The only cure for pancreatic cancer is surgical resection, although this malignancy is difficult to detect early. At the time of diagnosis, approximately 60% of patients are already beyond the possibility of surgical resection.20–23 GEM is currently used as the standard therapy for unresectable pancreatic cancer. Noninferiority of S-1 compared with GEM was shown in GEST study conducted in Japan, but the superiority of the combination of GEM and S-1 over GEM monotherapy has not yet been conclusively proven.24 The establishment of combination therapy with GEM has been performed many times to date. One large randomized controlled phase III trial with erlotinib showed significantly prolonged survival time (P=0.038),25 but the difference was only about 10 days. In another study, MST was 11.1 months for the FOLFIRINOX group, compared with 6.8 months in the GEM group, showing a significant difference (P<0.001). However, markedly more adverse events were noted in the FOLFIRINOX group.26 Taking into account toxicity and economic aspects, the development of new drugs for advanced pancreatic cancer is urgently required.
The present study investigated a novel cancer vaccine therapy for pancreatic cancer using a KIF20A-derived peptide in combination with GEM. To the best of our knowledge, this is the first report to use the KIF20A-derived peptide in a clinical trial. We observed no severe adverse events related to the treatment in this trial (Table 2). Specific adverse events caused by this vaccine treatment were local redness and induration at the injection site; however, no events >grade 3 were observed. In several papers we have examined—their authors show that the intradermic administration of vaccine has proven superior to subcutaneous administrations.27
We tried to administer the KIF20A-derived peptide emulsified with incomplete Freund’s adjuvant as close as possible to the dermis—so as to activate the dendritic cells.
Because the volume was 2 mL, it was too much to inject the intradermic administration. We think the data of this study were able to prove that IFN-γ-producing cells could be enhanced by this message. Immunologic responses in this trial were measured by local redness and induration at the injection site and antigen-specific T-cell responses against the vaccinated peptide. No dose-limiting toxicity was observed in any dose cohort. We injected peptide vaccine biweekly after 8 times weekly injection (2 courses) to avoid the risk of exhaustion of the immune response. We chose right inguinal lesion or left inguinal lesion alternately as injection site. Local redness and induration as CTCAE grade 2 at the injection site were observed in all 3 patients with the 3 mg vaccination (Table 2). However, achievement of SD was seen in 2 of the 3 patients receiving 0.5 mg vaccination, 1 of 3 patients receiving 1 mg, and 1 of 3 patients receiving 3 mg (Table 2). In this study, we consider that the optimum peptide dosage for future clinical trials could be set at a level of at least 0.5 mg or more.
As a point of immunologic monitoring, IFN-γ-producing cells were induced in 4 of 9 patients (P2, P3, P6, and P7), and IFN-γ-producing cells were increased in 4 of the 9 patients (P1, P5, P8, and P9). Patient 4 in whom IFN-γ-producing cells response was absent was suffering from acute cholangitis during vaccination. Prior to vaccination, the proportion of lymphocyte in this patient was only 13%. Yamamoto et al28 previously reported that peptide-reactive cellular and humoral responses to vaccinated peptides in postvaccination PBMCs and sera were lower for advanced pancreatic cancer patients than for patients with other solid cancers. They commented that these results suggest that immunity in advanced pancreatic cancer is more depressed than in other epithelial cancers. Alternatively, a more suitable peptide repertoire might be provided for pancreatic cancer patients. Miyazawa et al29 reported that VEGFR2-169 peptide-specific positive CTL responses were observed in 11 of 18 patients who received at least one course of vaccination. Ishikawa et al30 reported URLC10-177 peptide-specific positive CTL responses in 4 of 7 patients. KIF20A peptide vaccine therefore induced or further increased peptide-specific