Tris-CAR-T Cell Therapy for Recurrent Glioblastoma

NCT05577091 | Recruiting Phase 1 DMC

• 1 other identifier: TTSW2021-01
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Recurrent Glioblastoma

Keywords

Recurrent Glioblastoma; Immunotherapy; Adverse Events

Outcome Measures

Primary Outcomes (1)

• Safety: any adverse events associated with one or multiple autologous Tris-CAR-T cell infusions will be assessed by CTCAE v5.0.

  Assesing the type, frequency, severity, and duration of adverse events as a result of autologous Tris-CAR-T cell infusion via physical, laboratory and imaging examination.

  6 months

Secondary Outcomes (3)

• CAR-T pharmacokinetics: the distribution, persistence of autologous Tris-CAR-T cell in the cerebrospinal fluid (CSF) and peripheral blood will be measured by qPCR.

  6 months

• CAR-T pharmacodynamics: chemokines and cytokines produced by autologous Tris-CAR-T cell in the cerebrospinal fluid (CSF) and peripheral blood will be measured by Olink Proteomics.

  6 months

• CAR-T therapeutic effect evaluation: the therapeutic effect of autologous Tris-CAR-T cell will be assessed by iRANO.

  12 months

Study Arms (1)

Autologous Tris-CAR-T cell

EXPERIMENTAL

Patients with supratentorial tumors for which CAR T cells will be delivered into the tumor resection cavity.

Genetic: Inverse correlated dual-target, truncated IL7Ra modified CAR -expressing autologous T-lymphocytes.

Interventions

Inverse correlated dual-target, truncated IL7Ra modified CAR -expressing autologous T-lymphocytes. GENETIC

Intratumoral or intraventricular administration via Ommaya reservoir. Dose level 0: 1×10\^7 autologous Tris-CAR-T cells, at least one dose, maximum 6 doses, 2 patients. Dose level 1: 1×10\^8/ 5×10\^6 autologous Tris-CAR-T cells, at least one dose, maximum 6 doses, 2 patients. The dose of Dose level 1 will refer to the adverse effect of Dose level 0. When dose-related side effects occurred in 2 patients in the Dose level 0, the dose should be reduced to 5×10\^6 cells. In Dose levels 0 and 1, the second dose will be infused 28 days after the first dose, and the subsequent doses will be administered weekly. Dose level 2: 5×10\^7 autologous Tris-CAR-T cells, weekly administered, maximum 8 weeks, 4 patients. If the results of Dose levels 0 and 1 suggested that dose-related toxic side effects could have occurred in the 1×10\^7cells dose, the researcher would re-determine the dosage of the multidose clinical exploration study.

Also known as: Autologous Tris-CAR-T cell.

Autologous Tris-CAR-T cell

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age: 18 years to 70 years (including cut-off values).
• Patients with history of glioblastoma are diagnosed with recurrent glioblastoma and residual tumor after intracranial tumor resection/biopsy performed in Beijing Tiantan Hospital.
• Patients who finished radiotherapy or temozolomide/bevacizumab or other drugs for at least 4 weeks. All toxicities of prior treatment should be defined as less than or equal to grade 1 (except for toxicities such as hair loss or leukoplakia) according to the Common Terminology Standard for Adverse Events (CTCAE 5.0).
• Patients who is suitable for craniotocerebrospinal fluid shunt and attachment (Ommaya device) implantation confirmed by a competent physician.
• Patients and/or legal representative is able to sign written informed consent.
• Kanovsky Performance Status (KPS) ≥ 70.
• According to the researchers' judgment, the life expectancy ≥ 8 weeks.
• White blood cells (WBC) \> 3.50×10\^9/L (performed within 14 days prior to PBMC collection unless otherwise noted).
• Platelet ≥ 200×10\^9/L (performed within 14 days prior to PBMC collection unless otherwise noted).
• Hemoglobin ≥ 120 g/L (performed within 14 days prior to PBMC collection unless otherwise noted).
• Total bilirubin ≤ 20 μmol/L (performed within 14 days prior to PBMC collection unless otherwise noted).
• Aspartic acid aminotransferase (AST) ≤ 2.5×42 U/L (performed within 14 days prior to PBMC collection unless otherwise noted).
• Alanine aminotransferase (ALT) ≤ 2.5×41 U/L (performed within 14 days prior to PBMC collection unless otherwise noted).
• Serum creatinine ≤ 90 μmol/L (performed within 14 days prior to PBMC collection unless otherwise noted).
• Blood oxygen saturation ≥ 95% (performed within 14 days prior to PBMC collection unless otherwise noted).

You may not qualify if:

• Kanovsky Performance Status (KPS) ≤ 70.
• Highly allergic constitution or severe allergies history.
• Those who have psychiatric or psychological diseases and cannot cooperate with treatment and efficacy assessment.
• Receive other drug trials within 60 days before enrollment, or receive other routine treatment in non-experimental designs for glioblastoma, such as stereotactic radiation therapy or placement of carmustine wafers.
• Combined with infection, active infection, fever of unknown cause.
• Combined with serious or unstable heart, lung, liver, kidney and hematopoietic system diseases, including active hepatitis.
• Combined with inflammation and immune system diseases (such as rheumatoid arthritis), or known immunosuppressive diseases.
• Combined with neurological diseases, such as diffuse leptomeningeal disease, or neurodegenerative diseases.
• Known allergies to immunotherapy and related cellular products.
• Patients who have received any gene therapy before.
• Long-term use of immunosuppressants is required for any reason.
• Patients with a history of organ transplantation or who are waiting for organ transplantation.
• Special cases: pregnancy or lactation.
• Other circumstances in which the investigators believe the patient is unsuitable for this trial.

