A phase 1 trial extension to assess immunologic efficacy and safety of prime-boost vaccination with VXM01, an oral T cell vaccine against VEGFR2, in patients with advanced pancreatic cancer

References

• Hodi FSS, O'Day SJJ, McDermott DFF, Weber RWW, Sosman JAA, Haanen JBB, Gonzalez R, Robert C, Schadendorf D, Hassel JCC et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010; 363:711-23; PMID:20525992; https://doi.org/10.1056/NEJMoa1003466
   PubMed Web of Science ®Google Scholar
• Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB et al. Safety, activity, and immune correlates of anti-pd-1 antibody in cancer. N Engl J Med 2012; 366:2443-54; PMID:22658127; https://doi.org/10.1056/NEJMoa1200690
   PubMed Web of Science ®Google Scholar
• Morrissey K, Yuraszeck T, Li CC, Zhang Y, Kasichayanula S. Immunotherapy and novel combinations in oncology: current landscape, challenges, and opportunities. Clin Transl Sci 2016; 9:89-104; PMID:26924066; https://doi.org/10.1111/cts.12391
   PubMed Web of Science ®Google Scholar
• Palucka AK, Coussens LM. The basis of oncoimmunology. Cell 2016; 164:1233-47; PMID:26967289; https://doi.org/10.1016/j.cell.2016.01.049
   PubMed Web of Science ®Google Scholar
• Rosenberg SA, Restifo NP. Adoptive cell transfer as personalized immunotherapy for human cancer. Science 2015; 348:62-8; PMID:25838374; https://doi.org/10.1126/science.aaa4967
   PubMed Web of Science ®Google Scholar
• Khalil DN, Smith EL, Brentjens RJ, Wolchok JD. The future of cancer treatment: immunomodulation, CARs and combination immunotherapy. Nat Rev Clin Oncol 2016; 13:273-90; PMID:26977780; https://doi.org/10.1038/nrclinonc.2016.25
   PubMed Web of Science ®Google Scholar
• Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA: Cancer J Clin 2016; 66:7-30; PMID:26742998; https://doi.org/10.3322/caac.21332
   PubMed Web of Science ®Google Scholar
• Garrido-Laguna I, Hidalgo M. Pancreatic cancer: from state-of-the-art treatments to promising novel therapies. Nat Rev Clin Oncol 2015; 12:319-34; PMID:25824606; https://doi.org/10.1038/nrclinonc.2015.53
   PubMed Web of Science ®Google Scholar
• Rishi A, Goggins M, Wood LD, Hruban RH. Pathological and molecular evaluation of pancreatic neoplasms. Semin Oncol 2015; 42:28-39; PMID:25726050; https://doi.org/10.1053/j.seminoncol.2014.12.004
   PubMed Web of Science ®Google Scholar
• Waddell N, Pajic M, Patch A, Chang DK, Kassahn KS, Bailey P, Johns AL, Miller D, Nones K, Quek K et al. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature 2015; 518:495-501; PMID:25719666; https://doi.org/10.1038/nature14169
   PubMed Web of Science ®Google Scholar
• Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM. Projecting cancer incidence and deaths to 2030: The unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res 2014; 74:2913-21; PMID:24840647; https://doi.org/10.1158/0008-5472.CAN-14-0155
   PubMed Web of Science ®Google Scholar
• Wang-Gillam A, Li CP, Bodoky G, Dean A, Shan YS, Jameson G, MacArulla T, Lee KH, Cunningham D, Blanc JF et al. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): A global, randomised, open-label, phase 3 trial. Lancet 2016; 387:545-57; PMID:26615328; https://doi.org/10.1016/S0140-6736(15)00986-1
   PubMed Web of Science ®Google Scholar
• Foley K, Kim V, Jaffee E, Zheng L. Current progress in immunotherapy for pancreatic cancer. Cancer Lett. 2016 Oct 10; 348(1):244-51; https://doi.org/10.1016/j.canlet.2015.12.020
