Loc3CAR is a Phase I clinical trial evaluating the use of autologous B7-H3-CAR T cells for participants ≤ 21 years old with primary CNS neoplasms. B7-H3-CAR T cells will be locoregionally administered via a CNS reservoir catheter. Study participants will be divided into two cohorts: cohort A with B7-H3-positive relapsed/refractory non-brainstem primary CNS tumors, and cohort B with diffuse midline gliomas (DMG). Participants will receive four (4) B7-H3-CAR T cell infusions over a 4 week period. The purpose of this study is to find the maximum (highest) dose of B7-H3-CAR T cells that are safe to give patients with primary brain tumors.
Primary objectives
* To determine the safety, maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) for the locoregional delivery of autologous B7-H3-CAR T cells in patients ≤ 21 years of age with recurrent/refractory B7-H3+ primary CNS tumors (Cohort A) or DMG (Cohort B).
Secondary objectives
* To assess the efficacy, defined as sustained objective response, a partial response (PR) or complete response (CR) observed anytime on active treatment with B7-H3-CAR T cells in patients with relapsed/refractory B7-H3+ primary CNS tumors (Cohort A) or DMG (Cohort B).
* To characterize and monitor neurologic toxicities in patients while on study (Cohort A and B).

开始日期2023-04-27

申办/合作机构

St. Jude Children's Research Hospital, Inc.

NCT04897321 / Recruiting临床1期IIT

B7-H3-Specific Chimeric Antigen Receptor Autologous T-Cell Therapy for Pediatric Patients With Solid Tumors (3CAR)

3CAR is being done to investigate an immunotherapy for patients with solid tumors. It is a Phase I clinical trial evaluating the use of autologous T cells genetically engineered to express B7-H3-CARs for patients ≤ 21 years old, with relapsed/refractory B7-H3+ solid tumors. This study will evaluate the safety and maximum tolerated dose of B7-H3-CAR T cells.The purpose of this study is to find the maximum (highest) dose of B7-H3-CAR T cells that are safe to give to patients with B7-H3-positive solid tumors.
Primary objective
To determine the safety of one intravenous infusion of autologous, B7-H3-CAR T cells in patients (≤ 21 years) with recurrent/refractory B7-H3+ solid tumors after lymphodepleting chemotherapy
Secondary objective
To evaluate the antitumor activity of B7-H3-CAR T cells
Exploratory objectives
* To evaluate the tumor environment after treatment with B7-H3-CAR T cells
* To assess the immunophenotype, clonal structure and endogenous repertoire of B7-H3-CAR T cells and unmodified T cells
* To characterize the cytokine profile in the peripheral blood after treatment with B7-H3-CAR T cells

开始日期2022-07-06

申办/合作机构

St. Jude Children's Research Hospital, Inc.

100 项与 B7-H3-CAR T cells(St. Jude Children's Research Hospital) 相关的临床结果

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100 项与 B7-H3-CAR T cells(St. Jude Children's Research Hospital) 相关的转化医学

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100 项与 B7-H3-CAR T cells(St. Jude Children's Research Hospital) 相关的专利（医药）

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项与 B7-H3-CAR T cells(St. Jude Children's Research Hospital) 相关的文献（医药）

2024-10-01·CLINICAL CANCER RESEARCH

Redirecting B7-H3.CAR T Cells to Chemokines Expressed in Osteosarcoma Enhances Homing and Antitumor Activity in Preclinical Models

Article

作者: Nguyen, Phuong ; Talbot, Lindsay J. ; Fleming, Andrew ; Gottschalk, Stephen ; Shepphard, Heather ; Beckett, Alexandra ; Wang, Jian ; DeRenzo, Christopher ; Chabot, Ashley ; Chockley, Peter J. ; Ross, Aaron B.

Abstract:

Purpose::

Clinical efficacy of chimeric antigen receptor (CAR) T cells against pediatric osteosarcoma (OS) has been limited. One strategy to improve efficacy may be to drive chemokine-mediated homing of CAR T cells to tumors. We sought to determine the primary chemokines secreted by OS and evaluate the efficacy of B7-H3.CAR T cells expressing the cognate receptors.

Experimental Design::

We developed a pipeline to identify chemokines secreted by OS by correlating RNA-seq data with chemokine protein detected in media from fresh surgical specimens. We identified CXCR2 and CXCR6 as promising receptors for enhancing CAR T-cell homing against OS. We evaluated the homing kinetics and efficiency of CXCR2- and CXCR6.T cells and homing, cytokine production, and antitumor activity of CXCR2- and CXCR6.B7-H3.CAR T cells in vitro and in vivo.

