This project is to assess the immunogenicity, safety and overall survival impact of intramuscular injection of trivalent influenza vaccine in non-small cell lung cancer (NSCLC) patients with PD-1/PD-L1 inhibitor treatment.
Lung cancer is one of the most prevalent cancers in the world. Among them, non-small cell lung cancer (NSCLC) accounts for about 85%. Immune checkpoint inhibitors such as programmed death 1(PD-1) and PD-L1 are new treatments for NSCLC. About 290,000 to 650,000 people die from respiratory illnesses caused by seasonal flu all over the world. Cancer patients are one of the high-risk groups of influenza. Although the United States, Britain, Australia have issued guidelines recommending that cancer patients be vaccinated against influenza every year, due to concerns about the immune effect and safety of flu vaccination for cancer patients, multiple countries including China have not included cancer patients into priority influenza vaccination populations. Therefore, how to further prove the immunogenicity and safety of influenza vaccine in NSCLC patients is the key to promote influenza vaccines in NSCLC patients. This study will recruit 130 patients with NSCLC who have been treated with PD-1 / PD-L1 inhibitors for 6 months or more and 30 healthy participants. Among them, 100 NSCLC patients and 30 healthy participants will be intramuscularly inactivated with a trivalent influenza vaccine during the influenza seasons 2020-21 and 2021-22. Vaccinated participants' peripheral blood samples were collected at day0, 12 hours, day1, 2, 7, 21, 30, 60 and 6 months after vaccination. The influenza specific antibody titers, inflammatory chemokines and cytokines, antibody-dependent cellular cytotoxicity (ADCC) activity, T lymphocytes activity and the proportions of different T cells subgroups will be measured to evaluate the participants' immune response to the vaccine. In addition, for the subjects receiving the vaccine, the study will also group by age to compare the differences in immune effects between subjects aged 18-65 and subjects over 65. At last, this project will compare immune-related adverse events (irAEs) that occurred after receiving PD-1 / PD-L1 inhibitor therapy and survival time between NSCLC patients who receive influenza vaccine and those who do not receive influenza vaccine.
Study Type
OBSERVATIONAL
Enrollment
160
Including nivolumab, pembrolizumab, atezolizumab, and durvalumab, et al.
Including two type A viruses, H1N1 and H3N2, and one type B virus, B/Brisbane.
School of Public Health, Li Ka Shing Faculty of Medicine, University of Hong Kong
Hong Kong, Hong Kong, China
Shanghai Pulmonary Hospital
Shanghai, Shanghai Municipality, China
Titers of anti-nucleoprotein(NP) or anti-hemagglutinin(HA) antibody (IgG and IgM)
The titers of anti-HA IgG and IgM antibodies ,and anti-NP IgG and IgM antibodies are measured by enzyme linked immunosorbent assay (ELISA).
Time frame: Day 0 after vaccination
Titers of anti-nucleoprotein(NP) or anti-hemagglutinin(HA) antibody (IgG and IgM)
The titers of anti-HA IgG and IgM antibodies ,and anti-NP IgG and IgM antibodies are measured by enzyme linked immunosorbent assay (ELISA).
Time frame: Day 2 after vaccination
Titers of anti-nucleoprotein(NP) or anti-hemagglutinin(HA) antibody (IgG and IgM)
The titers of anti-HA IgG and IgM antibodies ,and anti-NP IgG and IgM antibodies are measured by enzyme linked immunosorbent assay (ELISA).
Time frame: Day 7 after vaccination
Titers of anti-nucleoprotein(NP) or anti-hemagglutinin(HA) antibody (IgG and IgM)
The titers of anti-HA IgG and IgM antibodies ,and anti-NP IgG and IgM antibodies are measured by enzyme linked immunosorbent assay (ELISA).
Time frame: Day 21 after vaccination
Titers of anti-nucleoprotein(NP) or anti-hemagglutinin(HA) antibody (IgG and IgM)
The titers of anti-HA IgG and IgM antibodies ,and anti-NP IgG and IgM antibodies are measured by enzyme linked immunosorbent assay (ELISA).
Time frame: Day 30 after vaccination
Titer of neutralization antibody
Titer of neutralization antibody is measured by neutralization test.
Time frame: Day 0 after vaccination
Titer of neutralization antibody
Titer of neutralization antibody is measured by neutralization test.