   Google Scholar
• Royal RE, Levy C, Turner K, Mathur A, Hughes M, Kammula US, Sherry RM, Topalian SL, Yang JC, Lowy I et al. Phase 2 trial of single agent ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma. J Immunother 2010; 33:828-33; PMID:20842054; https://doi.org/10.1097/CJI.0b013e3181eec14c
   PubMed Web of Science ®Google Scholar
• Soares KC, Rucki AA, Wu AA, Olino K, Xiao Q, Chai Y, Wamwea A, Bigelow E, Lutz E, Liu L et al. PD-1/PD-L1 blockade together with vaccine therapy facilitates effector T-cell infiltration into pancreatic tumors. J Immunother 2015; 38:1-11; PMID:25415283; https://doi.org/10.1097/CJI.0000000000000062
   PubMed Web of Science ®Google Scholar
• Le DT, Wang-Gillam A, Picozzi V, Greten TF, Crocenzi T, Springett G, Morse M, Zeh H, Cohen D, Fine RL et al. Safety and survival with GVAX pancreas prime and Listeria monocytogenes-expressing mesothelin (CRS-207) boost vaccines for metastatic pancreatic cancer. J Clin Oncol 2015; 33:1325-33; PMID:25584002; https://doi.org/10.1200/JCO.2014.57.4244
   PubMed Web of Science ®Google Scholar
• Salman B, Zhou D, Jaffee EM, Edil BH, Zheng L. Vaccine therapy for pancreatic cancer. Oncoimmunology 2013; 2:e26662; PMID:24498551; https://doi.org/10.4161/onci.26662
   PubMed Web of Science ®Google Scholar
• Yamamoto K, Ueno T, Kawaoka T, Hazama S, Fukui M, Suehiro Y, Hamanaka Y, Ikematsu Y, Imai K, Oka M et al. MUC1 peptide vaccination in patients with advanced pancreas or biliary tract cancer. Anticancer Res 2005; 25:3575-9; PMID:16101182
   PubMed Web of Science ®Google Scholar
• Bernhardt SL, Gjertsen MK, Trachsel S, Moller M, Eriksen J A, Meo M, Buanes T, Gaudernack G. Telomerase peptide vaccination of patients with non-resectable pancreatic cancer: A dose escalating phase I/II study. Br J Cancer 2006; 95:1474-82; PMID:17060934; https://doi.org/10.1038/sj.bjc.6603437
   PubMed Web of Science ®Google Scholar
• Abate-Daga D, Rosenberg S a, Morgan R a. Pancreatic cancer. Oncoimmunology 2014; 3:e29194; PMID:25083334; https://doi.org/10.4161/onci.29194
   PubMed Web of Science ®Google Scholar
• Kunk PR, Bauer TW, Slingluff CL, Rahma OE. From bench to bedside a comprehensive review of pancreatic cancer immunotherapy. J Immunother cancer 2016; 4:14; PMID:26981244; https://doi.org/10.1186/s40425-016-0119-z
   PubMed Web of Science ®Google Scholar
• Wachsmann M, Pop L, Vitetta E. Pancreatic ductal adenocarcinoma: A review of immunologic aspects. J Investig Med. 2012; 60:643-63; PMID:22406516; https://doi.org/10.2310/JIM.0b013e31824a4d79
   PubMed Web of Science ®Google Scholar
• Kleeff J, Beckhove P, Esposito I, Herzig S, Huber PE, Löhr JM, Friess H. Pancreatic cancer microenvironment. Int J Cancer 2007; 121:699-705; PMID:17534898; https://doi.org/10.1002/ijc.22871
   PubMed Web of Science ®Google Scholar
• Klug F, Prakash H, Huber PE, Seibel T, Bender N, Halama N, Pfirschke C, Voss R, Timke C, Umansky L et al. Low-dose irradiation programs macrophage differentiation to an iNOS+/M1 phenotype that orchestrates effective T cell immunotherapy. Cancer Cell 2013; 24:589-602; PMID:24209604; https://doi.org/10.1016/j.ccr.2013.09.014
   PubMed Web of Science ®Google Scholar
• Xiang R, Luo Y, Niethammer AG, Reisfeld RA. Oral DNA vaccines target the tumor vasculature and microenvironment and suppress tumor growth and metastasis. Immunol Rev 2008; 222:117-28; PMID:18363997; https://doi.org/10.1111/j.1600-065X.2008.00613.x