Results::

T cells transgenically expressing CXCR2 or CXCR6 exhibited ligand-specific enhanced migration over T cells modified with nonfunctional control receptors. Differential homing kinetics were observed, with CXCR2.T-cell homing quickly and plateauing early, whereas CXCR6.T cells took longer to home but achieved a similar plateau. When expressed in B7-H3.CAR T cells, CXCR2- and CXCR6 modification conferred enhanced homing toward OS in vitro and in vivo. CXCR2- and CXCR6-B7-H3.CAR-treated mice experienced prolonged survival in a metastatic model compared with B7-H3.CAR T-cell-treated mice.

Conclusions::

Our patient-based pipeline identified targets for chemokine receptor modification of CAR T cells targeting OS. CXCR2 and CXCR6 expression enhanced the homing and anti-OS activity of B7-H3.CAR T cells. These findings support clinical evaluation of CXCR-modified CAR T cells to improve adoptive cell therapy for patients with OS.

2024-09-10·JOURNAL OF CLINICAL ONCOLOGY

STRIvE-02: A First-in-Human Phase I Study of Systemically Administered B7-H3 Chimeric Antigen Receptor T Cells for Patients With Relapsed/Refractory Solid Tumors.

Article

作者: Park, Julie R ; Seidel, Kristy ; Wendler, Jason ; Ullom, Heidi B ; Pinto, Navin ; Cheeney, Safia H E ; Orentas, Rimas J ; Jensen, Michael C ; Vitanza, Nicholas A ; Gardner, Rebecca A ; Burleigh, Katelyn ; Gustafson, Joshua A ; Rawlings-Rhea, Stephanie D ; Huang, Wenjun ; Wilson, Ashley L ; Brown, Christopher ; Gustafson, Heather H ; Pattabhi, Sowmya ; Taylor, Mallory R ; Albert, Catherine M

PURPOSE:

B7-H3 is an immunoregulatory protein overexpressed by many pediatric solid tumors with limited expression on critical organs, making it an attractive immunotherapy target. We present a first-in-human phase I clinical trial systemically administered B7-H3 chimeric antigen receptor (CAR) T cells for young patients with relapsed or refractory solid tumors.

PATIENTS AND METHODS:

Patients were enrolled onto a phase I trial to examine the safety of B7-H3-specific CARs at various dose levels (DLs) using a standard 3 + 3 dose escalation design.

RESULTS:

Sixteen patients (range, 11-24 years; median, 18.5 years) were enrolled, and nine were treated at DL1 (0.5 × 10⁶ CAR T cells/kg; n = 3) or DL2 (1 × 10⁶ CAR T cells/kg; n = 6). There were no first infusion dose-limiting toxicities. Maximum first-infusion circulating CAR T cells detected in the peripheral blood were 4.98 cells/μL (range, 0-4.98 cells/μL) with detection of CAR T cells colocalizing with tumor cells at the site of metastatic disease in one patient. Patients were eligible for subsequent infusions. An objective partial response by PERCIST criteria was observed 28 days after a second CAR T cell infusion in a patient who did not have an objective response after the first infusion. The second infusion demonstrated marked enhancement of CAR T cell expansion to 1,590 cells/μL and was accompanied by cytokine release syndrome and dose-limiting transaminitis. Detailed peripheral blood cytokine profiling revealed elevated IL-21 levels preinfusion 2 compared with infusion 1.

CONCLUSION:

B7-H3 CAR T cells are tolerable and demonstrate limited antitumor activity without acute on-target, off-tumor toxicity. High levels of CAR T cell expansion may be necessary to achieve objective responses, but undefined host and tumor microenvironment factors appear to be critical (ClinicalTrials.gov identifier: NCT04483778).

2024-08-01·CLINICAL CANCER RESEARCH

Chimeric Antigen Receptor T Cell with an Inducible Caspase-9 Suicide Gene Eradicates Uveal Melanoma Liver Metastases via B7-H3 Targeting

Article

作者: Verdijk, Robert M. ; Maggs, Luke ; Ferrone, Cristina R. ; Ventin, Marco ; Ksander, Bruce R. ; Haq, Rizwan ; Ryeom, Sandra ; Sun, Yi ; Arya, Shahrzad ; Boland, Genevieve M. ; Jia, Jingyu ; Jager, Martine J. ; Gelmi, Maria C. ; Cattaneo, Giulia ; Jenkins, Russell W. ; Wang, Xinhui

Abstract:

Purpose::

Uveal melanoma (UM) is the most common intraocular malignant tumor. Despite successful treatment of the primary tumor, about 50% of patients will recur with systemic diseases for which there are no effective treatment strategies. Here we investigated the preclinical efficacy of a chimeric antigen receptor (CAR) T-cell–based immunotherapy targeting B7-H3.

