Immunogene-modified T (IgT) Cells Against Glioblastoma Multiforme

Official title

Immunogene-modified Antigen-specific T (IgT) Cells for the Treatment of Glioblastoma Multiforme

Overview

This study aims to treat patients who have been diagnosed with brain cancer glioblastoma multiforme (GBM) including diffuse intrinsic pontine glioma (DIPG) and diffuse midline glioma (DMG). The treatment combines two different approaches to fight cancer: immune modulators and antigen-specific T cells. Immune checkpoint antibodies have been tested on various tumors with good outcomes. GBM is known to express increased levels of certain antigens that can be targeted by T cells including chimeric antigen receptor-modified T (CAR-T) cells and tumor antigen specific cytotoxic lymphocytes (CTLs). In this study, the gene-modified T cells specific for GBM antigens will be combined with immune modulatory gene-modified dendritic cells (DCs) as individualized treatment regimens to treat patients.

Detailed description

Background:

Glioblastoma multiforme (GBM) is the most dangerous and aggressive form of brain cancer. Chimeric antigen receptor (CAR)-modified T cells have been shown to mediate long-term durable remissions in recurrent or refractory hematopoietic malignancies, and thus the CAR-T therapy approach is also considered a promising treatment against GBM. Some surface antigens such as GD2 and CD56 have been targeted as potential GBM antigens. In addition, certain antigens are highly specific in GBM, such as epidermal growth factor receptor variant EGFRviii and metastasis related antigen CD44v6.

Tumor microenvironment is known to suppressive anti-cancer immune responses. Many immune checkpoint inhibitors have demonstrated marked anti-tumor activities. For example, CD276 is a member of the B7 family of immune checkpoint proteins, and CD276-specific CAR-T cell therapy have been considered a potential brain tumor microenvironment treatment. Besides immune checkpoint inhibitor antibodies, antigen-specific T cells modified with immune modulatory genes (IgT) such as genes encoding immune checkpoint inhibitors may be applied. Combination of tumor targeting and immune modulatory activities, the IgT cells could target both the tumor cells and the tumor microenvironment.

Interventions

• Biological Antigen-specific IgT cells
  Tumor antigen-specific IgT cells are infused intravenously . Drug: cyclophosphamide 250 mg/m\^2 d1-3; Drug: Fludarabine 25mg/m\^2 d1-3

Primary outcome measures

• Safety of infusion of autologous IgT cells with cyclophosphamide and fludarabine as lymphodepleting chemotherapy in patients with recurrent glioblastoma using the NCI CTCAE V4.0 criteria. [Time frame: 1 years]

Secondary outcome measures (4)

• Treatment response rate of recurrent glioblastoma [Time frame: 6 months]
• Overall survival Rate [Time frame: 2 years]
• Progression-free survival rate [Time frame: 2 years]
• Persistence and proliferation of IgT cells in patients [Time frame: 2 years]

Eligibility criteria

Inclusion criteria

• abilities to understand and the willingness to provide written informed consent;
• patients are ≥ 6 and ≤ 70 years old;
• recurrent glioblastoma or brain tumor patients with measurable tumors. Patients have received standard care of medication, such as gross total resection with concurrent radio-chemotherapy (\~54 - 60 Gy, TMZ). Patients must either not be receiving dexamethasone or receiving ≤ 4 mg/day at the time of leukopheresis;
• karnofsky performance score (KPS) ≥ 60;
• life expectancy >3 months;
• satisfactory bone marrow, liver and kidney functions as defined by the following: absolute neutrophile count ≥ 1500/mm\^3; hemoglobin > 10 g/dL; platelets > 100000 /mm\^3; Bilirubin < 1.5×ULN; alanine aminotransferase (ALT) or aspartate aminotransferase (AST) < 2.5×ULN; creatinine < 1.5×ULN;
• peripheral blood absolute lymphocyte count must be above 0.8×10\^9/L;
• satisfactory heart functions;
• patients must be willing to follow the instructions of doctors;
• women of reproductive potential (between 15 and 49 years old) must have a negative pregnancy test within 7 days of study start. Male and female patients of reproductive potential must agree to use birth control during the study and 3 months post study.

Exclusion criteria

• a prior history of gliadel implantation 4 weeks before this study start or currently receiving antibody based therapies;
• HIV positive;
• tuberculosis infection not under control;
• history of autoimmune disease, or other diseases require long-term administration of steroids or immunosuppressive therapies;
• history of allergic disease, or allergy to immune cells or study product excipients;
• patients already enrolled in other immune cell clinical study;
• patients, in the opinion of investigators, may not be eligible or not able to comply with the study.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Shenzhen Geno-immune Medical Institute — Shenzhen

Publications

• Liu Z, Zhou J, Yang X, Liu Y, Zou C, Lv W, Chen C, Cheng KK, Chen T, Chang LJ, Wu D, Mao J. Safety and antitumor activity of GD2-Specific 4SCAR-T cells in patients with glioblastoma. Mol Cancer. 2023 Jan 9;22(1):3. doi: 10.1186/s12943-022-01711-9. PMID 36617554

Identifiers

NCT: NCT03170141 · GIMI-IRB-17003

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