TY - JOUR
T1 - Exploratory open-label clinical study to determine the S-588410 cancer peptide vaccine-induced tumor-infiltrating lymphocytes and changes in the tumor microenvironment in esophageal cancer patients
AU - Daiko, H.
AU - Marafioti, T.
AU - Fujiwara, T.
AU - Shirakawa, Yasuhiro
AU - Nakatsura, T.
AU - Kato, K.
AU - Puccio, I.
AU - Hikichi, T.
AU - Yoshimura, S.
AU - Nakagawa, T.
AU - Furukawa, M.
AU - Stoeber, K.
AU - Nagira, M.
AU - Ide, N.
AU - Kojima, T.
N1 - Funding Information:
The authors thank all study participants, their families and the clinical research teams at all our centers for their contribution to this study. Quality control for IHC date was performed by Mikinori Torii and Emi Kashiwagi at Shionogi Co., Ltd. research laboratories. Medical writing support was provided by Motofumi Iguchi (Medical Affairs Department, Shionogi & Co., Ltd., Japan) and Jesse Quigley Jones (MIMS Hong Kong) and funded by Shionogi Co. Ltd.
Funding Information:
The study was funded by Shionogi & Co., Ltd. Acknowledgements
Funding Information:
The authors thank all study participants, their families and the clinical research teams at all our centers for their contribution to this study. Quality control for IHC date was performed by Mikinori Torii and Emi Kashiwagi at Shionogi Co., Ltd. research laboratories. Medical writing support was provided by Motofumi Iguchi (Medical Affairs Department, Shionogi & Co., Ltd., Japan) and Jesse Quigley Jones (MIMS Hong Kong) and funded by Shionogi Co. Ltd.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/11/1
Y1 - 2020/11/1
N2 - Cancer vaccines induce cancer-specific T-cells capable of eradicating cancer cells. The impact of cancer peptide vaccines (CPV) on the tumor microenvironment (TME) remains unclear. S-588410 is a CPV comprising five human leukocyte antigen (HLA)-A*24:02-restricted peptides derived from five cancer testis antigens, DEPDC1, MPHOSPH1, URLC10, CDCA1 and KOC1, which are overexpressed in esophageal cancer. This exploratory study investigated the immunologic mechanism of action of subcutaneous S-588410 emulsified with MONTANIDE ISA51VG adjuvant (median: 5 doses) by analyzing the expression of immune-related molecules, cytotoxic T-lymphocyte (CTL) response and T-lymphocytes bearing peptide-specific T-cell receptor (TCR) sequencing in tumor tissue or blood samples from 15 participants with HLA-A*24:02-positive esophageal cancer. Densities of CD8+, CD8+ Granzyme B+, CD8+ programmed death-1-positive (PD-1+) and programmed death-ligand 1-positive (PD-L1+) cells were higher in post- versus pre-vaccination tumor tissue. CTL response was induced in all patients for at least one of five peptides. The same sequences of peptide-specific TCRs were identified in post-vaccination T-lymphocytes derived from both tumor tissue and blood, suggesting that functional peptide-specific CTLs infiltrate tumor tissue after vaccination. Twelve (80%) participants had treatment-related adverse events (AEs). Injection site reaction was the most frequently reported AE (grade 1, n = 1; grade 2, n = 11). In conclusion, S-588410 induces a tumor immune response in esophageal cancer. Induction of CD8+ PD-1+ tumor-infiltrating lymphocytes and PD-L1 expression in the TME by vaccination suggests S-588410 in combination with anti-PD-(L)1 antibodies may offer a clinically useful therapy. Trial registration UMIN-CTR registration identifier: UMIN000023324.
AB - Cancer vaccines induce cancer-specific T-cells capable of eradicating cancer cells. The impact of cancer peptide vaccines (CPV) on the tumor microenvironment (TME) remains unclear. S-588410 is a CPV comprising five human leukocyte antigen (HLA)-A*24:02-restricted peptides derived from five cancer testis antigens, DEPDC1, MPHOSPH1, URLC10, CDCA1 and KOC1, which are overexpressed in esophageal cancer. This exploratory study investigated the immunologic mechanism of action of subcutaneous S-588410 emulsified with MONTANIDE ISA51VG adjuvant (median: 5 doses) by analyzing the expression of immune-related molecules, cytotoxic T-lymphocyte (CTL) response and T-lymphocytes bearing peptide-specific T-cell receptor (TCR) sequencing in tumor tissue or blood samples from 15 participants with HLA-A*24:02-positive esophageal cancer. Densities of CD8+, CD8+ Granzyme B+, CD8+ programmed death-1-positive (PD-1+) and programmed death-ligand 1-positive (PD-L1+) cells were higher in post- versus pre-vaccination tumor tissue. CTL response was induced in all patients for at least one of five peptides. The same sequences of peptide-specific TCRs were identified in post-vaccination T-lymphocytes derived from both tumor tissue and blood, suggesting that functional peptide-specific CTLs infiltrate tumor tissue after vaccination. Twelve (80%) participants had treatment-related adverse events (AEs). Injection site reaction was the most frequently reported AE (grade 1, n = 1; grade 2, n = 11). In conclusion, S-588410 induces a tumor immune response in esophageal cancer. Induction of CD8+ PD-1+ tumor-infiltrating lymphocytes and PD-L1 expression in the TME by vaccination suggests S-588410 in combination with anti-PD-(L)1 antibodies may offer a clinically useful therapy. Trial registration UMIN-CTR registration identifier: UMIN000023324.
KW - Cancer peptide vaccine
KW - Esophageal cancer
KW - PD-1
KW - PD-L1
KW - Tumor-infiltrating lymphocytes
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U2 - 10.1007/s00262-020-02619-3
DO - 10.1007/s00262-020-02619-3
M3 - Article
C2 - 32500232
AN - SCOPUS:85086020263
VL - 69
SP - 2247
EP - 2257
JO - Cancer Immunology and Immunotherapy
JF - Cancer Immunology and Immunotherapy
SN - 0340-7004
IS - 11
ER -