Experimental Design::

B7-H3 expression on primary and metastatic human UM samples and cell lines was assessed by RNA sequencing, flow cytometry, and immunohistochemistry. Antitumor activity of CAR T cells targeting B7-H3 was tested in vitro with UM cell lines, patient-derived organotypic tumor spheroids from patients with metastatic UM, and in immunodeficient and humanized murine models.

Results::

B7-H3 is expressed at high levels in >95% UM tumor cells in vitro and in vivo. We generated a B7-H3 CAR with an inducible caspase-9 (iCas9) suicide gene controlled by the chemical inducer of dimerization AP1903, which effectively kills UM cells in vitro and eradicates UM liver metastases in murine models. Delivery of iCas9.B7-H3 CAR T cells in experimental models of UM liver metastases demonstrates a durable antitumor response, even upon tumor rechallenge or in the presence of a significant metastatic disease burden. We demonstrate effective iCas9.B7-H3 CAR T-cell elimination in vitro and in vivo in response to AP1903. Our studies demonstrate more effective tumor suppression with iCas9.B7-H3 CAR T cells as compared to a B7-H3-targeted humanized monoclonal antibody.

Conclusions::

These studies support a phase I clinical trial with iCas9.B7-H3 CAR T cells to treat patients with metastatic UM.

项与 B7-H3-CAR T cells(St. Jude Children's Research Hospital) 相关的新闻（医药）

2024-05-13

·BioBAY

研发动态丨博生吉宣布完成全球首例通用现货型CAR-Vδ1T细胞药物（UTAA06）实体瘤患者给药

近日，BioBAY园内企业博生吉宣布完成全球首例通用现货型CAR-Vδ1T细胞药物（UTAA06）实体瘤患者给药，目前一切顺利，受试者无不良反应。该研究（NCT06372236）是一项研究者发起（IIT）的临床试验，主要目的是评价UTAA06注射液治疗晚期恶性实体肿瘤患者的安全性和有效性的单中心、开放、单臂临床研究。UTAA06注射液是一款基于I型γδT细胞开发的通用现货型B7-H3-CAR-Vδ1T细胞产品，适应症为晚期恶性实体肿瘤，主要针对肿瘤细胞膜表面B7-H3表达强度为1+及以上，且肿瘤细胞膜的阳性染色比例≥50%的实体瘤患者。在我国，每年有高达482万以上的新发肿瘤患者，且患者死亡人数达到了257万以上。其中，大部分为实体肿瘤患者，因此恶性肿瘤，尤其是实体肿瘤已经成为一个严重威胁我国公众健康的重大医学问题。但是，手术和放化疗等癌症传统手段的治疗效果欠佳，亟待发展更加有效的临床治疗方法。最新研究表明以B7-H3为靶点的新一代药物（CAR-T或ADC药物等）有望成为改善恶性实体肿瘤患者治疗效果的新选择。博生吉公司自主研发的B7-H3-CAR-Vδ1T细胞产品，展现出杰出的肿瘤归巢能力和细胞毒能力，且不受到MHC的限制，具有开发成为通用现货型细胞产品的潜力。▌文章来源：细胞与基因治疗领域责编：赵家帅审核：任旭推荐阅读研发动态丨宜联生物：cMET靶向ADC在美完成1期临床首例受试者给药研发动态丨典晶生物首款三靶点融合抗体EB-105的IND申请获得美国FDA批准研发动态丨全国首个！景昱医疗新型双靶点STN+ Aaxon8触点可充电脑起搏器成功完成临床植入

抗体药物偶联物细胞疗法免疫疗法临床1期临床申请

100 项与 B7-H3-CAR T cells(St. Jude Children's Research Hospital) 相关的药物交易

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研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
组蛋白H3中K27M点突变的弥漫性中线胶质瘤	临床1期	美国	St. Jude Children's Research Hospital, Inc.	2023-04-27
室管膜瘤	临床1期	美国	St. Jude Children's Research Hospital, Inc.	2023-04-27
胶质母细胞瘤	临床1期	美国	St. Jude Children's Research Hospital, Inc.	2023-04-27
高级别胶质瘤	临床1期	美国	St. Jude Children's Research Hospital, Inc.	2023-04-27
髓母细胞瘤	临床1期	美国	St. Jude Children's Research Hospital, Inc.	2023-04-27
非典型畸胎瘤	临床1期	美国	St. Jude Children's Research Hospital, Inc.	2023-04-27