Breakthrough in COVID-19 Fight: Kagawa University Launches Groundbreaking Vaccine Trial for Cancer Patients
Shinichiro Fujii, Team Leader, Immune Cell Therapy Research Team, RIKEN Center for Biomedical Sciences (Deputy Program Director/Project Leader, Drug Discovery and Medical Technology Infrastructure Program, Cutting Edge Research Platform Collaboration (TRIP) Division), Kagawa University School of Medicine A joint research team led by Professor Norimitsu Kadowaki of the Department of Hematology, Immunology, and Respiratory Medicine (Director of Kagawa University Hospital) is investigating the novel coronavirus infection (COVID-19).[1]B-cell malignancy, a high-risk group[2]Investigator-initiated Phase I trial of aAVC-CoV-2, a novel COVID-19 vaccine in patients[3]We plan to start this year.
In this clinical trial, we will aim to provide T-cell therapy to vaccine recipients who cannot sufficiently induce antibody production with conventional COVID-19 mRNA vaccines.[4]By inducing immunity, the new coronavirus (SARS-CoV-2)[5]We hope to demonstrate its effectiveness in preventing infection.
Team Leader Fujii and his colleagues believe that natural immunity against cancer and infectious diseases[6]and acquired immunity[6]Artificial adjuvant vector cells (aAVC) that activate[7]We have independently developed a vaccine and have been conducting research on it Note 1). This time, the joint research team has developed aAVC-CoV-2, which is equipped with the spike protein of SARS-CoV-2, as a new vaccine against COVID-19. Previous non-clinical studies have reported high spike protein-specific T cell responses and antibody production due to aAVC-CoV-2 (Note 2), and good results have been obtained in infection prevention studies. Based on these results, we will conduct an investigator-initiated phase I clinical trial of aAVC-CoV-2 in collaboration with Kagawa University, aiming to obtain evidence of safety and immunological efficacy in humans.
Background/Points of clinical trial
The current COVID-19 mRNA vaccine, which encodes the SARS-CoV-2 spike protein, aims to induce neutralizing antibodies, provides protection against infection in many healthy people, and helps prevent the global SARS-CoV-2 pandemic. contributed to the suppression. However, during the pandemic period, it was found that vaccine-induced antibody production was low in people at high risk of infection, especially patients with hematopoietic tumors, and the rate of severe illness and mortality after infection was high (Note 3). Although the number of people infected with COVID-19 and the rate of severe illness are currently stable, new SARS-CoV-2 mutant strains with altered antigenicity are still emerging one after another. It is expected that there will continue to be concerns about the emergence of highly transmissible viruses and infection among high-risk groups who are at high risk of becoming seriously ill.
In particular, B-cell malignancies (e.g., B-cell lymphoma, multiple myeloma) and acute myeloid leukemia following chemotherapy.[8]If a highly susceptible risk group such as a patient becomes infected with COVID-19, the virus may not be eliminated and the infection may persist, resulting in a lack of progress in treatment of the underlying disease or inability to be discharged from hospital. There are many reports from clinical sites that this is the case Note 4). In addition, in the highly susceptible risk group, new mutant strains may arise in the body due to repeated infections or prolonged infection, and these new mutant strains may It may also be a threat to other people. Therefore, there is a strong need to develop new vaccines for people for whom current vaccines are difficult to respond to.
CD8-positive T cells in antiviral immunity[4]major histocompatibility complex (MHC) on infected cells[9]Killer T cells recognize viral antigens presented to[4]By killing viral antigens, it prevents virus amplification and latent infection, and plays a role in reducing the severity of the disease. During the COVID-19 pandemic, in cases of hematopoietic malignancies, groups with low numbers of CD8+ T cells had a higher number of deaths after infection compared to groups with higher numbers of CD8+ T cells, and the number of CD8+ T cells was the most correlated with prognosis. There have also been reports that there are some cases (Note 5). In addition, antibodies and killer T cells are induced by epitopes.[10]Because the virus is different, killer T cells may be induced even if the virus mutates and antibodies are not induced, and it is expected to be effective against mutant strains.
