We are witnessing a new era of immune-mediated cancer therapies and vaccine development. As the field of cancer vaccines advances into clinical trials, overcoming low immunogenicity is a limiting step in achieving full success of this therapeutic approach. Recent discoveries in the many biological roles of chemokines in tumor immunology allow their exploitation in enhancing recruitment of antigen presenting cells (APCs) and effector cells to appropriate anatomical sites. This knowledge, combined with advances in gene therapy and virology, allows researchers to employ chemokines as potential vaccine adjuvants. This review will focus on recent murine and human studies that use chemokines as therapeutic anti-cancer vaccine adjuvants.
References
[1]
Dell’Agnola, C.; Biragyn, A. Clinical utilization of chemokines to combat cancer: The double-edged sword. Expert Rev. Vaccines 2007, 6, 267–283, doi:10.1586/14760584.6.2.267.
[2]
Luther, S.A.; Cyster, J.G. Chemokines as regulators of T cell differentiation. Nat. Immunol. 2001, 2, 102–107, doi:10.1038/84205.
[3]
Castellino, F.; Huang, A.Y.; Altan-Bonnet, G.; Stoll, S.; Scheinecker, C.; Germain, R.N. Chemokines enhance immunity by guiding naive CD8+ T cells to sites of CD4+ T cell-dendritic cell interaction. Nature 2006, 440, 890–895, doi:10.1038/nature04651.
[4]
Lechner, M.G.; Russell, S.M.; Bass, R.S.; Epstein, A.L. Chemokines, costimulatory molecules and fusion proteins for the immunotherapy of solid tumors. Immunotherapy 2011, 3, 1317–1340, doi:10.2217/imt.11.115.
[5]
Franciszkiewicz, K.; Boissonnas, A.; Boutet, M.; Combadière, C.; Mami-Chouaib, F. Role of chemokines and chemokine receptors in shaping the effector phase of the antitumor immune response. Cancer Res. 2012, 72, 6325–6332, doi:10.1158/0008-5472.CAN-12-2027.
[6]
Zlotnik, A.; Yoshie, O. The chemokine superfamily revisited. Immunity 2012, 36, 705–716, doi:10.1016/j.immuni.2012.05.008.
[7]
Belperio, J.A.; Keane, M.P.; Arenberg, D.A.; Addison, C.L.; Ehlert, J.E.; Burdick, M.D.; Strieter, M. CXC chemokines in angiogenesis. J. Leukoc Biol. 2000, 68, 1–8.
[8]
Coscia, M.; Biragyn, A. Cancer immunotherapy with chemoattractant peptides. Semin. Cancer Biol. 2004, 14, 209–218, doi:10.1016/j.semcancer.2003.10.008.
[9]
McColl, S.R. Chemokines and dendritic cells: A crucial alliance. Immunol. Cell Biol. 2002, 80, 489–496, doi:10.1046/j.1440-1711.2002.01113.x.
[10]
Dieu, M.C.; Vanbervliet, B.; Vicari, A.; Bridon, J.M.; Oldham, E.; A？t-Yahia, S.; Brière, F.; Zlotnik, A.; Lebecque, S.; Caux, C. Selective recruitment of immature and mature dendritic cells by distinct chemokines expressed in different anatomic sites. J. Exp. Med. 1998, 188, 373–386, doi:10.1084/jem.188.2.373.
[11]
Sallusto, F.; Palermo, B.; Lenig, D.; Miettinen, M.; Matikainen, S.; Julkunen, I.; Forster, R.; Burgstahler, R.; Lipp, M.; Lanzavecchia, A. Distinct patterns and kinetics of chemokine production regulate dendritic cell function. Eur. J. Immunol. 1999, 29, 1617–1625, doi:10.1002/(SICI)1521-4141(199905)29:05<1617::AID-IMMU1617>3.0.CO;2-3.
