CAR T Cell Therapy for Solid Tumors: Bright Future or Dark Reality?

What promotes post traumatic growth? A systematic review

Immunotherapy aiming at suppressing tumor development by relying on modifying or strengthening the immune system prevails among cancer treatments and points out a new direction for cancer therapy. B7 homolog 3 protein (B7-H3, also known as CD276), a newly identified immunoregulatory protein member of the B7 family, is an attractive and promising target for cancer immunotherapy because it is overexpressed in tumor tissues while showing limited expression in normal tissues and participating in tumor microenvironment (TME) shaping and development. Thus far, numerous B7-H3-based immunotherapy strategies have demonstrated potent antitumor activity and acceptable safety profiles in preclinical models. Herein, we present the expression and biological function of B7-H3 in distinct cancer and normal cells, as well as B7-H3-mediated signal pathways in cancer cells and B7-H3-based tumor immunotherapy strategies. This review provides a comprehensive overview that encompasses B7-H3’s role in TME to its potential as a target in cancer immunotherapy.

/pdf/b7-h3-cd276-an-emerging-cancer-immunotherapy-5dznlnega8.pdf

B7-H3/CD276: An Emerging Cancer Immunotherapy.

Abstract Diffuse intrinsic pontine glioma (DIPG) remains a fatal brainstem tumor demanding innovative therapies. As B7-H3 (CD276) is expressed on central nervous system (CNS) tumors, we designed B7-H3–specific chimeric antigen receptor (CAR) T cells, confirmed their preclinical efficacy, and opened BrainChild-03 (NCT04185038), a first-in-human phase I trial administering repeated locoregional B7-H3 CAR T cells to children with recurrent/refractory CNS tumors and DIPG. Here, we report the results of the first three evaluable patients with DIPG (including two who enrolled after progression), who received 40 infusions with no dose-limiting toxicities. One patient had sustained clinical and radiographic improvement through 12 months on study. Patients exhibited correlative evidence of local immune activation and persistent cerebrospinal fluid (CSF) B7-H3 CAR T cells. Targeted mass spectrometry of CSF biospecimens revealed modulation of B7-H3 and critical immune analytes (CD14, CD163, CSF-1, CXCL13, and VCAM-1). Our data suggest the feasibility of repeated intracranial B7-H3 CAR T-cell dosing and that intracranial delivery may induce local immune activation. Significance: This is the first report of repeatedly dosed intracranial B7-H3 CAR T cells for patients with DIPG and includes preliminary tolerability, the detection of CAR T cells in the CSF, CSF cytokine elevations supporting locoregional immune activation, and the feasibility of serial mass spectrometry from both serum and CSF. This article is highlighted in the In This Issue feature, p. 1 

Intraventricular B7-H3 CAR T Cells for Diffuse Intrinsic Pontine Glioma: Preliminary First-in-Human Bioactivity and Safety

Summary: CD19- and B-cell maturation antigen (BCMA)–directed chimeric antigen receptor (CAR) T cells have enabled unprecedented responses in a subset of refractory patients with B-cell and plasma cell malignancies, leading to their approval by the FDA for the treatment of leukemia, lymphoma, and myeloma. These “living drugs” can become part of a synthetic immune system, persisting at least a decade in some patients. However, despite this tremendous impact, significant unmet treatment needs remain for patients with hematologic malignancies and solid cancers. In this perspective, we highlight recent innovations that advance the field toward production of a more potent and universal cellular immunotherapy of the future. Next-generation CAR T cells will incorporate advances in gene engineering and synthetic biology to enhance functionality and persistence, and reduce treatment-associated toxicities. The combination of autologous CAR T cells with various allogeneic cell treatment strategies designed to target the immunosuppressive tumor microenvironment will broaden the impact of future CAR T-cell therapies. 

Next-Generation CAR T-cell Therapies

Objective We conducted a first-in-human study to evaluate the bioactivity and safety of B7-H3-targeted chimeric antigen receptor (CAR) autologous T cells for treating recurrent anaplastic meningioma. Methods Tumor tissues from a patient with recurrent anaplastic meningioma were evaluated for B7-H3 expression. B7-H3-targeted CAR-T cells were delivered into the intracranial tumor resection cavity using an Ommaya device at a maximum dose of 1.5 × 107 cells. Magnetic resonance imaging (MRI) screening and multiple serum indexes were regularly monitored. The patient received surgical intervention after three-cycle infusions, allowing analysis for CAR-T-cell infiltration and target antigen expression in post-CAR-T therapy tumor tissues. Results Immunochemical analysis demonstrated high and homogeneous B7-H3 expression in tumor samples. MRI results indicated that the tumor near the delivery device was relatively stable compared with the rapid progression of tumors distant from the device. We found CAR-T-cell trafficking to regions of B7-H3+ tumor tissues near the device, but not to tumor tissues distant from the device. Decreased B7-H3 expression was observed near the region of CAR-T-cell infiltration after therapy. The intracavitary delivery of B7-H3-targeted CAR-T cells was well-tolerated and not associated with any toxic effects of grade 3 or higher. Conclusion Our results suggested that although intracavitary administration of B7-H3-targeted CAR-T cells was safe and resulted in local bioactivity, addressing antigen loss and CAR-T-cell trafficking may further enhance the applications of B7-H3-targeted CAR-T-cell therapy.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/cti2.1137

Bioactivity and safety of B7-H3-targeted chimeric antigen receptor T cells against anaplastic meningioma.

Health-Related Quality of Life and Posttraumatic Growth in Low-Grade Gliomas in China: A Prospective Study.

Timing and Outcomes of Tracheostomy in Patients with Hemorrhagic Stroke.

Objective: Published studies have shown hyperglycemia is associated with poor outcome in patients with intracerebral hemorrhage (ICH). However, the association between blood glucose and outcome in ...

Association of blood glucose with 30-day mortality in patients with intracerebral hemorrhage undergoing neurosurgical treatment

/pdf/letter-to-the-editor-is-there-any-relationship-between-438kvotq4j.pdf

Letter to the Editor. Is there any relationship between estrogen receptor/progesterone receptor status and recurrence of meningioma?

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