.
References
1.
SiegelR., NaishadhamD., JemalA.. Cancer statistics, 2012.CA Cancer J Clin.2012; 62(1): 10–29
JackmanD.M., MillerV.A., CioffrediL.A.. Impact of epidermal growth factor receptor and KRAS mutations on clinical outcomes in previously untreated non-small cell lung cancer patients: results of an online tumor registry of clinical trials.Clin Cancer Res.2009; 15(16): 5267–5273.
4.
WuY.L., ParkK., SooR.A.. INSPIRE: a phase III study of the BLP25 liposome vaccine (L-BLP25) in Asian patients with unresectable stage III non-small cell lung cancer.BMC Cancer.2011; 11: 430.
5.
TyagiP., MirakhurB.. MAGRIT: the largest-ever phase III lung cancer trial aims to establish a novel tumor-specific approach to therapy.Clin Lung Cancer.2009; 10(5): 371–374.
6.
QuoixE., RamlauR., WesteelV.. Therapeutic vaccination with TG4010 and first-line chemotherapy in advanced non-small-cell lung cancer: a controlled phase 2B trial.Lancet Oncol.2011; 12(12): 1125–1133.
7.
HayesT.G., FalchookG.F., VaradhacharyG.R.. Phase I trial of oral talactoferrin alfa in refractory solid tumors.Invest New Drugs.2006; 24(3): 233–240.
8.
NemunaitisJ., DillmanR.O., SchwarzenbergerP.O.. Phase II study of belagenpumatucel-L, a transforming growth factor beta-2 antisense gene-modified allogeneic tumor cell vaccine in non-small-cell lung cancer.J Clin Oncol.2006; 24(29): 4721–4730.
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.
11.
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.
12.
TopalianS.L., HodiF.S., BrahmerJ.R.. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer.N Engl J Med.2012; 366(26): 2443–2454.
13.
DigumartiR., WangY., RamanG.. A randomized, double-blind, placebo-controlled, phase II study of oral talactoferrin in combination with carboplatin and paclitaxel in previously untreated locally advanced or metastatic non-small cell lung cancer.J Thorac Oncol.2011; 6(6): 1098–1103.
14.
ButtsC., MurrayN., MaksymiukA.. Randomized phase IIB trial of BLP25 liposome vaccine in stage IIIB and IV non-small-cell lung cancer.J Clin Oncol.2005; 23(27): 6674–6681.
15.
ButtsC., MaksymiukA., GossG.. Updated survival analysis in patients with stage IIIB or IV non-small-cell lung cancer receiving BLP25 liposome vaccine (L-BLP25): phase IIB randomized, multicenter, open-label trial.J Cancer Res Clin Oncol.2011; 137(9): 1337–1342.
16.
RamlauR., QuoixE., RolskiJ.. A phase II study of Tg4010 (Mva-Muc1-IL2) in association with chemotherapy in patients with stage III/IV non-small cell lung cancer.J Thorac Oncol.2008; 3(7): 735–744.
17.
Neninger VinagerasE., de la TorreA., Osorio RodríguezM.. Phase II randomized controlled trial of an epidermal growth factor vaccine in advanced non-small-cell lung cancer.J Clin Oncol.2008; 26(9): 1452–1458.
18.
VansteenkisteJ., ZielinskiM., LinderA.. Final results of a multicenter, double-blind, randomized, placebo-controlled phase II study to assess the efficacy of MAGE-A3 immunotherapeutic as adjuvant therapy in stage IB/II non-small cell lung cancer (NSCLC).ASCO Meeting Abstracts.2007; 25(18 suppl): 7554.
19.
VaradhacharyA., WolfJ.S., PetrakK.. Oral lactoferrin inhibits growth of established tumors and potentiates conventional chemotherapy.Int J Cancer.2004; 111(3): 398–403.
20.
HirshV., Paz-AresL., BoyerM.. Randomized phase III trial of paclitaxel/carboplatin with or without PF-3512676 (Toll-like receptor 9 agonist) as first-line treatment for advanced non-small-cell lung cancer.J Clin Oncol.2011; 29(19): 2667–2674.
21.
HoS.B., NiehansG.A., LyftogtC.. Heterogeneity of mucin gene expression in normal and neoplastic tissues.Cancer Res.1993; 53(3): 641–651.
22.
RegimbaldL.H., PilarskiL.M., LongeneckerB.M.. The breast mucin MUC1 as a novel adhesion ligand for endothelial intercellular adhesion molecule 1 in breast cancer.Cancer Res.1996; 56(18): 4244–4249.
23.
BurchellJ., GendlerS., Taylor-PapadimitriouJ.. Development and characterization of breast cancer reactive monoclonal antibodies directed to the core protein of the human milk mucin.Cancer Res.1987; 47(20): 5476–5482.
24.
SamuelJ., BudzynskiW.A., ReddishM.A.. Immunogenicity and antitumor activity of a liposomal MUC1 peptide-based vaccine.Int J Cancer.1998; 75(2): 295–302.
25.
PalmerM., ParkerJ., ModiS.. Phase I study of the BLP25 (MUC1 peptide) liposomal vaccine for active specific immunotherapy in stage IIIB/IV non-small-cell lung cancer.Clin Lung Cancer.2001; 3(1): 49–58.
26.