[12]
Smith, C.M.; Wilson, N.S.; Waithman, J.; Villadangos, J.A.; Carbone, F.R.; Heath, W.R.; Belz, G.T. Cognate CD4+ T cell licensing of dendritic cells in CD8+ T cell immunity. Nat. Immunol. 2004, 5, 1143–1148, doi:10.1038/ni1129.
[13]
Mandl, J.N.; Liou, R.; Klauschen, F.; Vrisekoop, N.; Monteiro, J.P.; Yates, A.J.; Huang, A.Y.; Germain, R.N. Quantification of lymph node transit times reveals differences in antigen surveillance strategies of naive CD4+ and CD8+ T cells. Proc. Natl. Acad. Sci. USA 2012, 109, 18036–18041, doi:10.1073/pnas.1211717109.
[14]
Hugues, S.; Scholer, A.; Boissonnas, A.; Nussbaum, A.; Combadière, C.; Amigorena, S.; Fetler, L. Dynamic imaging of chemokine-dependent CD8+ T cell help for CD8+ T cell responses. Nat. Immunol. 2007, 8, 921–930.
[15]
Kaiser, A.; Donnadieu, E.; Abastado, J.P.; Trautmann, A.; Nardin, A. CC chemokine ligand 19 secreted by mature dendritic cells increases naive T cell scanning behavior and their response to rare cognate antigen. J. Immunol. 2005, 175, 2349–2356.
[16]
Molon, B.; Gri, G.; Bettella, M.; Gómez-Moutón, C.; Lanzavecchia, A.; Martínez-A, C.; Ma？es, S.; Viola, A. T cell costimulation by chemokine receptors. Nat. Immunol. 2005, 6, 465–471.
[17]
Moser, B.; Loetscher, P. Lymphocyte traffic control by chemokines. Nat. Immunol. 2001, 2, 123–128, doi:10.1038/84219.
[18]
Fujita, Y.; Taguchi, H. Overview and outlook of Toll-like receptor ligand-antigen conjugate vaccines. Ther. Deliv. 2012, 3, 749–760.
Duthie, M.S.; Windish, H.P.; Fox, C.B.; Reed, S.G. Use of defined TLR ligands as adjuvants within human vaccines. Immunol. Rev. 2011, 239, 178–196, doi:10.1111/j.1600-065X.2010.00978.x.
[21]
Ribas, A.; Butterfield, L.H.; Glaspy, J.A.; Economou, J.S. Current developments in cancer vaccines and cellular immunotherapy. J. Clin. Oncol. 2003, 21, 2415–2432, doi:10.1200/JCO.2003.06.041.
[22]
Rosenberg, S.A. A new era for cancer immunotherapy based on the genes that encode cancer antigens. Immunity 1999, 10, 281–287, doi:10.1016/S1074-7613(00)80028-X.
[23]
Schlom, J. Therapeutic cancer vaccines: Current status and moving forward. J. Natl. Cancer Inst. 2012, 104, 599–613, doi:10.1093/jnci/djs033.
[24]
He, S.; Wang, L.; Wu, Y.; Li, D.; Zhang, Y. CCL3 and CCL20-recruited dendritic cells modified by melanoma antigen gene-1 induce anti-tumor immunity against gastric cancer ex vivo and in vivo. J. Exp. Clin. Cancer Res. 2010, doi:10.1186/1756-9966-29-37.
Cao, Q.; Jin, Y.; Jin, M.; He, S.; Gu, Q.; Qiu, Y.; Ge, H.; Yoneyama, H.; Zhang, Y. Therapeutic effect of MIP-1alpha-recruited dendritic cells on preestablished solid and metastatic tumors. Cancer Lett. 2010, 295, 17–26, doi:10.1016/j.canlet.2010.02.009.
[27]
Jiang, X.B.; Lu, X.L.; Hu, P.; Liu, R.E. Improved therapeutic efficacy using vaccination with glioma lysate-pulsed dendritic cells combined with IP-10 in murine glioma. Vaccine 2009, 27, 6210–6216, doi:10.1016/j.vaccine.2009.08.002.