The Immune Cell Therapy Research Team has independently developed aAVC vaccine as an immunotherapy for cancer and infectious diseases (Note 6). aAVC is a vaccine system that uses natural killer T (NKT) cells, which are innate immune lymphocytes.[11]The activation of dendritic cells in the body triggers[12]It is a vaccine platform technology that can promote the maturation of the immune system and activate both innate and acquired immunity. aAVC carries a complex of alpha-galactosylceramide (α-GalCer), a glycolipid that activates NKT cells, and CD1d molecules on the cell surface, and carries the cancer antigen or viral antigen protein of the target disease into the cell. These are cells expressed in
Glycolipids attached to aAVC via the CD1d protein activate NKT cells, and the aAVC itself is destroyed in the body and taken up by dendritic cells. This series of reactions maximizes the function of dendritic cells, allowing them to act as a vaccine (Figure 1). WT1 has already been used in patients with relapsed or treatment-resistant acute myeloid leukemia.[13]We have conducted an investigator-initiated phase I clinical trial of aAVC-WT1 expressing the antigen, and have confirmed its safety in humans, immunological effects on both innate and acquired immunity, and a certain level of therapeutic efficacy.Note 6) .
Figure 1 Mechanism of action of aAVC
Glycolipid (α-GalCer) attached to aAVC via CD1d protein activates NKT cells. aAVC itself is destroyed by NK cells and NKT cells in the body and taken up by dendritic cells, and NKT cells induce maturation of dendritic cells. The dendritic cells efficiently induce CD4-positive T cells and CD8-positive T cells. IFN-γ is type II interferon.
In addition, we have developed aAVC-CoV-2 equipped with the spike protein of SARS-CoV-2 and conducted non-clinical safety tests.[14]Confirm safety and conduct non-clinical pharmacological efficacy tests[14]spike protein-specific CD4- and CD8-positive T cells are induced at a high rate in the lungs and spleen, and they are also known to be memory T cells.[15](Note 7).
Based on these non-clinical studies, we aim to conduct clinical trials to obtain proof of concept of drug efficacy in humans.From November 2023, we will be selected for the AMED-SCARDA Vaccine/New Modality Research and Development Project, Preparations were underway for clinical trials for the development of an infectious disease vaccine using artificial adjuvant vector cell (aAVC) technology, a new vaccine model that induces sexual immunity.
This project is centered on team leader Fujii of the RIKEN Immune Cell Therapy Research Team, Professor Fumitaka Nagamura of the TR and Clinical Trial Center at the Institute of Medical Science, the University of Tokyo, Specially Appointed Professor Kotone Matsuyama of the Nippon Medical School School of Medicine, and the National Institute of Infectious Diseases. With the support of Hideyoshi Fukushi, Director of the Disease Research Institute, and Kenji Suzuki, Advisor of the Myeloma Amyloidosis Center, Japanese Red Cross Medical Center, Professor Kadowaki of the Department of Hematology, Immunology, and Respiratory Medicine, Kagawa University School of Medicine (Director of Kagawa University Hospital) ) are planning to conduct an investigator-initiated phase I clinical trial.
[Key points of physician-initiated phase I clinical trial]
◆aAVC induces innate immunity and acquired immunity with a single administration, and also produces memory immunity that lasts for over 1 year.[16]It was developed as a “multifunctional cancer vaccine system” that brings out the following. The feature of this system is that by using allogeneic cells that have been irradiated, it is possible to manufacture and store cell therapy drugs in large quantities with stable quality, and anyone can use it.
◆In this investigator-initiated Phase I clinical trial, we will conduct a clinical trial of aAVC-CoV-2, which was developed focusing on the spike protein of SARS-CoV-2, targeting B cell malignant tumors. In the future, it is expected that the target diseases will expand. Additionally, since aAVC is a vaccine system, it is also possible to develop aAVC expressing other viral antigens.
◆Kagawa University Hospital, which has supported the development of aAVC, has decided to conduct an investigator-initiated phase I clinical trial at the hospital.
Note 1)
Fujii S et al. Antigen mRNA-transfected, allogeneic fibroblasts loaded with NKT-cell ligand confer antitumor immunity.Blood.2009. 113:4262-72.
Shimizu K et al. Vaccination with antigen-transfected, NKT cell ligand-loaded, human cells elicits robust in situ immune responses by dendritic cells. Cancer Res. 2013. 73:62-73.
Shimizu K et al. Systemic DC activation modulates the tumor microenvironment and shapes the long-lived tumor-specific memory mediated by CD8+ T cells. Cancer Res.2016, 76:3756-66.
Yamasaki S et al. In vivo dendritic cell targeting cellular vaccine induces CD4+ Tfh cell-dependent antibody against influenza virus. Sci Rep. 2016, 6:35173.
Fujii S et al. Cancer immunotherapy using artificial adjuvant vector cells to deliver NY-ESO-1 antigen to dendritic cells in situ. Cancer Sci. 2022, 113:864.