T-cell responses at a higher rate compared with these reports. Four of the 9 patients achieved SD, whereas the other 5 patients showed PD (Table 2). Achievement of SD was seen in 2 of the 3 patients receiving 0.5 mg vaccination, 1 of 3 patients receiving 1 mg, and 1 of 3 patients receiving 3 mg (Table 2). There is no evidence that the SD was mediated by the vaccine. This could simply be the natural history of this disease, but it is interesting to note that all 4 patients who achieved SD showed antigen-specific T-cell response of ++ or +++ reactions for KIF20A peptide. In contrast, 3 of the 5 patients who experienced PD showed antigen-specific T-cell response from negative to 1+ reaction. A tendency toward a correlation between antigen-specific T-cell response and clinical outcome was suggested, but no significant relationship was proved (P=0.074). However, the population was too small to be evaluated in this clinical trial. Many prior peptide vaccine studies have demonstrated significant immunogenicity against the peptides utilized in the vaccine without translating into significant clinical benefits. This will be our next focus but prior to that the important thing is to identify a new peptide that possesses high immunogenicity. This protocol was well tolerated, and peptide-specific IFN-γ-producing cells were found to be induced or increased by the KIF20A-derived peptide vaccine at a high rate, even in combination with the anticancer agent, GEM. Although safety and immunogenicity are promising, no conclusions can be made about efficacy at this level of study. We are proceeding on to conduct a phase II clinical trial among patients with advanced pancreatic cancer by combining KIF20A-derived peptide with GEM as the first line. Therefore, additional efficacy data would be required before committing to a large randomized controlled trial.
The authors thank Prof. Yusuke Nakamura, Dr Takuya Tsunoda, Dr Koji Yoshida, Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, for their excellent advice and cooperation and providing all the peptides.
All authors have declared there are no financial conflictsof interest with regard to this work.
1. Jemal A, Siegel R, Ward E, et al..Cancer statistics, 2008.CA Cancer J Clin.2008;58:71–96.
2. Sener SF, Fremgen A, Menck HR, et al..Pancreatic cancer: a report of treatment and survival trends for 100,313 patients diagnosed from 1985–1995 using the National Cancer Database.J Am Coll Surg.1999;189:1–7.
3. Bramhall SR, Allum WH, Jones AG, et al..Treatment and survival in 13,560 patients with pancreatic cancer, and incidence of the disease, in the West Midlands: an epidemiological study.Br J Surg.1995;82:111–115.
4. Rothenberg ML, Moore MJ, Cripps MC, et al..A phase II trial of gemcitabine in patients with 5-FU-refractory pancreas cancer.Ann Oncol.1996;7:347–353.
5. Burris HA I, Moore MJ, Andersen J, et al..Improvement in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreatic cancer: a randomized trial.J Clin Oncol.1997;15:2403–2413.
6. Berlin JD, Catalano P, Thomas JP, et al..Phase III study of gemcitabine combination with fluorouracil versus gemcitabine alone in patients with advanced pancreatic carcinoma: Eastern Cooperative Oncology Group Trial E2297.J Clin Oncol.2002;20:3270–3275.
7. van der Bruggen P, Traversari C, Chomez P, et al..A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma.Science.1991;254:1643–1647.
8. Kawakami Y, Eliyahu S, Sakaguchi K, et al..Identification of the immunodominant peptides of the MART-1 human melanoma antigen recognized by the majority of HLA-A2-restricted tumor infiltrating lymphocytes.J Exp Med.1994;180:347–352.
9. Shichijo S, Nakao M, Imai Y, et al..A gene encoding antigenic peptides of human squamous cell carcinoma recognized by cytotoxic T lymphocytes.J Exp Med.1998;187:277–288.
10. Salgaller ML, Afshar A, Marincola FM, et al..Recognition of multiple epitopes in the human melanoma antigen gp100 by peripheral blood lymphocytes stimulated in vitro with synthetic peptides.Cancer Res.1995;55:4972–4979.
11. Rosenberg SA, Yang JC, Schwartzentruber DJ, et al..Immunologic and therapeutic evaluation of a synthetic peptide vaccine for the treatment of patients with metastatic melanoma.Nat Med.1998;4:321–327.