   PubMed Web of Science ®Google Scholar
• Niethammer AG, Xiang R, Becker JC, Wodrich H, Pertl U, Karsten G, Eliceiri BP, Reisfeld RA. A DNA vaccine against VEGF receptor 2 prevents effective angiogenesis and inhibits tumor growth. Nat Med 2002; 8:1369-75; PMID:12415261; https://doi.org/10.1038/nm1202-794
   PubMed Web of Science ®Google Scholar
• Reisfeld RA, Niethammer AG, Luo Y, Xiang R. DNA vaccines designed to inhibit tumor growth by suppression of angiogenesis. Int Arch Allergy Immunol 2004; 133:295-304; PMID:14988601; https://doi.org/10.1159/000077009
   PubMedGoogle Scholar
• Fraser A, Paul M, Goldberg E, Acosta CJ, Leibovici L. Typhoid fever vaccines: Systematic review and meta-analysis of randomised controlled trials. Vaccine 2007; 25:7848-57; PMID:17928109; https://doi.org/10.1016/j.vaccine.2007.08.027
   PubMed Web of Science ®Google Scholar
• Niethammer AG, Lubenau H, Mikus G, Knebel P, Hohmann N, Leowardi C, Beckhove P, Akhisaroglu M, Ge Y, Springer M et al. Double-blind, placebo-controlled first in human study to investigate an oral vaccine aimed to elicit an immune reaction against the VEGF-Receptor 2 in patients with stage IV and locally advanced pancreatic cancer. BMC Cancer 2012; 12:361; PMID:22906006; https://doi.org/10.1186/1471-2407-12-361
   PubMed Web of Science ®Google Scholar
• Shibuya M. Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) signaling in angiogenesis: A crucial target for anti- and pro-angiogenic therapies. Genes Cancer 2011; 2:1097-105; PMID:22866201; https://doi.org/10.1177/1947601911423031
   PubMedGoogle Scholar
• Shibuya M. Vascular endothelial growth factor and its receptor system: Physiological functions in angiogenesis and pathological roles in various diseases. J. Biochem 2013; 153:13-9; PMID:23172303; https://doi.org/10.1093/jb/mvs136
   PubMed Web of Science ®Google Scholar
• Bruce D, Tan PH. Vascular endothelial growth factor receptors and the therapeutic targeting of angiogenesis in cancer: Where do we go from here? Cell Commun Adhes 2011; 18:85-103; PMID:22017472; https://doi.org/10.3109/15419061.2011.619673
   PubMed Web of Science ®Google Scholar
• Suzuki H, Onishi H, Wada J, Yamasaki A, Tanaka H, Nakano K, Morisaki T, Katano M. VEGFR2 is selectively expressed by FOXP3high CD4+ Treg. Eur J Immunol 2010; 40:197-203; PMID:19902430; https://doi.org/10.1002/eji.200939887
   PubMed Web of Science ®Google Scholar
• Voron T, Colussi O, Marcheteau E, Pernot S, Nizard M, Pointet A-L, Latreche S, Bergaya S, Benhamouda N, Tanchot C et al. VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors. J Exp Med 2015; 212:139-48; PMID:25601652; https://doi.org/10.1084/jem.20140559
   PubMed Web of Science ®Google Scholar
• Sennino B, McDonald DM. Controlling escape from angiogenesis inhibitors. Nat Rev Cancer 2012; 12:699-709; PMID:23001349; https://doi.org/10.1038/nrc3366
   PubMed Web of Science ®Google Scholar
• Spratlin JL, Cohen RB, Eadens M, Gore L, Camidge DR, Diab S, Leong S, O'Bryant C, Chow LQM, Serkova NJ et al. Phase I pharmacologic and biologic study of ramucirumab (imc-1121b), a fully human immunoglobulin G1 monoclonal antibody targeting the vascular endothelial growth factor receptor-2. J Clin Oncol 2010; 28:780-7; PMID:20048182; https://doi.org/10.1200/JCO.2009.23.7537
   PubMed Web of Science ®Google Scholar