TrevorK.T., HershE.M., BraileyJ.. Transduction of human dendritic cells with a recombinant modified vaccinia Ankara virus encoding MUC1 and IL-2.Cancer Immunol Immunother.2001; 50(8): 397–407.
RochlitzC., FiglinR., SquibanP.. Phase I immunotherapy with a modified vaccinia virus (MVA) expressing human MUC1 as antigen-specific immunotherapy in patients with MUC1-positive advanced cancer.J Gene Med.2003; 5(8): 690–699.
MokT.S., WuY.L., ThongprasertS.. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma.N Engl J Med.2009; 361(10): 947–957.
31.
GonzalezG., CrombetT., TorresF.. Epidermal growth factor-based cancer vaccine for non-small-cell lung cancer therapy.Ann Oncol.2003; 14(3): 461–466.
32.
RamosT.C., VinagerasE.N., FerrerM.C.. Treatment of NSCLC patients with an EGF-based cancer vaccine: report of a phase I trial.Cancer Biol Ther.2006; 5(2): 145–149.
33.
RodriguezP.C., NeningerE., GarcíaB.. Safety, immunogenicity and preliminary efficacy of multiple-site vaccination with an epidermal growth factor (EGF) based cancer vaccine in advanced non small cell lung cancer (NSCLC) patients.J Immune Based Ther Vaccines.2011; 9: 7.
34.
MarchandM., van BarenN., WeynantsP.. Tumor regressions observed in patients with metastatic melanoma treated with an antigenic peptide encoded by gene MAGE-3 and presented by HLA-A1.Int J Cancer.1999; 80(2): 219–230.
35.
NemunaitisJ., JahanT., RossH.. Phase 1/2 trial of autologous tumor mixed with an allogeneic GVAX vaccine in advanced-stage non-small-cell lung cancer.Cancer Gene Ther.2006; 13(6): 555–562.
36.
KongF., JirtleR.L., HuangD.H.. Plasma transforming growth factor-beta1 level before radiotherapy correlates with long term outcome of patients with lung carcinoma.Cancer.1999; 86(9): 1712–1719.
37.
ParikhP.M., VaidA., AdvaniS.H.. Randomized, double-blind, placebo-controlled phase II study of single-agent oral talactoferrin in patients with locally advanced or metastatic non-small-cell lung cancer that progressed after chemotherapy.J Clin Oncol.2011; 29(31): 4129–4136.
38.
PhanG.Q., YangJ.C., SherryR.M.. Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma.Proc Natl Acad Sci U S A.2003; 100(14): 8372–8377.
39.
HodiF.S., O'DayS.J., McDermottD.F.. Improved survival with ipilimumab in patients with metastatic melanoma.N Engl J Med.2010; 363(8): 711–723.
40.
RobertC., ThomasL., BondarenkoI.. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma.N Engl J Med.2011; 364(26): 2517–2526.
41.
TopalianS.L., DrakeC.G., PardollD.M.. Targeting the PD-1/B7-H1(PD-L1) pathway to activate anti-tumor immunity.Curr Opin Immunol.2012; 24(2): 207–212.
42.
OkazakiT., HonjoT.. PD-1 and PD-1 ligands: from discovery to clinical application.Int Immunol.2007; 19(7): 813–824.
43.
DessureaultS., NoyesD., LeeD.. A phase-I trial using a universal GM-CSF-producing and CD40L-expressing bystander cell line (GM.CD40L) in the formulation of autologous tumor cell-based vaccines for cancer patients with stage IV disease.Ann Surg Oncol.2007; 14(2): 869–884.
44.
GovindanR., PageN., MorgenszternD.. Changing epidemiology of small-cell lung cancer in the United States over the last 30 years: analysis of the surveillance, epidemiologic, and end results database.J Clin Oncol.2006; 24(28): 4539–4544.
45.
GrantS.C., KrisM.G., HoughtonA.N.. Long survival of patients with small cell lung cancer after adjuvant treatment with the anti-idiotypic antibody BEC2 plus Bacillus Calmette-Guérin.Clin Cancer Res.1999; 5(6): 1319–1323.
46.
GiacconeG., DebruyneC., FelipE.. Phase III study of adjuvant vaccination with Bec2/bacille Calmette-Guerin in responding patients with limited-disease small-cell lung cancer (European Organisation for Research and Treatment of Cancer 08971-08971B; Silva Study).J Clin Oncol.2005; 23(28): 6854–6864.
47.
ChiapporiA.A., SolimanH., JanssenW.E.. INGN-225: a dendritic cell-based p53 vaccine (Ad.p53-DC) in small cell lung cancer: observed association between immune response and enhanced chemotherapy effect.Expert Opin Biol Ther.2010; 10(6): 983–991.
48.
FuentesR., AllmanR., MasonM.D.. Ganglioside expression in lung cancer cell lines.Lung Cancer.1997; 18(1): 21–33.
49.
McCafferyM., YaoT.J., WilliamsL.. Immunization of melanoma patients with BEC2 anti-idiotypic monoclonal antibody that mimics GD3 ganglioside: enhanced immunogenicity when combined with adjuvant.Clin Cancer Res.1996; 2(4): 679–686.
50.
NikitinaE.Y., ChadaS., Muro-CachoC.. An effective immunization and cancer treatment with activated dendritic cells transduced with full-length wild-type p53.Gene Ther.2002; 9(5): 345–352.
