The Role of B7-H4 in Tumor Vaccine

The Role and Mechanism of B7-H4/ATF3 Axis From Glioma Associated Macrophages in Treatment Resistance of Cancer Vaccine

Glioma patients have poor prognosis because of limited choices of treatment. Therapeutic cancer vaccines have been proved to improve survival in glioma, but resistance is a new challenge for vaccine treatment, and the mechanism is unclear. The applicant found in previous papers that glioma cells induced B7-H4 overexpression in macrophages, and the expression level of B7-H4 is highly correlated with vaccine resistance. Preliminary experiments indicated that B7-H4 protein in macrophages inhibited the expression of ATF3, STAT1 and CXCL9/10, which also resulted in decreased T cell infiltration in glioma model of mouse and was a negative factor of vaccine benefits. Therefore, the applicant hypothesize that B7-H4 inhibits STAT1 transcription by reducing expression of ATF3, resulting in decreased phosphorylated-STAT1 in nucleus, which inhibiting expression and secretion of chemokines 9/10. Thereby, reduced infiltration of T cells in microenvironment will be followed, which ultimately promotes resistance of vaccine treatment in glioma. The follow-up plan of this project will be conducted based on the cells, organoid platform and animal experiments to confirm the role and mechanism of macrophage-derived B7-H4 in secretion of chemokines for T cells and treatment resistance of vaccines. Moreover, the DC vaccine produced by team of the applicant will be used to assess the probability of reversing vaccine resistance when intervening B7-H4 axis. Finally, a model for evaluating clinical benefits from vaccine will be established based on data from clinical trials combining with expression of B7-H4 and clinicopathologic features. This study will provide new evidences for the treatment of cancer vaccines in gliomas.

Study Overview

• Status: Recruiting
• Conditions: Glioma
• Intervention / Treatment: Biological: tumor vaccine

• Study Type: Observational
• Enrollment (Estimated): 160

Contacts and Locations

Study Locations

• China
  • Shanghai
    • Shanghai, Shanghai, China, 200040
      • Recruiting
      • Di Chen
      • Contact: Di Chen, MD; Phone Number: 54602851; Email: dichen18@fudan.edu.cn
      • Principal Investigator: Di Chen, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Patients undergoing glioma surgery at Huashan Hospital

Description

Inclusion Criteria:

Inclusion Criteria:

The patients with glioma in the Department of Neurosurgery of Huashan Hospital Affiliated to Fudan University who meet the following three conditions can be enrolled

1. They were 18-80 years old, male and female;
2. The pathological results of frozen section during operation were gliomas;
3. Tissue (6 mm * 6 mm) can be used for cell sorting on the basis of not affecting clinical routine diagnosis;
4. Sign informed consent.

Exclusion Criteria:

Patients who meet any of the following criteria will not be included in this study:

1. Participants in other clinical trials;
2. Pregnant women.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
glioma patients receiving conventional treatment; surgery+radiotherapy+chemotherapy
glioma patients with tumor vaccine; surgery+radiotherapy+chemotherapy+tumor vaccine	Biological: tumor vaccine; DC vaccine produced by the Team

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
IHC analysis	Different expression level of proteins (CD3,CD8,B7-H4 et.ac) in Gliomas with different grades and molecular subgroups (100 cases) will be measured using immunohistochemical.	36 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Transcriptomics	The issues collected will be used for transcriptome sequencing to measure gene expression level.	36 months
Immunomics	The issues collected will be used for TCR/BCR sequencing to measure clonality of lymphocytes	36 months
Radiomics	The features from images will be extracted using algorithm of Deep-learning or Radiomics	36 months
Genomics	The issues collected will be used for whole genome sequencing or whole exome sequencing to measure gene mutations.	36 months
Proteomics	The issues collected will be used for proteomic sequencing to measure gene expression level in protein	36 months

Collaborators and Investigators

• Sponsor: Huashan Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): November 26, 2023
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: November 26, 2023
• First Submitted That Met QC Criteria: November 26, 2023
• First Posted (Estimated): December 5, 2023

Study Record Updates

• Last Update Posted (Estimated): December 5, 2023
• Last Update Submitted That Met QC Criteria: November 26, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: immunotherapy; glioma; cancer vaccine; macrophage; treatment resistance
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioma
• Other Study ID Numbers: KY2023-997; 8230162487 (Other Grant/Funding Number: The National Natural Science Foundation of China)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No