HER2 chimeric antigen receptor T cell immunotherapy is an effective treatment for diffuse intrinsic pontine glioma

Abstract

Background Diffuse intrinsic pontine glioma (DIPG) and other diffuse midline gliomas (DMG) of the thalamus and spinal cord are rare but devastating high-grade glial tumors of childhood with no curative treatment. Despite aggressive treatment attempts the prognosis has remained poor. Chimeric antigen receptor (CAR) T cell therapy has been identified as a promising new approach in the treatment of DMG tumors; however, additional targets are urgently required given known tumor heterogeneity and the prospect of antigen escape of this cancer. Methods Using cell surface mass spectrometry, we detected high HER2 cell surface protein across a panel of patient-derived DIPG cells, thereby identifying an existing CAR T cell therapy for use in DIPG. Primary human T cells were transduced to express a second-generation HER2 CAR and interrogated for efficacy against patient-derived DIPG cells. Results HER2 CAR T cells demonstrated potent and antigen-specific cytotoxicity and cytokine secretion when co-cultured with patient-derived DIPG cells. Furthermore, HER2 CAR T cells provided a significant regression in intracranial DIPG xenograft tumors. Conclusions HER2 CAR T cells are already in clinic development and are well tolerated in pediatric patients. Here we provide strong preclinical evidence for the inclusion of DIPG patients in future pediatric CNS tumor HER2 CAR T cell clinical trials.

National trends in the treatment of adult diffuse midline gliomas: a rare clinical scenario

“…Mass spectrometry of DIPG cells has also identi ed high HER 2 cell surface protein expression thus allowing for existing CAR T-cell therapy. When co cultured with DIPG cells, HER 2 CAR T cells induced antigenspeci c toxicity and cytokine production [25]. As clinical trials proceed, the future for DMG treatment is a bit more promising.…”

Chimeric Antigen Receptor T Cell and Chimeric Antigen Receptor NK Cell Therapy in Pediatric and Adult High-Grade Glioma—Recent Advances

“…The literature also contains research results showing the use of HER2 as a target antigen for CAR-T therapy in the treatment of pHGG. HER2 overexpression is found in many cancers such as breast, stomach and ovarian cancer, but also in CNS cancers, including DIPG [37][38][39]. Wang et al constructed second-generation CAR-T cells targeting HER2 + tumor cells.…”

“…Anti-HER2 CAR-T cells led to a significant reduction in the volume of tumors in the tested mice, and consequently no tumor was detected in these mice 6 weeks after drug administration. Due to the development of graft-versus-host disease (GvHD), the experiment was terminated and it was impossible to assess the potential recurrence caused by the survival of a small number of cancer cells which were undetectable in tests [39].…”

Current immunotherapeutic approaches to diffuse intrinsic pontine glioma

“…The HER2 protein is a member of the EGFR family, and its overexpression is seen in many solid tumours, including DIPG, with breast cancer being the most notable ( Oh and Bang, 2020 ). Wang et al (2023a) investigated the use of anti-HER2 CAR-T cells as a therapeutic in DIPG and other DMGs. Results showed HER2-specific immune targeting and cytokine release when co-cultured in vitro with patient-derived DIPG cells.…”

“…Anti-HER2 CAR-T cells also reduce tumour size in in vivo DIPG xenografts. The authors concluded that the CAR-T cells may show efficacy in DIPG patients, although a clinical trial is needed to confirm their hypothesis ( Wang et al, 2023a ). Vascular endothelial growth factor (VEGF) is a molecule regulating angiogenesis.…”