[28]
Kang, T.H.; Bae, H.C.; Kim, S.H.; Seo, S.H.; Son, S.W.; Choi, E.Y.; Seong, S.Y.; Kim, T.W. Modification of dendritic cells with interferon-gamma-inducible protein-10 gene to enhance vaccine potency. J. Gene Med. 2009, 11, 889–898, doi:10.1002/jgm.1371.
[29]
Lu, J.; Zhang, Q.; Liang, C.M.; Xia, S.J.; Zhong, C.P.; Wang, D.W. Antitumor immunity by a dendritic cell vaccine encoding secondary lymphoid chemokine and tumor lysate on murine prostate cancer. Asian J. Androl. 2008, 10, 883–889, doi:10.1111/j.1745-7262.2008.00431.x.
[30]
Shih, N.Y.; Yang, H.Y.; Cheng, H.T.; Hung, Y.M.; Yao, Y.C.; Zhu, Y.H.; Wu, Y.C.; Liu, K.J. Conditioning vaccination site with irradiated MIP-3alpha-transfected tumor cells enhances efficacy of dendritic cell-based cancer vaccine. J. Immunother. 2009, 32, 363–369, doi:10.1097/CJI.0b013e31819d29d8.
[31]
Liang, C.M.; Ye, S.L.; Zhong, C.P.; Zheng, N.; Bian, W.; Sun, R.X.; Chen, J.; Li, R.L.; Zhou, S.; Liu, Y.K. More than chemotaxis: A new anti-tumor DC vaccine modified by rAAV2-SLC. Mol. Immunol. 2007, 44, 3797–804, doi:10.1016/j.molimm.2007.03.026.
[32]
Li, B.; Li, Q.; Zhao, Q.L.; Wei, X.B.; Zhang, X.H.; Wu, C.Q.; Zhong, C.P. Murine dendritic cells modified with CXCL10 gene and tumour cell lysate mediate potent antitumour immune responses in mice. Scand. J. Immunol. 2007, 65, 8–13, doi:10.1111/j.1365-3083.2006.01861.x.
Yang, S.C.; Hillinger, S.; Riedl, K.; Zhang, L.; Zhu, L.; Huang, M.; Atianzar, K.; Kuo, B.Y.; Gardner, B.; Batra, R.K.; et al. Intratumoral administration of dendritic cells overexpressing CCL21 generates systemic antitumor responses and confers tumor immunity. Clin. Cancer Res. 2004, 10, 2891–2901, doi:10.1158/1078-0432.CCR-03-0380.
[35]
Westermann, J.; Nguyen-Hoai, T.; Baldenhofer, G.; H？pken, U.E.; Lipp, M.; D？rken, B.; Pezzutto, A. CCL19 (ELC) as an adjuvant for DNA vaccination: Induction of a TH1-type T-cell response and enhancement of antitumor immunity. Cancer Gene Ther. 2007, 14, 523–532.
[36]
Nguyen-Hoai, T.; Baldenhofer, G.; Ahmed, M.S.; Pham-Duc, M.; Gries, M.; Lipp, M.; D？rken, B.; Pezzutto, A.; Westermann, J. CCL19 (ELC) improves TH1-polarized immune responses and protective immunity in a murine Her2/neu DNA vaccination model. J. Gene Med. 2012, 14, 128–137, doi:10.1002/jgm.1651.
[37]
Yamano, T.; Kaneda, Y.; Hiramatsu, S.H.; Huang, S.; Tran, A.N.; Giuliano, A.E.; Hoon, D.S. Immunity against breast cancer by TERT DNA vaccine primed with chemokine CCL21. Cancer Gene Ther. 2007, 14, 451–459.
[38]
Dorgham, K.; Abadie, V.; Iga, M.; Hartley, O.; Gorochov, G.; Combadière, B. Engineered CCR5 superagonist chemokine as adjuvant in anti-tumor DNA vaccination. Vaccine 2008, 26, 3252–3260, doi:10.1016/j.vaccine.2008.04.003.