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Time frame: Day 21 after vaccination
Titer of neutralization antibody
Titer of neutralization antibody is measured by neutralization test.
Time frame: Day 30 after vaccination
Titer of neutralization antibody
Titer of neutralization antibody is measured by neutralization test.
Time frame: Day 60 after vaccination
Titer of neutralization antibody
Titer of neutralization antibody is measured by neutralization test.
Time frame: Month 6 after vaccination
Multiple chemokine and cytokine levels in peripheral blood
IFN-γ, IL-1β, IL-2,IL-3,IL-4,IL-5,IL-6,IL-8 (CXCL8),IL-9,IL-10,IL-11,IL-12,IL-13,GM-CSF,TNF-α, IP-10 (CXCL10), MCP-1 (CCL2), and TARC (CCL17) in peripheral blood are measured by cytometry bead assay.
Time frame: Day 0 after vaccination
Multiple chemokine and cytokine levels in peripheral blood
IFN-γ, IL-1β, IL-2,IL-3,IL-4,IL-5,IL-6,IL-8 (CXCL8),IL-9,IL-10,IL-11,IL-12,IL-13,GM-CSF,TNF-α, IP-10 (CXCL10), MCP-1 (CCL2), and TARC (CCL17) in peripheral blood are measured by cytometry bead assay.
Time frame: 12 hours after vaccination
Multiple chemokine and cytokine levels in peripheral blood
IFN-γ, IL-1β, IL-2,IL-3,IL-4,IL-5,IL-6,IL-8 (CXCL8),IL-9,IL-10,IL-11,IL-12,IL-13,GM-CSF,TNF-α, IP-10 (CXCL10), MCP-1 (CCL2), and TARC (CCL17) in peripheral blood are measured by cytometry bead assay.
Time frame: Day 1 after vaccination
Multiple chemokine and cytokine levels in peripheral blood
IFN-γ, IL-1β, IL-2,IL-3,IL-4,IL-5,IL-6,IL-8 (CXCL8),IL-9,IL-10,IL-11,IL-12,IL-13,GM-CSF,TNF-α, IP-10 (CXCL10), MCP-1 (CCL2), and TARC (CCL17) in peripheral blood are measured by cytometry bead assay.
Time frame: Day 2 after vaccination
The numbers and proportions of T lymphocyte subpopulations in peripheral blood
The numbers and proportions of CD4+ T cells, CD8+ T cells, naïve T cells and effector memory T cells in peripheral blood are measured by multiple flow cytometry.
Time frame: Day 0 after vaccination
The numbers and proportions of T lymphocyte subpopulations in peripheral blood
The numbers and proportions of CD4+ T cells, CD8+ T cells, naïve T cells and effector memory T cells in peripheral blood are measured by multiple flow cytometry.
Time frame: 12 hours after vaccination
The numbers and proportions of T lymphocyte subpopulations in peripheral blood
The numbers and proportions of CD4+ T cells, CD8+ T cells, naïve T cells and effector memory T cells in peripheral blood are measured by multiple flow cytometry.
Time frame: Day 1 after vaccination
The numbers and proportions of T lymphocyte subpopulations in peripheral blood
The numbers and proportions of CD4+ T cells, CD8+ T cells, naïve T cells and effector memory T cells in peripheral blood are measured by multiple flow cytometry.
Time frame: Day 2 after vaccination
The numbers and proportions of T lymphocyte subpopulations in peripheral blood
The numbers and proportions of CD4+ T cells, CD8+ T cells, naïve T cells and effector memory T cells in peripheral blood are measured by multiple flow cytometry.
Time frame: Day 7 after vaccination
The numbers and proportions of T lymphocyte subpopulations in peripheral blood
The numbers and proportions of CD4+ T cells, CD8+ T cells, naïve T cells and effector memory T cells in peripheral blood are measured by multiple flow cytometry.
Time frame: Day 21 after vaccination
The numbers and proportions of T lymphocyte subpopulations in peripheral blood
The numbers and proportions of CD4+ T cells, CD8+ T cells, naïve T cells and effector memory T cells in peripheral blood are measured by multiple flow cytometry.
Time frame: Day 30 after vaccination
The numbers and proportions of T lymphocyte subpopulations in peripheral blood
The numbers and proportions of CD4+ T cells, CD8+ T cells, naïve T cells and effector memory T cells in peripheral blood are measured by multiple flow cytometry.
