Delving into the Latest Updates on B7-H3-CAR T cells(St. Jude Children's Research Hospital) with Synapse

Overview

Basic Info

Drug Type

Autologous CAR-T

Synonyms-

Target

CD276

Mechanism

CD276 modulators(CD276 antigen modulators), Immunologic cytotoxicity, T lymphocyte replacements

Therapeutic Areas

NeoplasmsNervous System DiseasesCongenital Disorders+ [4]

Active Indication

Diffuse midline glioma, point mutation K27M in histone H3EpendymomaGlioblastoma+ [16]

Inactive Indication-

Originator Organization

St. Jude Children's Research Hospital, Inc.

Active Organization

St. Jude Children's Research Hospital, Inc.

Inactive Organization-

Drug Highest PhasePhase 1

First Approval Date-

Regulation-

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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).

Start Date27 Apr 2023

Sponsor / Collaborator

St. Jude Children's Research Hospital, Inc.

NCT04897321 / RecruitingPhase 1IIT

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

Start Date06 Jul 2022

Sponsor / Collaborator

St. Jude Children's Research Hospital, Inc.

100 Clinical Results associated with B7-H3-CAR T cells(St. Jude Children's Research Hospital)

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100 Translational Medicine associated with B7-H3-CAR T cells(St. Jude Children's Research Hospital)

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100 Patents (Medical) associated with B7-H3-CAR T cells(St. Jude Children's Research Hospital)

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36

Literatures (Medical) associated with B7-H3-CAR T cells(St. Jude Children's Research Hospital)

01 Dec 2024·MOLECULAR IMMUNOLOGY

Preclinical assessment of the efficacy of B7-H3 CAR-T in renal cell carcinoma

Article

Author: Li, Huizhong ; Dotti, Gianpietro ; Savoldo, Barbara ; Rao, Enyu ; Zhao, Haifang ; Du, Hongwei ; Wang, Shiyuan ; Cao, Jiale ; Li, Hongxia ; Wang, Fei

B7-H3 is a type I transmembrane protein that belongs to the B7 immune checkpoint protein family, is aberrantly expressed in cancer cells, but rarely expressed in normal tissues, making it an attractive target for cancer therapy. Here, we found B7-H3 is highly expressed in the renal cell carcinoma (RCC) tumor tissues and RCC cell lines, but is undetectable in normal renal tissues. Therefore, we engineered second-generation CAR-T cells targeting B7-H3, incorporating either CD28 or 4-1BB co-stimulatory domains. Both CAR-T cell variants demonstrated potent antitumor activity against RCC tumors in vitro and in metastatic and orthotopic RCC mouse models. Furthermore, the B7-H3 CAR-T cells exhibited remarkable proliferation and robust cytokine release when co-cultured with RCC cancer cells. These findings demonstrated that targeting B7-H3 by CAR-T cells potentially offering a new treatment option for RCC patients.

01 Oct 2024·CLINICAL CANCER RESEARCH

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

Article

Author: Nguyen, Phuong ; Talbot, Lindsay J. ; Gottschalk, Stephen ; Fleming, Andrew ; 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.

10 Sep 2024·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

Author: Park, Julie R ; Seidel, Kristy ; Wendler, Jason ; Ullom, Heidi B ; Cheeney, Safia H E ; Pinto, Navin ; 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).

100 Deals associated with B7-H3-CAR T cells(St. Jude Children's Research Hospital)

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Diffuse midline glioma, point mutation K27M in histone H3	Phase 1	US	St. Jude Children's Research Hospital, Inc.	27 Apr 2023
Ependymoma	Phase 1	US	St. Jude Children's Research Hospital, Inc.	27 Apr 2023
Glioblastoma	Phase 1	US	St. Jude Children's Research Hospital, Inc.	27 Apr 2023
High grade glioma	Phase 1	US	St. Jude Children's Research Hospital, Inc.	27 Apr 2023
Medulloblastoma	Phase 1	US	St. Jude Children's Research Hospital, Inc.	27 Apr 2023
Teratoid Tumor, Atypical	Phase 1	US	St. Jude Children's Research Hospital, Inc.	27 Apr 2023
Adrenal Cortex Neoplasms	Phase 1	US	St. Jude Children's Research Hospital, Inc.	06 Jul 2022
Carcinoma	Phase 1	US	St. Jude Children's Research Hospital, Inc.	06 Jul 2022
Clear Cell Sarcoma	Phase 1	US	St. Jude Children's Research Hospital, Inc.	06 Jul 2022
Desmoplastic Small Round Cell Tumor	Phase 1	US	St. Jude Children's Research Hospital, Inc.	06 Jul 2022