[39]
Nguyen-Hoai, T.; Baldenhofer, G.; Sayed Ahmed, M.S.; Pham-Duc, M.; Vu, M.D.; Lipp, M.; D？rken, B.; Pezzutto, A.; Westermann, J. CCL21 (SLC) improves tumor protection by a DNA vaccine in a Her2/neu mouse tumor model. Cancer Gene Ther. 2012, 19, 69–76, doi:10.1038/cgt.2011.69.
[40]
Iga, M.; Boissonnas, A.; Mahé, B.; Bonduelle, O.; Combadière, C.; Combadière, B. Single CX3CL1-Ig DNA administration enhances T cell priming in vivo. Vaccine 2007, 25, 4554–4563, doi:10.1016/j.vaccine.2007.04.028.
[41]
Sun, W.; Qian, H.; Zhang, X.; Zhou, C.; Liang, X.; Wang, D.; Fu, M.; Zhang, S.; Lin, C. Induction of protective and therapeutic antitumour immunity using a novel tumour-associated antigen-specific DNA vaccine. Immunol. Cell Biol. 2006, 84, 440–447, doi:10.1111/j.1440-1711.2006.01453.x.
[42]
Liu, R.; Zhou, C.; Wang, D.; Ma, W.; Lin, C.; Wang, Y.; Zhang, Y.; Zhang, S. Enhancement of DNA vaccine potency by sandwiching antigen-coding gene between secondary lymphoid tissue chemokine (SLC) and IgG Fc fragment genes. Cancer Biol. Ther. 2006, 5, 427–434, doi:10.4161/cbt.5.4.2528.
[43]
Qin, H.; Zhou, C.; Wang, D.; Ma, W.; Liang, X.; Lin, C.; Zhang, Y.; Zhang, S. Enhancement of antitumour immunity by a novel chemotactic antigen DNA vaccine encoding chemokines and multiepitopes of prostate-tumour-associated antigens. Immunology 2006, 117, 419–430, doi:10.1111/j.1365-2567.2006.02322.x.
[44]
Yamano, T.; Kaneda, Y.; Huang, S.; Hiramatsu, S.H.; Hoon, D.S. Enhancement of immunity by a DNA melanoma vaccine against TRP2 with CCL21 as an adjuvant. Mol. Ther. 2006, 13, 194–202, doi:10.1016/j.ymthe.2005.05.018.
[45]
Aravindaram, K.; Yu, H.H.; Lan, C.W.; Wang, P.H.; Chen, Y.H.; Chen, H.M.; Yagita, H.; Yang, N.S. Transgenic expression of human gp100 and RANTES at specific time points for suppression of melanoma. Gene Ther. 2009, 16, 1329–1339, doi:10.1038/gt.2009.90.
[46]
Elzaouk, L.; Pavlovic, J.; Moelling, K. Analysis of antitumor activity elicited by vaccination with combinations of interleukin-12 DNA with gp100 DNA or the chemokine CCL21 in vivo. Hum. Gene Ther. 2006, 17, 859–870, doi:10.1089/hum.2006.17.859.
[47]
Novak, L.; Igoucheva, O.; Cho, S.; Alexeev, V. Characterization of the CCL21-mediated melanoma-specific immune responses and in situ melanoma eradication. Mol. Cancer Ther. 2007, 6, 1755–1764, doi:10.1158/1535-7163.MCT-06-0709.
[48]
Zibert, A.; Balzer, S.; Souquet, M.; Quang, T.H.; Paris-Scholz, C.; Roskrow, M.; Dilloo, D. CCL3/MIP-1alpha is a potent immunostimulator when coexpressed with interleukin-2 or granulocyte-macrophage colony-stimulating factor in a leukemia/lymphoma vaccine. Hum. Gene Ther. 2004, 15, 21–34, doi:10.1089/10430340460732436.
