Immunogene-modified T (IgT) Cells Against Glioblastoma Multiforme

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

This study aims to treat patients who have been diagnosed with brain cancer including glioblastoma multiforme (GBM). 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 antigen-specific T cells. Thus, in this study, the gene-modified T cells specific for GBM antigens will be combined with immune modulatory genes to treat patients in dose escalation cohorts.

Study Overview

• Status: Enrolling by invitation
• Conditions: Glioblastoma Multiforme; Glioblastoma Multiforme of Brain
• Intervention / Treatment: Biological: Antigen-specific IgT cells

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 CD19+ B cell malignancies, and thus the CAR-T therapy approach is considered a promising treatment against GBM. Certain antigens are highly specific in GBM, such as epidermal growth factor receptor variant iii, EGFRviii. EGFRviii is a variant form of EGFR protein, and one of the potential target antigens in GBM. Alternative antigens such as GD2 and MucI have also been targeted as potential GBM antigens.

Tumor microenvironment is known to suppressive anti-cancer immune responses. Many immune checkpoint inhibitors have demonstrated marked anti-tumor activities. Instead of infusing antibodies, this study aims to infuse antigen-specific T cells modified with immune modulatory genes (IgT) such as genes encoding immune checkpoint inhibitors. Combination of tumor targeting and immune modulatory activities, the IgT cells could target both the tumor cells and the tumor microenvironment.

• Study Type: Interventional
• Enrollment (Anticipated): 20
• Phase: Phase 1

Contacts and Locations

Study Locations

• China
  • Guangdong
    • Shenzhen, Guangdong, China, 518000
      • Shenzhen Geno-Immune Medical Institute
    • Shenzhen, Guangdong, China, 518100
      • ShenZhen People's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 80 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. abilities to understand and the willingness to provide written informed consent;
2. patients are ≥ 1 and ≤ 80 years old;
3. 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;
4. Malignant cells are target antigen positive confirmed by immunostaining, quantitative PCR or sequencing;
5. karnofsky performance score (KPS) ≥ 60;
6. life expectancy >3 months;
7. 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;
8. peripheral blood absolute lymphocyte count must be above 0.8×10^9/L;
9. satisfactory heart functions;
10. patients must be willing to follow the orders of doctors;
11. 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:

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Antigen-specific IgT cells; Patients will receive non-myeloablative chemotherapy consisting of fludarabine and/or cyclophosphamide, followed by intravenous infusion of autologous IgT cells. A standard 3+3 escalation approach will be used to obtain the safe dosage of IgT cells. The tested IgT cell dosage ranges from 0.5×10^5 /kg to 2.5×10^7 /kg	Biological: Antigen-specific IgT cells; Tumor antigen-specific IgT cells are infused intravenously or directly to the tumor location of the patients in a three-day split-dose regimen（day 0,10%; day1, 30%; day2, 60%）to complete a total targeted dose. Drug: cyclophosphamide 250 mg/m^2 d1-3; Drug: Fludarabine 25mg/m^2 d1-3

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	incidents of treatment related adverse events as assessed by CTCAE V4.0.	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treatment response rate of recurrent glioblastoma	Defined as the proportion of patients who achieved complete remission (CR), partial remission (PR), stable disease (SD), or progressive disease (PD).	6 months
Overall survival Rate	Percentage of participants with objective response as determined by the investigator based on Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1)	2 years
Progression-free survival rate	Progression-free Survival (PFS) as determined by the investigator based on RECIST v1.1	2 years
Persistence and proliferation of IgT cells in patients	IgT cell percentage in the peripheral blood by flow cytometry or qPCR	2 years
Production of specific immune check point modulatory proteins	Specific immune modulators in peripheral blood will be measured by ELISA	2 years

Collaborators and Investigators

• Sponsor: Shenzhen Geno-Immune Medical Institute

Study record dates

Study Major Dates

• Study Start (Actual): May 31, 2020
• Primary Completion (Actual): August 1, 2020
• Study Completion (Anticipated): December 31, 2023

Study Registration Dates

• First Submitted: May 25, 2017
• First Submitted That Met QC Criteria: May 25, 2017
• First Posted (Actual): May 30, 2017

Study Record Updates

• Last Update Posted (Estimate): January 16, 2023
• Last Update Submitted That Met QC Criteria: January 13, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Keywords: Gene Therapy; GBM; PD-L1; PD1; CAR T
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma
• Other Study ID Numbers: GIMI-IRB-17003

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

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