Sponsors & Collaborators

• Beijing Tiantan Hospital: lead
• Beijing Neurosurgical Institute: collaborator
• Tasly Pharmaceutical Group Co., Ltd: collaborator

Study Sites (1)

Beijing Tiantan Hospital

Beijing, Beijing Municipality, 100070, China

RECRUITING

Related Publications (5)

• Bagley SJ, Logun M, Fraietta JA, Wang X, Desai AS, Bagley LJ, Nabavizadeh A, Jarocha D, Martins R, Maloney E, Lledo L, Stein C, Marshall A, Leskowitz R, Jadlowsky JK, Christensen S, Oner BS, Plesa G, Brennan A, Gonzalez V, Chen F, Sun Y, Gladney W, Barrett D, Nasrallah MP, Hwang WT, Ming GL, Song H, Siegel DL, June CH, Hexner EO, Binder ZA, O'Rourke DM. Intrathecal bivalent CAR T cells targeting EGFR and IL13Ralpha2 in recurrent glioblastoma: phase 1 trial interim results. Nat Med. 2024 May;30(5):1320-1329. doi: 10.1038/s41591-024-02893-z. Epub 2024 Mar 13.

  PMID: 38480922 BACKGROUND

• Choi BD, Gerstner ER, Frigault MJ, Leick MB, Mount CW, Balaj L, Nikiforow S, Carter BS, Curry WT, Gallagher K, Maus MV. Intraventricular CARv3-TEAM-E T Cells in Recurrent Glioblastoma. N Engl J Med. 2024 Apr 11;390(14):1290-1298. doi: 10.1056/NEJMoa2314390. Epub 2024 Mar 13.

  PMID: 38477966 BACKGROUND

• Brown CE, Hibbard JC, Alizadeh D, Blanchard MS, Natri HM, Wang D, Ostberg JR, Aguilar B, Wagner JR, Paul JA, Starr R, Wong RA, Chen W, Shulkin N, Aftabizadeh M, Filippov A, Chaudhry A, Ressler JA, Kilpatrick J, Myers-McNamara P, Chen M, Wang LD, Rockne RC, Georges J, Portnow J, Barish ME, D'Apuzzo M, Banovich NE, Forman SJ, Badie B. Locoregional delivery of IL-13Ralpha2-targeting CAR-T cells in recurrent high-grade glioma: a phase 1 trial. Nat Med. 2024 Apr;30(4):1001-1012. doi: 10.1038/s41591-024-02875-1. Epub 2024 Mar 7.

  PMID: 38454126 BACKGROUND

• Majzner RG, Ramakrishna S, Yeom KW, Patel S, Chinnasamy H, Schultz LM, Richards RM, Jiang L, Barsan V, Mancusi R, Geraghty AC, Good Z, Mochizuki AY, Gillespie SM, Toland AMS, Mahdi J, Reschke A, Nie EH, Chau IJ, Rotiroti MC, Mount CW, Baggott C, Mavroukakis S, Egeler E, Moon J, Erickson C, Green S, Kunicki M, Fujimoto M, Ehlinger Z, Reynolds W, Kurra S, Warren KE, Prabhu S, Vogel H, Rasmussen L, Cornell TT, Partap S, Fisher PG, Campen CJ, Filbin MG, Grant G, Sahaf B, Davis KL, Feldman SA, Mackall CL, Monje M. GD2-CAR T cell therapy for H3K27M-mutated diffuse midline gliomas. Nature. 2022 Mar;603(7903):934-941. doi: 10.1038/s41586-022-04489-4. Epub 2022 Feb 7.

  PMID: 35130560 BACKGROUND

• Vitanza NA, Johnson AJ, Wilson AL, Brown C, Yokoyama JK, Kunkele A, Chang CA, Rawlings-Rhea S, Huang W, Seidel K, Albert CM, Pinto N, Gust J, Finn LS, Ojemann JG, Wright J, Orentas RJ, Baldwin M, Gardner RA, Jensen MC, Park JR. Locoregional infusion of HER2-specific CAR T cells in children and young adults with recurrent or refractory CNS tumors: an interim analysis. Nat Med. 2021 Sep;27(9):1544-1552. doi: 10.1038/s41591-021-01404-8. Epub 2021 Jul 12.

  PMID: 34253928 BACKGROUND

MeSH Terms

Conditions

Glioblastoma

Condition Hierarchy (Ancestors)

Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Study Officials

• Tao Jiang, Prof.

  Beijing Tiantan Hospital

  STUDY CHAIR

Central Study Contacts

Wei Zhang, Prof.

CONTACT

+861059976686; zhangwei02@bjtth.org

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Department of neurosurgery

Model Details: Recipients with the Ommaya reservoir implanted will be assigned to three courses. Arm A: Two patients, 1×10\^7 autologous Tris-CAR-T, at least 1 dose, maximum 6 doses. Arm B: Two patients 1×10\^8 autologous Tris-CAR-T, at least 1 dose, maximum 6 doses. Arm C: Six patients 5×10\^7 autologous Tris-CAR-T, maximum 8 doses.

Study Record Dates

• First Submitted: October 1, 2022
• First Posted: October 13, 2022
• Study Start: September 30, 2023
• Primary Completion: November 1, 2024
• Study Completion (Estimated): November 1, 2032
• Last Updated: April 12, 2024

Record last verified: 2024-04

Data Sharing

• IPD Sharing: Will not share

Locations

CN (1)