Fujii S et al. Reinvigoration of innate and adaptive immunity via therapeutic cellular vaccine for patients with AML. Molecular Therapy Oncolytics. 2022, 27:315-332.
Shimizu K et al. Combination of cancer vaccine with CD122-biased IL-2/anti-IL-2 Ab complex shapes the stem-like effector NK and CD8+ T cells against tumor. J Immunother Cancer. 2023, 11(7):e006409.
Yamasaki S et al. Tumor epitope spreading by a novel multivalent therapeutic cellular vaccine targeting cancer antigens to invariant NKT-triggered dendritic cells in situ. Front Immunol. 2024, 15:1345037.
Note 2)
Shimizu K et al. A single immunization with cellular vaccine confers dual protection against SARS-CoV-2 and cancer. Cancer Sci. 2022, 113(8):2536-2547.
Note 3)
Ribas A et al. How to Provide the Needed Protection from COVID-19 to Patients with Hematologic Malignancies. Blood Cancer Discov. 2021, 2(6):562.
Salmanton-Garcia J et al. Decoding the historical tale: COVID-19 impact on haematological malignancy patients-EPICOVIDEHA insights from 2020 to 2022. EClinicalMedicine 2024, 71:102553
注4）Lee CY et al. Prolonged SARS-CoV-2 Infection in Patients with Lymphoid Malignancies. Cancer Discov. 2022, 12(1):62.
注5）Bange EM et al. CD8+ T cells contribute to survival in patients with COVID-19 and hematologic cancer.
Night With. 2021, 27(7):1280.
Note 6)
Fujii S et al. Immune Networks and Therapeutic Targeting of iNKT Cells in Cancer. Trends Immunol. 2019, 40: 984
Fujii S et al. NKT-licensed in vivo dendritic cell-based immunotherapy as cellular immunodrugs for cancer treatment. Crit Rev Oncogenesis. 2024, 29(1):45.
注7）Fujii S et al. Reinvigoration of innate and adaptive immunity via therapeutic cellular vaccine for patients with AML. Mol Ther Oncolytics. 2022, 27:315.
Future expectations
If the aAVC-CoV-2 developed in this study is approved as a drug in the future, it will be useful not only for patients with B-cell malignancies who cannot induce antibodies but also for patients with weakened immunity for whom conventional vaccines cannot provide sufficient protection. It is hoped that this will be an effective countermeasure for those who have.
supplementary explanation
[1] Novel coronavirus infection (COVID-19)
Emerging infectious diseases, SARS-CoV-2 ([5](see) is caused by infection.
[2] B cell malignancy
A malignant tumor that occurs during the maturation process of B lymphocytes.
[3] Investigator-initiated phase I clinical trial
A physician-initiated clinical trial is one in which a physician plans and plans a clinical trial himself, submits a clinical trial notification, and conducts the clinical trial. The purpose of phase I clinical trials is primarily to confirm the safety of the investigational drug, the pharmacokinetics of the drug, and the maximum dose of the drug.
[4] T cells, CD8 positive T cells, キラーT cells
T cells are a type of lymphocyte that differentiates and matures in the thymus tissue. It is in charge of acquired immunity and exerts various functions by receiving antigen information from antigen-presenting cells. Among T cells, CD8-positive T cells express a characteristic protein called CD8 on their cell surface, and when activated, they differentiate into killer T cells, which play a role in killing virus-infected cells and cancer cells. .
[5] Novel coronavirus (SARS-CoV-2)
A virus that causes a new type of pneumonia that occurred in Wuhan, China at the end of December 2019. It was named “SARS-CoV-2” because it is a sister species to the virus (SARS-CoV) that causes SARS (Severe Acute Respiratory Syndrome). The disease name is COVID-19 ([1]reference).
[6] natural immunity, acquired immunity
Innate immunity is an innate immune system that is responsible for the initial defense against various types of antigens, and acquired immunity recognizes and eliminates specific foreign substances using antibodies and various cellular immune responses.
[7] Artificial adjuvant vector cell (aAVC)
Artificial cells are being researched for cancer immunotherapy. Allogeneic cells (NIH3T3 cells for mice, HEK293 cells for humans) are transfected with mRNA of the CD1d molecule and mRNA of the target antigen molecule, and alpha-galactosylceramide (α-GalCer) is expressed on CD1d. cells. α-GalCer is a glycolipid that activates NKT cells. An adjuvant is something that amplifies the immune response, and a vector is a carrier. aAVC stands for artificial adjuvant vector cells.