[49]
Li, N.; Qin, H.; Li, X.; Zhou, C.; Wang, D.; Ma, W.; Lin, C.; Zhang, Y.; Wang, S.; Zhang, S. Potent systemic antitumor immunity induced by vaccination with chemotactic-prostate tumor associated antigen gene-modified tumor cell and blockade of B7-H1. J. Clin. Immunol. 2007, 27, 117–130, doi:10.1007/s10875-006-9053-z.
[50]
Inoue, H.; Iga, M.; Xin, M.; Asahi, S.; Nakamura, T.; Kurita, R.; Nakayama, M.; Nakazaki, Y.; Takayama, K.; Nakanishi, Y.; et al. TARC and RANTES enhance antitumor immunity induced by the GM-CSF-transduced tumor vaccine in a mouse tumor model. Cancer Immunol. Immunother. 2008, 57, 1399–1411, doi:10.1007/s00262-008-0476-7.
[51]
Herrlinger, U.; Aulwurm, S.; Strik, H.; Weit, S.; Naumann, U.; Weller, M. MIP-1alpha antagonizes the effect of a GM-CSF-enhanced subcutaneous vaccine in a mouse glioma model. J. Neurooncol. 2004, 66, 147–154, doi:10.1023/B:NEON.0000013497.04322.fc.
[52]
Nomura, T.; Hasegawa, H.; Kohno, M.; Sasaki, M.; Fujita, S. Enhancement of anti-tumor immunity by tumor cells transfected with the secondary lymphoid tissue chemokine EBI-1-ligand chemokine and stromal cell-derived factor-1alpha chemokine genes. Int. J. Cancer 2001, 91, 597–606, doi:10.1002/1097-0215(200002)9999:9999<::AID-IJC1107>3.0.CO;2-J.
[53]
Biragyn, A.; Schiavo, R.; Olkhanud, P.; Sumitomo, K.; King, A.; McCain, M.; Indig, F.E.; Almanzar, G.; Baatar, D. Tumor-associated embryonic antigen-expressing vaccines that target CCR6 elicit potent CD8+ T cell-mediated protective and therapeutic antitumor immunity. J. Immunol. 2007, 179, 1381–1388.
Weber, J. Adenovirus CCL-21 Transduced MART-1/gp100/Tyrosinase/NY-ESO-1 Peptide-Pulsed Dendritic Cells Matured.
[56]
Lee, J. Vaccine Therapy in Treating Patients With Stage IIIB, Stage IV, or Recurrent Non-Small Cell Lung Cancer.
[57]
Dubinett, S. A Vaccine Trial for Patients With Stage IIIB, IV, or Recurrent Non-Small Cell Lung Cancer (VTNSCLC).
[58]
Gray, J. Combination Immunotherapy of GM.CD40L Vaccine With CCL21 in Lung Cancer.
[59]
Brenner, M. Using Gene Modified Neuroblastoma Cells for the Treatment of Relapsed/Refractory Neuroblastoma (CYCHE).
[60]
Louis, C. A Phase I/II Study Of Immunization With Lymphotactin And Interleukin 2 Gene Modified Neuroblastoma Tumor Cells (CHESAT).
[61]
Brenner, M. Allogeneic Neuroblastoma Cells for Relapsed/ Refractory Neuroblastoma, CYCHEALL.
[62]
Thomas, S. Immunotherapy for Asymptomatic Phase Lymphoplasmacytic Lymphoma. Available online: http://clinicaltrials.gov/ct2/show/NCT012098712013 (accessed on 20 July 2013).
[63]
Banchereau, J.; Steinman, R.M. Dendritic cells and the control of immunity. Nature 1998, 392, 245–252, doi:10.1038/32588.
[64]
Frankenberger, B.; Schendel, D.J. Third generation dendritic cell vaccines for tumor immunotherapy. Eur. J. Cell Biol. 2012, 91, 53–58, doi:10.1016/j.ejcb.2011.01.012.
