Neoplasms

All Conditions

Rare Diseases

Glioma

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Neuroepithelioma

All Drugs and Chemicals

Vaccines

Immunomodulating Agents

surgery+radiotherapy+chemotherapy+tumor vaccine

tumor vaccine

Di Chen, MD

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.

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

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.

The issues collected will be used for transcriptome sequencing to measure gene expression level.

The issues collected will be used for TCR/BCR sequencing to measure clonality of lymphocytes

The issues collected will be used for proteomic sequencing to measure gene expression level in protein

The features from images will be extracted using algorithm of Deep-learning or Radiomics

The issues collected will be used for whole genome sequencing or whole exome sequencing to measure gene mutations.

Huashan Hospital

Professor

Carcinoma

Carcinoma, Squamous Cell

Head and Neck Neoplasms

Squamous Cell Carcinoma of Head and Neck

Neoplasms, Squamous Cell

Anti-Infective Agents

Micronutrients

Hematinics

Vitamins

Pyrimethamine

Antimalarials

Antiprotozoal Agents

Antiparasitic Agents

Folic Acid

Vitamin B Complex

Folic Acid Antagonists

Enzyme Inhibitors

Folinic Acid

Folate

Vitamin B9

Pyrimethamine will be taken by mouth at a dose of 50 mg once daily for 14 days (+/-2 days) with the last dose the day prior to surgery.

Patients will be instructed to take their dose at approximately the same time each day.

Paul Zolkind, M.D.

Ben Major, Ph.D.

Douglas Adkins, M.D.

Sidharth Puram, M.D., Ph.D.

Ryan Jackson, M.D.

Patrik Pipkorn, M.D., MSCI

Jason Rich, M.D.

Randal Paniello, M.D., Ph.D.

Wade Thorstad, M.D.

Hiram Gay, M.D.

Esther Lu, M.S., Ph.D.

Peter Oppelt, M.D.

NRF2 activation, observed in up to 40% of head and neck squamous cell carcinoma (HNSCC) tumors, plays a critical role in tumor progression, metastasis, and radiation therapy resistance. The investigators have recently discovered that pyrimethamine (PYR) and its analogs have an inhibitory effect on NRF2 activity in vitro and in mouse models via inhibition of dihydrofolate reductase (DHFR).

Pyrimethamine is an established drug that has been used for decades for treatment of protozoan infections and malaria. A growing body of research shows that it has potential antitumor activity, however its activity on growing human tumors has not been previously studied. The primary efficacy goal of this study is to evaluate the activity of pyrimethamine on human tumors as demonstrated by inhibition of DHFR and downregulation of NRF2 pathway activity. On-target inhibition of DHFR by pyrimethamine results in the stabilization and increased protein expression of human DHFR.

The primary efficacy hypothesis of this study is that treatment with pyrimethamine will result in a 50% increase in DHFR protein within the tumor cells as measured by quantitative western blot analysis. Secondarily, among those tumors classified as NRF2-active on pre-treatment biopsy, the investigators hypothesize there will be a 50% reduction in NRF2 activity as measured by SureQuant targeted proteomic analysis.

Pyrimethamine as an Inhibitor of NRF2 in HPV-unrelated Locally Advanced Head and Neck Squamous Cell Carcinoma

Early Phase I Window of Opportunity Biomarker and Safety Trial to Test Pyrimethamine as an Inhibitor of NRF2 in HPV-unrelated, Locally Advanced Head and Neck Squamous Cell Carcinoma

Tilde Sciences

Washington University School of Medicine

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
The Role of B7-H4 in Tumor Vaccine	NCT06156150	Glioma	tumor vaccine	18 Years - 80 Years	Huashan Hospital
Pyrimethamine as an Inhibitor of NRF2 in HPV-unrelated Locally Advanced Head and Neck Squamous Cell Carcinoma	NCT05678348	Head and Neck C... Cancer of the H...	Pyrimethamine	18 Years -	Washington University School of Medicine

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