• Spratlin J. Ramucirumab (IMC-1121B): Monoclonal antibody inhibition of vascular endothelial growth factor receptor-2. Curr. Oncol. Rep. 2011; 13:97-102; PMID:21222245; https://doi.org/10.1007/s11912-010-0149-5
   PubMed Web of Science ®Google Scholar
• Okamoto I, Arao T, Miyazaki M, Satoh T, Okamoto K, Tsunoda T, Nishio K, Nakagawa K. Clinical phase I study of elpamotide, a peptide vaccine for vascular endothelial growth factor receptor 2, in patients with advanced solid tumors. Cancer Sci 2012; 103:2135-8; PMID:22957712; https://doi.org/10.1111/cas.12014
   PubMed Web of Science ®Google Scholar
• Miyazawa M, Ohsawa R, Tsunoda T, Hirono S, Kawai M, Tani M, Nakamura Y, Yamaue H. Phase I clinical trial using peptide vaccine for human vascular endothelial growth factor receptor 2 in combination with gemcitabine for patients with advanced pancreatic cancer. Cancer Sci 2010; 101:433-9; PMID:19930156; https://doi.org/10.1111/j.1349-7006.2009.01416.x
   PubMed Web of Science ®Google Scholar
• Yamaue H, Tsunoda T, Tani M, Miyazawa M, Yamao K, Mizuno N, Okusaka T, Ueno H, Boku N, Fukutomi A et al. Randomized phase II/III clinical trial of elpamotide for patients with advanced pancreatic cancer: PEGASUS-PC Study. Cancer Sci 2015; 106:883-90; PMID:25867139; https://doi.org/10.1111/cas.12674
   PubMed Web of Science ®Google Scholar
• Schmitz-Winnenthal FH, Hohmann N, Niethammer AG, Friedrich T, Lubenau H, Springer M, Breiner KM, Mikus G, Weitz J, Ulrich A et al. Anti-angiogenic activity of VXM01, an oral T-cell vaccine against VEGF receptor 2, in patients with advanced pancreatic cancer: A randomized, placebo-controlled, phase 1 trial. Oncoimmunology 2015; 4:e1001217; PMID:26137397; https://doi.org/10.1080/2162402X.2014.1001217
   PubMed Web of Science ®Google Scholar
• Lesterhuis WJ, Salmons J, Nowak AK, Rozali EN, Khong A, Dick IM, Harken JA, Robinson BW, Lake RA. Synergistic effect of CTLA-4 blockade and cancer chemotherapy in the induction of anti-tumor immunity. PLoS One 2013; 8:1-8; PMID:23626745; https://doi.org/10.1371/journal.pone.0061895
   PubMed Web of Science ®Google Scholar
• Ding ZC, Huang L, Blazar BR, Yagita H, Mellor AL, Munn DH, Zhou G. Polyfunctional CD4+ T cells are essential for eradicating advanced B-cell lymphoma after chemotherapy. Blood 2012; 120:2229-39; PMID:22859605; https://doi.org/10.1182/blood-2011-12-398321
   PubMed Web of Science ®Google Scholar
• Kim SH, Lee JM, Gupta SN, Han JK, Choi BI. Dynamic contrast-enhanced MRI to evaluate the therapeutic response to neoadjuvant chemoradiation therapy in locally advanced rectal cancer. J Magn Reson Imag 2014; 40:730-7; PMID:24307571; https://doi.org/10.1002/jmri.24387
   PubMed Web of Science ®Google Scholar
• Stieltjes B, Meissner M, Ing D, Zimmer F, Burkholder I, Kroll A, Combs SE, Vogt-schaden M, Giesel FL, Zoubaa S et al. Biopsy targeting gliomas. Invest Radiol 2010; 45:755-68; PMID:20829706; https://doi.org/10.1097/RLI.0b013e3181ec9db0
   PubMedGoogle Scholar
• Sommerfeldt N, Beckhove P, Ge Y, Schütz F, Choi C, Bucur M, Domschke C, Sohn C, Schneeweis A, Rom J et al. Heparanase: A new metastasis-associated antigen recognized in breast cancer patients by spontaneously induced memory T lymphocytes. Cancer Res 2006; 66:7716-23; PMID:16885374; https://doi.org/10.1158/0008-5472.CAN-05-2363
   PubMed Web of Science ®Google Scholar
