Tris-CAR-T Cell Therapy for Recurrent Glioblastoma

Официальное название

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

Обзор

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.

Подробное описание

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.

Вмешательства

• Генная терапия Inverse correlated dual-target, truncated IL7Ra modified CAR -expressing autologous T-lymphocytes.
  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, t

Первичные конечные точки

• Safety: any adverse events associated with one or multiple autologous Tris-CAR-T cell infusions will be assessed by CTCAE v5.0. [Срок оценки: 6 months]

Вторичные конечные точки (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. [Срок оценки: 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. [Срок оценки: 6 months]
• CAR-T therapeutic effect evaluation: the therapeutic effect of autologous Tris-CAR-T cell will be assessed by iRANO. [Срок оценки: 12 months]

Критерии участия

Критерии включения

• 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).
• Seronegative of the combination of human immunodeficiency virus (HIV) antibody (Ab) (performed within 14 days prior to PBMC collection unless otherwise noted).
• Fertile women: a negative serum pregnancy test (performed within 14 days prior to PBMC collection unless otherwise noted).
• The patient agrees that contraception should be used in patients of childbearing age for at least 3 months from screening to the last infusion of Tris-CAR-T cells. The period of childbearing age is defined as unsurgically neutered (men and women) or without menopause for more than 1 year (women only).

Критерии исключения

• 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Китай · 1 центр

• Beijing Tiantan Hospital — Пекин

Публикации

• 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 E PMID 38480922
• 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
• 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 re PMID 38454126
• 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, C PMID 35130560
• 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):1544-1 PMID 34253928

Идентификаторы

NCT: NCT05577091 · TTSW2021-01

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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