Tris-CAR-T Cell Therapy for Recurrent Glioblastoma

Recurrent Glioblastoma Clinical Trial

Official title: Phase 1 Study of Autologous Tris-CAR-T Cell Locoregional Immunotherapy for Recurrent Glioblastoma

Status Recruiting

Clinical Trial Summary

This is a Phase 1 study of recurrent glioblastoma locoregional adoptive therapy with autologous peripheral blood T cells lentivirally transduced to express a dual-target, truncated IL7Ra modified chimeric antigen receptor (CAR), delivered by Ommaya reservoir, a pre-indwelled catheter in the tumor resection cavity or ventricle. Patients with pathological confirmation of glioblastoma and radiological evidence of recurrence are candidates for this clinical trial. If the patient meets all other eligibility criteria, and meets none of the exclusion criteria, will have leukapheresis, and a subsequent Ommaya reservoir implantation. T cells will be isolated from the PBMC sample and then be bioengineered into a 4th generation CAR-T cell, Tris-CAR-T cells.

Recipients will be assigned to three courses in the order of enrollment. The first 2 patients will be assigned to the low-dose group. The second 2 patients will be assigned to the high dose group. The first 4 patients will have at least one dose of autologous Tris-CAR-T cells delivery via the Ommaya reservoir, at a maximum of 6 doses. The interval between the first and the second dose is 28 days, and the rest doses will be administered weekly. The last 6 patients will be assigned to the consecutive multidose group, and will receive a weekly dose of autologous Tris-CAR-T cells for a maximum of 8 weeks. All patients will undergo studies including MRI to evaluate the effect of the CAR-T cells, physical examination, and cerebrospinal fluid cytokine assays to evaluate side effects. All patients will undergo a long-term follow-up.

The hypothesis is that an adequate amount of Tris-CAR-T cells can be manufactured to complete all the three courses. The other hypothesis is that Tris-CAR-T cells can safely and effectively be administered through the Ommaya reservoir to allow the CAR-T cells to directly interact with the tumor cells for each patient enrolled in the study. The primary aim of the study will be to evaluate the safety of Tris-CAR-T administration. Secondary aims of the study will include evaluating CAR-T cell distribution within cerebrospinal fluid and peripheral blood, tumor progress post-CAR-T cell infusion, and, if tissue samples from multiple time points are available, also evaluate the degree of target expression, biological characteristics of samples at diagnosis versus at recurrence or progression.

Clinical Trial Description

The autologous Tris-CAR-T cell, targeting both CD44 and CD133, the two inverse correlated targets, introduced truncated IL7Ra to the intracellular domain of the CAR molecule, and has shown ideal survival and tumor suppression in our previous studies. The cells will be tested for safety and kinetics in this clinical trial.

All patients are required to have an Ommaya reservoir in the tumor resection cavity before CAR-T cell infusion. Ommaya reservoir placement is done by surgery.

Autologous Tris-CAR-T cells will be manufactured via CliniMACS Instrument (Miltenyi Biotec). Cells will be thawed and sterily filled to infuse the patients. Each infusion will take between 5 and 10 minutes. We will then monitor the patient in the hospital for at least 3 days after the first dose of infusion. If the first infusion is tolerated well and the patient is assigned for multidose treatment, a second infusion may be given 28 days after the initial infusion for the first 4 patients (adverse effect assessment), and 7 days for the last 6 patients. Patients will be monitored in the hospital for no longer than 1 day. And the subsequent infusion will be done in the same manner. The treatment will be proceeded in the Department of Neurosurgery, Beijing Tiantan Hospital. Patients who receive multidose treatment will need to stay in Beijing for up to 8 weeks from the first infusion so we can monitor for side effects and will be readmitted to the hospital if patient develops a fever. If patient develops severe fevers after discharge from the hospital, the patient will be readmitted to the hospital for close monitoring for at least one night for safety observation and adverse effects management.

The first 4 patients will have follow-up visits at weeks 2, 3, and 4, then at months 3, 6, and 9 post-infusion. Patients of the consecutive multidose group will have follow-up visits at week 2, then at months 1 and 3 post-infusion. All patients receive long-term twice a year for a total of 15 years.

Medical tests before treatment--

Before being treated, the patient will receive a series of standard medical tests:

• Physical exam

• Blood routine, serum biochemical test, kidney and liver function

• Measurements of the tumor by routine MRI

Medical tests during and after treatment--

The patient will receive standard medical tests when they are getting the infusions and afterward:

• Physical exams

• Blood routine, serum biochemical test, kidney and liver function, serum and (or) cerebrospinal fluid analysis

• Measurements of the tumor by MRI. Cerebrospinal fluid may be drawn from the patient's existing Ommaya reservoir preferentially, or via lumbar puncture before each infusion and at each time of follow-up. This procedure can be done at the bedside under local anesthesia and about 1ml of cerebrospinal fluid will be removed. Additional cerebrospinal fluid may be removed when intracranial hypertension occurs or other clinical needs.

To learn more about the pharmacokinetics of autologous Tris-CAR-T cells, peripheral blood will be obtained simultaneously with the cerebrospinal fluid collection. The amount of blood taken will be based on clinical need, for approximately 5 mL each time.

If the tumor samples of the patients are obtained, we will request a sample to be used for research purposes.

The patient will receive supportive care for any acute or chronic cytotoxicity, including blood components, cytokine antagonists, glucocorticoids, antibiotics, and other interventions as appropriate. ;

Related Conditions & MeSH terms

• Glioblastoma
• Recurrence
• Recurrent Glioblastoma

• NCT number: NCT05577091
• Study type: Interventional
• Source: Beijing Tiantan Hospital
• Contact: Wei Zhang, Prof.
• Phone: +861059976686
• Email: zhangwei02@bjtth.org
• Status: Recruiting
• Phase: Phase 1
• Start date: September 30, 2023
• Completion date: November 1, 2032