We have worked to harness the innate and adaptive immune systems, re-57sulting in the induction of immunological memory against cancer. We have been promoting our artificial adjuvant vector cell (aAVC) project against cancer. NY-ESO-1 is an esophageal squamous cell carcinoma antigen and WT1 is a Wilms’ tumor antigen. In the current year, we established NY-ESO-1 ex-pressing aAVC (aAVC-NY-ESO-1) and showed the immunological and anti-tu-mor effect in a preclinical study in collaboration with Astellas Pharma Inc. For aAVC-WT1, we started a Phase II clinical study in collaboration with the Insti-tute of Medical Science, the University of Tokyo, Chiba University and Kagawa University. The COVID-19 pandemic has been ongoing since 2019. Recent data have reported the insufficient efficacy of the current COVID-19 vaccines in cancer patients. COVID-19 is a thus a serious issue in cancer patients and, since 2020, we therefore started a COVID-19 project to overcome the COVID-19 pandemic. To evaluate the CTL response against SARS-CoV-2, we first fo-cused on identification of immunodominant epitopes in the viral spike protein for HLA-A24, which is major HLA in Japan. We identified the “QYI peptide”, which can induce specific CTLs in 80% of HLA-A24+ unexposed healthy do-nors but in only 14% of HLA-A24+ patients with hematological malignancies. These QYI-specific CTLs are pre-existing memory CTLs against seasonal coro-naviruses and cross-reactive against SARS-CoV-2 (Figure). We demonstrated TCR cross-reactivity of these CTLs at the single cell level and obtained crystal structures of the HLA-A24-QYI peptide or the relevant peptides of seasonal coronaviruses. For high-risk groups such as cancer patients, a second line vac-cine is needed. To this end, we have developed SARS-CoV-2 spike protein-expressing aAVC-CoV-2 as a COVID-19 vaccine. We examined whether aAVC-CoV-2 can act as a promising second line vaccine for these high-risk groups. In a preclinical study, we obtained solid immunological evidence - aAVC-CoV-2 induced robust multifunctional SARS-CoV-2-specific T cells as well as anti-SARS-CoV-2 antibodies. Especially, we found long-term memory CTLs in aAVC-CoV-2-vaccinated mice.Figure: The role of pre-existing, cross-reactive killer T cells for SARS-CoV-2 in COVID-19When SARS-CoV-2-cross-reactive, memory killer T cells with high avidity are maintained, they can expand quickly in response to immunodominant epitopes in SARS-CoV-2 and also exert anti-viral effects.Recent Major PublicationsFujii S, Yamasaki S, Hanada K, Ueda S, Kawamura M, and Shimizu K. Cancer immunotherapy using artificial adju-vant vector cells to deliver NY-ESO-1 antigen to dendritic cells in situ. Cancer Sci 113, 864-874 (2022)Shimizu K, Iyoda T, Sanpei A, Nakazato H, Okada M, Ueda S, Kato-Murayama M, Murayama K, Shirouzu M, Harada N, Hidaka M, and Fujii S. Identification of TCR repertoires in functionally competent cytotoxic T cells cross-reactive to SARS-CoV-2. Commune Biol 4, 1365 (2021)Miyauchi K, Adachi Y, Tonouchi K, Yajima T, Harada Y, Fukuyama H, Deno S, Iwakura Y, Yoshimura A, Hasegawa H, Yugi K, Fujii S, Ohara O, Takahashi Y, and Kubo M. Influenza virus infection expands the breadth of anti-body responses through IL-4 signalling in B cells. Nat Commun 12, 3789 (2021)Invited presentationsFujii S. “A new therapeutic cancer vaccine inducing both innate and adaptive immunity, artificial adjuvant vector cells” The 29th Annual Meeting of the Japanese Society for Histocompatibility and Immunogenetics (Online) September 2021Fujii S. “Dendritic cell- based new immunotherapy” The 28th Annual Meeting of the Japanese Society of Immu-notoxicology (Online) September 2021Fujii S. “A new therapeutic cancer vaccine inducing multifunctional immunity, artificial adjuvant vector cells” 2021 The 1st JCA-AACR Precision Cancer Medicine International Conference (Online) September 2021Fujii S. “Immune response of first-in-human phase I clinical trial by WT1-expressing artificial adjuvant vector cells (aAVC-WT1)” The 25th Annual Meeting of Japanese Association of Cancer Immunology (Wakayama, Japan) July 2021Fujii S. “Immune responses of cancer immunotherapy with artificial adjuvant vector cells in Phase I trial” The 13th Annual Meeting of the Japanese Society of Immu-notherapy for Hematological disorders (Tokyo, Japan) June 2021Laboratory for ImmunotherapyTeam Leader: Shin-ichiro Fujii
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