12. Suzuki N, Maeda Y, Tanaka S, et al..Detection of peptide-specific cytotoxic T-lymphocyte precursors used for specific immunotherapy of pancreatic cancer.Int J Cancer.2002;98:45–50.
13. Okabe H, Satoh S, Kato T, et al..Genome-wide analysis of gene expression in human hepatocellular carcinomas using cDNA microarray: identification of genes involved in viral carcinogenesis and tumor progression.Cancer Res.2001;61:2129–2137.
14. Lin YM, Furukawa Y, Tsunoda T, et al..Molecular diagnosis of colorectal tumors by expression profiles of 50 genes expressed differentially in adenomas and carcinomas.Oncogene.2002;21:4120–4128.
15. Hasegawa S, Furukawa Y, Li M, et al..Genome-wide analysis of gene expression in intestinal-type gastric cancers using a complementary DNA microarray representing 23,040 genes.Cancer Res.2002;62:7012–7017.
16. Taniuchi K, Nakagawa H, Nakamura T, et al..Down-regulation of RAB6KIFL/KIF20A, a kinesin involved with membrane trafficking of discs large homologue 5, can attenuate growth of pancreatic cancer cell.Cancer Res.2005;65:105–112.
17. Okuno K, Sugiura F, Hida JI, et al..Phase I clinical trial of a novel peptide vaccine in combination with UFT/LV for metastatic colorectal cancer.Exp Ther Med.2011;2:73–79.
18. Kono K, Iinuma H, Akutsu Y, et al..Multicenter, phase II clinical trial of cancer vaccination for advanced esophageal cancer with three peptides derived from novel cancer-testis antigens.J Transl Med.2012;10:141.
19. Janetzki S, Panageas KS, Ben-Porat L, et al..Results and harmonization guidelines from two large-scale international Elispot proficiency panels conducted by the Cancer Vaccine Consortium (CVC/SVI).Cancer Immunol Immunother.2008;57:303–315.
20. Matsuno S, Egawa S, Shibuya K, et al..Pancreatic cancer: current status of treatment and survival of 16071 patients diagnosed from 1981-1996, using Japanese National Pancreatic Cancer Database.Int J Clin Oncol.2000;5:153–157.
21. Pantalone D, Ragionieri I, Nesi G, et al..Improved survival in small pancreatic cancer.Dig Surg.2001;18:41–46.
22. Casper ES, Green MR, Kelsen DP, et al..Phase II trial of gemcitabine (2,2′-difluorodeoxycytidine) in patients with adenocarcinoma of the pancreas.Invest New Drugs.1994;12:29–34.
23. Carmichael J, Fink U, Russell RC, et al..Phase II study of gemcitabine in patients with advanced pancreatic cancer.Br J Cancer.1996;73:101–105.
24. Ueno H, Ioka T, Ikeda M, et al..Randomized phase III study of gemcitabine plus S-1, S-1 alone, or gemcitabine alone in patients with locally advanced and metastatic pancreatic cancer in Japan and Taiwan: GEST study.J Clin Oncol.2013;31:1640–1648.
25. Moore MJ, Goldstein D, Hamm J, et al..Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group.J Clin Oncol.2007;25:1960–1966.
26. Conroy T, Desseigne F, Ychou M, et al..FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer.N Engl J Med.2011;364:1817–1825.
27. Launay O, Surenaud M, Desaint C, et al..Long-term CD4(+) and CD8(+) T-cell responses induced in HIV-uninfected volunteers following intradermal or intramuscular administration of an HIV-lipopeptide vaccine (ANRS VAC16).Vaccine.2013;31:4406–4415.
28. Yamamoto K, Mine T, Katagiri K, et al..Immunological evaluation of personalized peptide vaccination for patients with pancreatic cancer.Oncol Rep.2005;13:875–883.
29. Miyazawa M, Ohsawa R, Tsunoda T, et al..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;101:433–439.
30. Ishikawa H, Imano M, Shiraishi O, et al..Phase I clinical trial of vaccination with URLC10-derived peptide for patients with advanced esophageal cancer.Esophagus.2012;9:105–112.