Time frame: Day 60 after vaccination
The numbers and proportions of T lymphocyte subpopulations in peripheral blood
The numbers and proportions of CD4+ T cells, CD8+ T cells, naïve T cells and effector memory T cells in peripheral blood are measured by multiple flow cytometry.
Time frame: Month 6 after vaccination
Peripheral T cell activation and proliferation
The CD3, CD4, CD8 and CD69 expressions and cell count of peripheral T cells are measured by multiple flow cytometry upon carboxyfluorescein succinimidyl amino ester (CFSE) labeling and anti-CD3/28 beads activation.
Time frame: Day 0 after vaccination
Peripheral T cell activation and proliferation
The CD3, CD4, CD8 and CD69 expressions and cell count of peripheral T cells are measured by multiple flow cytometry upon carboxyfluorescein succinimidyl amino ester (CFSE) labeling and anti-CD3/28 beads activation.
Time frame: Day 30 after vaccination
Peripheral T cell activation and proliferation
The CD3, CD4, CD8 and CD69 expressions and cell count of peripheral T cells are measured by multiple flow cytometry upon carboxyfluorescein succinimidyl amino ester (CFSE) labeling and anti-CD3/28 beads activation.
Time frame: Day 60 after vaccination
Peripheral T cell activation and proliferation
The CD3, CD4, CD8 and CD69 expressions and cell count of peripheral T cells are measured by multiple flow cytometry upon carboxyfluorescein succinimidyl amino ester (CFSE) labeling and anti-CD3/28 beads activation.
Time frame: Month 6 after vaccination
Antibody-dependent cellular cytotoxicity (ADCC)
The ADCC activities of NK-92 cells cultured by the sera from vaccinated participants are measured by lactic acid dehydrogenase (LDH) release of A549 cells infected by H1N1 and H3N2.
Time frame: Day 0 after vaccination
Antibody-dependent cellular cytotoxicity (ADCC)
The ADCC activities of NK-92 cells cultured by the sera collected from vaccinated participants are measured by lactic acid dehydrogenase (LDH) release of A549 cells infected by H1N1 and H3N2.
Time frame: Day 30 after vaccination
Antibody-dependent cellular cytotoxicity (ADCC)
The ADCC activities of NK-92 cells cultured by the sera collected from vaccinated participants are measured by lactic acid dehydrogenase (LDH) release of A549 cells infected by H1N1 and H3N2.
Time frame: Day 60 after vaccination
Antibody-dependent cellular cytotoxicity (ADCC)
The ADCC activities of NK-92 cells cultured by the sera collected from vaccinated participants are measured by lactic acid dehydrogenase (LDH) release of A549 cells infected by H1N1 and H3N2.
Time frame: Month 6 after vaccination
Immune-related adverse events (irAEs)
The performances and the grades of irAEs according to Common Terminology Criteria for Adverse Events 5.0 (CTCAE 5.0) and their correlation with vaccination.
Time frame: June 2020- June 2023
Progression-free Survival (PFS)
PFS is calculated as the time from from PD-1/PD-L1 inhibitor starting to the disease progression or the death from any cause.
Time frame: June 2020- June 2023 (3 year)
Overall Survival (OS)
OS is calculated as the time from PD-1/PD-L1 inhibitor starting to the death from any cause.
Time frame: June 2020- June 2023 (3 year)
Objective Response Rate (ORR)
The proportion of patients whose tumors have shrunk to a certain amount and maintained for a certain period of time, including cases of complete response (CR) and partial response (PR) according to Response Evaluation Criteria In Solid Tumors 1.1 (RECIST 1.1).
Time frame: June 2020- June 2023 (3 year)
Disease Control Rate (DCR)
The proportion of patients achieve CR or PR or stable disease (SD) after PD-1/PD-L1 inhibitor treatment according to RECIST 1.1.
Time frame: June 2020- June 2023 (3 year)
Time to Treatment Failure (TFF)
The time from the start of PD-1/PD-L1 inhibitor to the withdrawal of the trial. The reasons for withdrawal include the patient's voluntary withdrawal, disease progression, adverse events and even deaths.
Time frame: June 2020- June 2023 (3 year)