• Schmitz-Winnenthal FH, Volk C, Z'graggen K, Galindo L, Nummer D, Ziouta Y, Bucur M, Weitz J, Schirrmacher V, Buchler MW et al. High frequencies of functional tumor-reactive T cells in bone marrow and blood of pancreatic cancer patients. Cancer Res 2005; 65:10079-87; PMID:16267034; https://doi.org/10.1172/JCI39608
   PubMed Web of Science ®Google Scholar
• Sommerfeldt N, Schütz F, Sohn C, Förster J, Schirrmacher V, Beckhove P. The shaping of a polyvalent and highly individual T-cell repertoire in the bone marrow of breast cancer patients. Cancer Res 2006; 66:8258-65; PMID:16912206; https://doi.org/10.1158/0008-5472.CAN-05-4201
   PubMed Web of Science ®Google Scholar
• Bonertz A, Weitz J, Pietsch DH, Rahbari NN, Schlude C, Ge Y, Juenger S, Vlodavsky I, Khazaie K, Jaeger D et al. Antigen-specific Tregs control T cell responses against a limited repertoire of tumor antigens in patients with colorectal carcinoma. J Clin Invest 2009; 119:3311-21; PMID:19809157; https://doi.org/10.1172/JCI39608
   PubMed Web of Science ®Google Scholar
• Jandus C, Bioley G, Dojcinovic D, Derré L, Baitsch L, Wieckowski S, Rufer N, Kwok WW, Tiercy JM, Luescher IF et al. Tumor antigen-specific FOXP3+ CD4 T cells identified in human metastatic melanoma: Peptide vaccination results in selective expansion of Th1-like counterparts. Cancer Res 2009; 69:8085-93; PMID:19808957; https://doi.org/10.1158/0008-5472.CAN-09-2226
   PubMed Web of Science ®Google Scholar
• Baumgaertner P, Rufer N, Devevre E, Derre L, Rimoldi D, Geldhof C, Voelter V, Liénard D, Romero P, Speiser DE. Ex vivo detectable human CD8 T-cell responses to cancer-testis antigens. Cancer Res 2006; 66:1912-6; PMID:16488988; https://doi.org/10.1158/0008-5472.CAN-05-3793
   PubMed Web of Science ®Google Scholar
• Vincent J, Mignot G, Chalmin F, Ladoire S, Bruchard M, Chevriaux A, Martin F, Apetoh L, Rébé C, Ghiringhelli F. 5-Fluorouracil selectively kills tumor-associated myeloid-derived suppressor cells resulting in enhanced T cell-dependent antitumor immunity. Cancer Res 2010; 70:3052-61; PMID:20388795; https://doi.org/10.1158/0008-5472.CAN-09-3690
   PubMed Web of Science ®Google Scholar
• Bracci L, Schiavoni G, Sistigu A, Belardelli F. Immune-based mechanisms of cytotoxic chemotherapy: Implications for the design of novel and rationale-based combined treatments against cancer. Cell Death Differ 2014; 21:15-25; PMID:23787994; https://doi.org/10.1038/cdd.2013.67
   PubMed Web of Science ®Google Scholar
• Zitvogel L, Kepp O, Kroemer G. Immune parameters affecting the efficacy of chemotherapeutic regimens. Nat Rev Clin Oncol 2011; 8:151-60; PMID:21364688; https://doi.org/10.1038/nrclinonc.2010.223
   PubMed Web of Science ®Google Scholar
• Macpherson AJ, Smith K. Mesenteric lymph nodes at the center of immune anatomy. J Exp Med 2006; 203:497-500; PMID:16533891; https://doi.org/10.1084/jem.20060227
   PubMed Web of Science ®Google Scholar
• Perez-Lopez A, Behnsen J, Nuccio S-P, Raffatellu M. Mucosal immunity to pathogenic intestinal bacteria. Nat Rev Immunol 2016; 16:135-48; PMID:26898110; https://doi.org/10.1038/nri.2015.17
   PubMed Web of Science ®Google Scholar
• Sandoval F, Terme M, Nizard M, Badoual C, Bureau M-F, Freyburger L, Clement O, Marcheteau E, Gey A, Fraisse G et al. Mucosal imprinting of vaccine-induced CD8+ T cells is crucial to inhibit the growth of mucosal tumors. Sci Transl Med 2013; 5:172ra20-172ra20; PMID:23408053; https://doi.org/10.1126/scitranslmed.3004888
   PubMed Web of Science ®Google Scholar