Personalized peptide vaccines induce predicted T cell responses against signet ring cell carcinoma-a case report

Abstract

T cell-based immunotherapies increasingly include personalized neoantigen vaccines that target tumor-specific mutations. However, despite their promise, current neoantigen vaccines show limited and unpredictable clinical benefit, with T cell responses observed in only a subset of patients. To overcome these limitations, we developed the VERDI (Vaccine Epitopes Ranked by Digital Intelligence) System-a cloud-based computational platform that integrates a patient’s human leukocyte antigen (HLA) class I and II genotype with selected tumor-associated antigens (TAAs), including cancer-testis antigens (CTAs), to identify peptides with high predicted immunogenicity and low risk of immune-related adverse events (irAEs). Using the VERDI System, we designed ten personalized peptide vaccines for a patient with metastatic signet ring cell carcinoma (SRCC), a rare and aggressive gastric cancer with limited treatment options. All ten VERDI vaccines were well tolerated and consistently induced tumor-specific T cell responses following a single administration, without the need for checkpoint inhibitors. The patient survived for 15 months-substantially longer than the reported median survival of 5.6 months in metastatic SRCC-highlighting the potential of this individualized, predictive vaccine platform to improve outcomes in advanced cancer.

Keywords

personalized vaccine / cancer-testis antigen / peptide vaccine / immunotherapy / HLA-matching / computational immunology / case report

References

[1] Lisziewicz RG, Oviedo F, Szasz AG, Ferres JL, Lori F, Lisziewicz J. HLA-genotype-based Predictive Diagnosis of T-cell Responses to SARS-CoV-2 Infection Powered by Machine Learning. Med Res Arch. 2023; 11: 11.

[2] Dolina JS, Lee J, Brightman SE, McArdle S, Hall SM, Thota RR, et al. Linked CD4⁺/CD8⁺ T cell neoantigen vaccination overcomes immune checkpoint blockade resistance and enables tumor regression . J Clin Invest. 2023; 133: e164258.

[3] Ostroumov D, Fekete-Drimusz N, Saborowski M, Kühnel F, Woller N. CD4 and CD8 T lymphocyte interplay in controlling tumor growth. Cell Mol Life Sci. 2018; 75: 689-713.

[4] Petrou C, Sarigiannis Y. Peptide synthesis: Methods, trends, and challenges. In: Koutsopoulos S, editor. Peptide Applications in Biomedicine, Biotechnology and Bioengineering. Woodhead Publishing: Cambridge; 2018. pp. 1-21.

[5] QuantiFERON-TB Gold Plus (QFT-Plus) ELISA Package Insert [Internet]. QIAGEN; c2013-25 [cited 2025 Apr 10]. Available from: https://www.qiagen.com/us/products/diagnostics-and-clinical-research/tb-management/quantiferon-tb-gold-plus-us

[6] Fukuyama T, Futawatari N, Ichiki Y, Shida A, Yamazaki T, Nishi Y, et al. Correlation Between Expression of the Cancer/Testis Antigen KK-LC-1 and Helicobacter pylori Infection in Gastric Cancer . In Vivo. 2017; 31: 403-7.

[7] Fukuyama T, Futawatari N, Yamamura R, Yamazaki T, Ichiki Y, Ema A, et al. Expression of KK-LC-1, a cancer/testis antigen, at non-tumour sites of the stomach carrying a tumour. Sci Rep. 2018; 8: 6131.

[8] Ansari S, Nikpour P. Identification of Cancer/Testis Antigens Related to Gastric Cancer Prognosis Based on Co-Expression Network and Integrated Transcriptome Analyses. Adv Biomed Res. 2023; 12: 52.

[9] Fukuyama T, Hanagiri T, Takenoyama M, Ichiki Y, Mizukami M, So T, et al. Identification of a new cancer/germline gene, KK-LC-1, encoding an antigen recognized by autologous CTL induced on human lung adenocarcinoma . Cancer Res. 2006; 66: 4922-8.

[10] Gerlinger M, Rowan AJ, Horswell S, Math M, Larkin J, Endesfelder D, et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med. 2012; 366: 883-92.

[11] Butterfield LH. Cancer vaccines. BMJ. 2015; 350: h988.

[12] Smyth EC, Nilsson M, Grabsch HI, van Grieken NC, Lordick F. Gastric cancer. Lancet. 2020; 396: 635-48.

[13] Wilke H, Muro K, van Cutsem E, Oh S, Bodoky G, Shimada Y, et al. ; RAINBOW Study Group. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 2014; 15: 1224-35.

[14] Machlowska J, Baj J, Sitarz M, Maciejewski R, Sitarz R. Gastric Cancer: Epidemiology, Risk Factors, Classification, Genomic Characteristics and Treatment Strategies. Int J Mol Sci. 2020; 21: 4012.

[15] Pernot S, Voron T, Perkins G, Lagorce-Pages C, Berger A, Taieb J. Signet-ring cell carcinoma of the stomach: Impact on prognosis and specific therapeutic challenge. World J Gastroenterol. 2015; 21: 11428-38.

[16] Picard M, Castells MC. Re-visiting Hypersensitivity Reactions to Taxanes: A Comprehensive Review. Clin Rev Allergy Immunol. 2015; 49: 177-91.

[17] Giles AJ, Hutchinson MND, Sonnemann HM, Jung J, Fecci PE, Ratnam NM, et al. Dexamethasone-induced immunosuppression: mechanisms and implications for immunotherapy. J Immunother Cancer. 2018; 6: 51.

[18] Cain DW, Cidlowski JA. Immune regulation by glucocorticoids. Nat Rev Immunol. 2017; 17: 233-47.

[19] Serin GM, Mahmutoglu AS, Polat Ş, Aksoy E, Tanyeri H. Internal jugular vein thrombosis as an initial presentation of signet-ring cell adenocarcinoma of unknown origin. J Med Cases. 2011; 2: 156-8.

[20] Dourdouna M, Tatsi E, Syriopoulou V, Michos A. Evaluation of T cell responses with the QuantiFERON SARS-CoV-2 assay in individuals with 3 doses of BNT162b2 vaccine, SARS-CoV-2 infection, or hybrid immunity. Diagn Microbiol Infect Dis. 2023; 106: 115948.

[21] Katsikis PD, Ishii KJ, Schliehe C. Challenges in developing personalized neoantigen cancer vaccines. Nat Rev Immunol. 2024; 24: 213-27.

[22] Rojas LA, Sethna Z, Soares KC, Olcese C, Pang N, Patterson E, et al. Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer. Nature. 2023; 618: 144-50.

[23] Blass E, Ott PA. Advances in the development of personalized neoantigen-based therapeutic cancer vaccines. Nat Rev Clin Oncol. 2021; 18: 215-29.

[24] Li H, Zong Z, Zhou T, Sun L, Wang A, Zhang K, et al. Trends of incidence and survival in patients with gastroenteropancreatic signet ring cell carcinoma: an analysis from the Surveillance, Epidemiology, and End Results program. J Gastrointest Oncol. 2019; 10: 979-88.

[25] Eichler H, Pignatti F, Schwarzer-Daum B, Hidalgo-Simon A, Eichler I, Arlett P, et al. Randomized Controlled Trials Versus Real World Evidence: Neither Magic Nor Myth. Clin Pharmacol Ther. 2021; 109: 1212-8.