[65]
Nishimura, F.; Dusak, J.E.; Eguchi, J.; Zhu, X.; Gambotto, A.; Storkus, W.J.; Okada, H. Adoptive transfer of type 1 CTL mediates effective anti-central nervous system tumor response: Critical roles of IFN-inducible protein-10. Cancer Res. 2006, 66, 4478–4487, doi:10.1158/0008-5472.CAN-05-3825.
[66]
Serra, H.M.; Baena-Cagnani, C.E.; Eberhard, Y. Is secondary lymphoid-organ chemokine (SLC/CCL21) much more than a constitutive chemokine? Allergy 2004, 59, 1219–1223, doi:10.1111/j.1398-9995.2004.00531.x.
[67]
Fushimi, T.; Kojima, A.; Moore, M.A.; Crystal, R.G. Macrophage inflammatory protein 3alpha transgene attracts dendritic cells to established murine tumors and suppresses tumor growth. J. Clin. Invest. 2000, 105, 1383–1393, doi:10.1172/JCI7548.
Wong, M.M.; Fish, E.N. Chemokines: Attractive mediators of the immune response. Semin. Immunol. 2003, 15, 5–14, doi:10.1016/S1044-5323(02)00123-9.
[70]
Marsland, B.J.; B？ttig, P.; Bauer, M.; Ruedl, C.; L？ssing, U.; Beerli, R.R.; Dietmeier, K.; Ivanova, L.; Pfister, T.; Vogt, L.; et al. CCL19 and CCL21 induce a potent proinflammatory differentiation program in licensed dendritic cells. Immunity 2005, 22, 493–505, doi:10.1016/j.immuni.2005.02.010.
[71]
Kumamoto, T.; Huang, E.K.; Paek, H.J.; Morita, A.; Matsue, H.; Valentini, R.F.; Takashima, A. Induction of tumor-specific protective immunity by in situ Langerhans cell vaccine. Nat. Biotechnol. 2002, 20, 64–69, doi:10.1038/nbt0102-64.
[72]
Terando, A.; Roessler, B.; Mulé, J.J. Chemokine gene modification of human dendritic cell-based tumor vaccines using a recombinant adenoviral vector. Cancer Gene Ther. 2004, 11, 165–173, doi:10.1038/sj.cgt.7700671.
[73]
Senovilla, L.; Vacchelli, E.; Garcia, P.; Eggermont, A.; Fridman, W.H.; Galon, J.; Zitvogel, L.; Kroemer, G.; Galluzzi, L. Trial watch: DNA vaccines for cancer therapy. Oncoimmunology 2013, 2, e23803, doi:10.4161/onci.23803.
[74]
Pavlenko, M.; Leder, C.; Pisa, P. Plasmid DNA vaccines against cancer: Cytotoxic T-lymphocyte induction against tumor antigens. Expert Rev. Vaccines 2005, 4, 315–327, doi:10.1586/14760584.4.3.315.
[75]
Fioretti, D.; Iurescia, S.; Fazio, V.M.; Rinaldi, M. DNA vaccines: Developing new strategies against cancer. J. Biomed. Biotechnol. 2010, doi:10.1155/2010/174378.
[76]
Mohit, E.; Rafati, S. Chemokine-based immunotherapy: Delivery systems and combination therapies. Immunotherapy 2012, 4, 807–840, doi:10.2217/imt.12.72.
[77]
Biragyn, A.; Surenhu, M.; Yang, D.; Ruffini, P.A.; Haines, B.A.; Klyushnenkova, E.; Oppenheim, J.J.; Kwak, L.W. Mediators of innate immunity that target immature, but not mature, dendritic cells induce antitumor immunity when genetically fused with nonimmunogenic tumor antigens. J. Immunol. 2001, 167, 6644–6653.