[8] acute myeloid leukemia
A disease in which immature cells (immature myeloid cells) in the bone marrow become cancerous and proliferate, occupying the bone marrow, making it impossible to produce normal blood cells, resulting in symptoms of anemia, bleeding, and infection. Chemotherapy and transplantation treatments are usually used.
[9] Major tissue fit complex (MHC)
A glycoprotein that exists on the surface of human cells. It carries antigens (fragments of substances considered foreign to the body, such as bacteria and viruses) that have been processed within the cells, and presents the antigen to immune-competent cells such as T cells. This antigen presentation activates immunocompetent cells and induces an immune response. The gene region that encodes MHC is called the MHC region.
[10] epitope
When T cells, B cells, etc. bind to antigens, they do not recognize the entire antigen, but rather recognize and bind to a relatively small part of the antigen. This site is called an epitope (antigenic determinant) and consists of a sequence of 6 to 10 amino acids and 5 to 8 monosaccharides.
[11] Natural killer T (NKT) cells
A type of innate immune lymphocyte. NKT cells express NK cell markers and one type of T cell receptor, and are core immunoregulatory cells that control allergic diseases, cancer, and autoimmune diseases.
[12] dendritic cells
Dendritic cells are white blood cells with dendrites. They act as cells (antigen-presenting cells) that convey information about foreign substances to naive (mandarin orange) T cells, and play the role of an essential control tower for immune reactions.
[13] WT1
WT1The gene is associated with the development of Wilms tumor, a type of renal malignancy in children, and the WT1 protein encoded by it regulates the transcription of various proliferation-related genes. Expression is observed in various tumors including acute myeloid leukemia.
[14] Non-clinical safety studies, non-clinical pharmacology drug efficacy studies
Non-clinical safety tests are tests that use animal experiments to evaluate whether a drug has any harmful effects on the human body. Non-clinical pharmacology drug efficacy tests are tests that use cells and animal models to confirm the effects and mechanisms of action of drugs. These tests are conducted during the development process of new drugs before human clinical trials begin, and play an important role in confirming the drug’s safety and effectiveness.
[15] memory T cells
T cells are cells that form the core of the adaptive immune system and are found in the blood and tissues. Depending on the molecules present on the cell surface, cells are broadly classified into two types: CD4-positive T cells and CD8-positive T cells. CD4-positive T cells have functions such as activating other immune cells when they recognize antigens, and are also called CD4-positive helper T cells. On the other hand, CD8-positive T cells are also called CD8-positive killer T cells because they have the ability to directly kill other cells. T cells that have been sensitized to antigens proliferate and become activated, and then some become memory immunized and acquire the ability to respond quickly when exposed to the antigen next time. These are called memory T cells.
[16] memory immunity
A type of immune response in which the structure of the antibody against a specific antigen is maintained, and a strong immune response can be generated against the second invasion of the antigen.
joint research team
RIKEN Center for Biomedical Sciences, Immune Cell Therapy Research Team
Team leader Shinichiro Fujii
(aAVC Drug Discovery Bridging Platform Unit, Platform Unit Leader,
Cutting Edge Research Platform Collaboration (TRIP) Business Headquarters Drug Discovery and Medical Technology Infrastructure Program
Deputy Program Director/Project Leader)
Kagawa University School of Medicine Hematology, Immunology, and Respiratory Medicine
Professor Norimitsu Kadowaki
(Director of Kagawa University Hospital)
research support
This research was conducted by RIKEN (DMP) and is part of the Strategic Center of Biomedical Advanced Vaccine Research and Development for Preparedness and Response (SCARDA) within the Japan Agency for Medical Research and Development (AMED). We received a grant from the Vaccine/New Modality Research and Development Project “Development of infectious disease vaccines using artificial adjuvant vector cell (aAVC) technology, a new vaccine model with multifunctional immunity induction (research representative: Shinichiro Fujii)”. Ta.
Presenter/Institutional Contact
*Please contact the presenter regarding the research content.
RIKEN Center for Biomedical Sciences, Immune Cell Therapy Research Team
Team leader Shinichiro Fujii
(Advanced Research Platform Collaboration (TRIP) Business Headquarters
Drug Discovery/Medical Technology Infrastructure Program Deputy Program Director/Project Leader)
Tel: 045-503-7063 Fax: 045-503-7061
Email: shin-ichiro.fujii [at] riken.jp
Kagawa University School of Medicine Hematology, Immunology, and Respiratory Medicine
Professor Norimitsu Kadowaki
(Director of Kagawa University Hospital)
RIKEN Public Relations Office Press Office
Tel: 050-3495-0247 Email: ex-press [at] ml.riken.jp
Kagawa University Hospital Clinical Research Support Center
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