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HER2 chimeric antigen receptor T cell immunotherapy is an effective treatment for diffuse intrinsic pontine glioma
Stacie S Wang1,2,3, Alexander J Davenport1, Melinda Iliopoulos1
1Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.
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.
Insights
Chimeric antigen receptor (CAR) T cell therapy targeting HER2 shows promise for treating diffuse intrinsic pontine glioma (DIPG). HER2 CAR T cells effectively reduced DIPG tumors in preclinical models, suggesting potential for clinical trials.
Area of Science:
- Oncology
- Immunotherapy
- Pediatric Cancer Research
Background:
- Diffuse intrinsic pontine glioma (DIPG) and diffuse midline gliomas (DMG) are aggressive childhood brain tumors with poor prognoses.
- Current treatments offer limited efficacy, necessitating novel therapeutic strategies.
- Chimeric antigen receptor (CAR) T cell therapy presents a promising avenue, but new targets are needed due to tumor heterogeneity and antigen escape.
Purpose of the Study:
- To identify novel cell surface targets for CAR T cell therapy in DIPG.
- To evaluate the efficacy of HER2-targeted CAR T cells against DIPG.
Main Methods:
- Cell surface mass spectrometry was used to identify HER2 expression in patient-derived DIPG cells.
- Primary human T cells were engineered to express a second-generation HER2 CAR.
- The efficacy of HER2 CAR T cells was assessed through in vitro co-culture assays and in vivo intracranial xenograft models.
Main Results:
- HER2 CAR T cells exhibited potent, antigen-specific cytotoxicity and cytokine secretion against DIPG cells in vitro.
- Significant regression of intracranial DIPG xenograft tumors was observed with HER2 CAR T cell treatment.
- HER2 CAR T cells demonstrated antigen-specific killing of DIPG cells.
Conclusions:
- High HER2 expression on DIPG cells validates HER2 as a therapeutic target.
- Preclinical data strongly support the inclusion of DIPG patients in ongoing or future clinical trials of HER2 CAR T cell therapy.
- HER2 CAR T cells, already in clinical development and well-tolerated in pediatric patients, offer a viable treatment option for DIPG.