[78]
Ruffini, P.A.; Biragyn, A.; Coscia, M.; Harvey, L.K.; Cha, S.C.; Bogen, B.; Kwak, L.W. Genetic fusions with viral chemokines target delivery of nonimmunogenic antigen to trigger antitumor immunity independent of chemotaxis. J. Leukoc. Biol. 2004, 76, 77–85, doi:10.1189/jlb.1003481.
[79]
Zaliauskiene, L.; Kang, S.; Sparks, K.; Zinn, K.R.; Schwiebert, L.M.; Weaver, C.T.; Collawn, J.F. Enhancement of MHC class II-restricted responses by receptor-mediated uptake of peptide antigens. J. Immunol. 2002, 169, 2337–2345.
[80]
Mahnke, K.; Guo, M.; Lee, S.; Sepulveda, H.; Swain, S.L.; Nussenzweig, M.; Steinman, R.M. The dendritic cell receptor for endocytosis, DEC-205, can recycle and enhance antigen presentation via major histocompatibility complex class II-positive lysosomal compartments. J. Cell Biol. 2000, 151, 673–684, doi:10.1083/jcb.151.3.673.
[81]
Schiavo, R.; Baatar, D.; Olkhanud, P.; Indig, F.E.; Restifo, N.; Taub, D.; Biragyn, A. Chemokine receptor targeting efficiently directs antigens to MHC class I pathways and elicits antigen-specific CD8+ T-cell responses. Blood 2006, 107, 4597–4605, doi:10.1182/blood-2005-08-3207.
[82]
Kryczek, I.; Wei, S.; Keller, E.; Liu, R.; Zou, W. Stroma-derived factor (SDF-1/CXCL12) and human tumor pathogenesis. Am. J. Physiol. Cell Physiol. 2007, 292, C987–C995, doi:10.1152/ajpcell.00406.2006.
[83]
Grupp, S.A.; Kalos, M.; Barrett, D.; Aplenc, R.; Porter, D.L.; Rheingold, S.R.; Teachey, D.T.; Chew, A.; Hauack, B.; Wright, J.F.; et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N. Engl. J. Med. 2013, 368, 1509–1518, doi:10.1056/NEJMoa1215134.
[84]
Scholler, J.; Brady, T.L.; Binder-Scholl, G.; Hwang, W.T.; Plesa, G.; Hege, K.M.; Vogel, A.N.; kalos, M.; Riley, J.L.; Riley, J.L.; et al. Decade-long safety and function of retroviral-modified chimeric antigen receptor T cells. Sci. Transl. Med. 2012, doi:10.1126/scitranslmed.3003761.
[85]
Porter, D.L.; Levine, B.L.; Kalos, M.; Bagg, A.; June, C.H. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N. Engl. J. Med. 2011, 365, 725–733, doi:10.1056/NEJMoa1103849.
[86]
Brahmer, J.R.; Tykodi, S.S.; Chow, L.Q.; Hwu, W.J.; Topalian, S.L.; Hwu, P.; Drake, C.G.; Camacho, L.H.; Kauh, J.; Odunsi, K.; et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N. Engl. J. Med. 2012, 366, 2455–2465, doi:10.1056/NEJMoa1200694.
[87]
Topalian, S.L.; Hodi, F.S.; Brahmer, J.R.; Gettinger, S.N.; Smith, D.C.; McDermott, D.F.; Powderly, J.D.; Carvajal, R.D.; Sosman, J.A.; Atkins, M.B.; et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 2012, 366, 2443–2454, doi:10.1056/NEJMoa1200690.
[88]
Lipson, E.J.; Sharfman, W.H.; Drake, C.G.; Wollner, I.; Taube, J.M.; Anders, R.A.; Xu, H.; Yao, S.; Pons, A.; Chen, L.; et al. Durable cancer regression off-treatment and effective reinduction therapy with an anti-PD-1 antibody. Clin. Cancer Res. 2013, 19, 462–468, doi:10.1158/1078-0432.CCR-12-2625.
