Administering CAR T cells before glioblastoma surgery improved tumor control and survival compared with treatment after surgery in two mouse models.
The study, led by researchers at the University of Geneva and Geneva University Hospitals, also identified surgery-induced changes in the tumor microenvironment that may restrict the effectiveness of postoperative immunotherapy.
Surgical resection remains the first-line treatment for glioblastoma, followed by radiotherapy and chemotherapy. CAR T cell trials in the disease have generally administered the engineered immune cells after surgery. However, the new findings suggest that the tissue-repair response triggered by surgery may make residual tumors harder to treat.
“The surgical procedure itself is not neutral, neither for the immune system nor for the tumor microenvironment, which will seek to defend the tumor against this assault,” said study leader Denis Migliorini in a press release.
The researchers examined immune changes following tumor resection in two mouse models and patient-derived glioblastoma tissue cultured ex vivo. Surgery increased levels of TREM2, a marker associated with immunosuppressive myeloid cells, around the resection cavity. This was followed by the appearance of exhaustion-like phenotypes in T cells.
To investigate whether treatment timing affected efficacy, the team administered GD2-targeting CAR T cells either three days before surgery or directly into the resection cavity during the operation. Preoperative treatment improved tumor control and prolonged survival compared with postoperative CAR T cell administration or surgery alone in both mouse models.
CAR T cells delivered before surgery also retained stronger effector function and were distributed around the resection cavity and residual tumor margins. Cells administered during surgery were largely confined to the cavity and showed more signs of exhaustion.
The team separately developed CAR T cells targeting TREM2-positive myeloid cells. When delivered into the resection cavity alongside GD2-targeting CAR T cells, the combination produced a modest improvement in survival and increased the persistence and proliferation of the tumor-targeting cells. However, adding TREM2-targeting cells before surgery reduced the benefit of preoperative GD2 CAR T treatment, indicating that the timing of myeloid-cell modulation will require careful investigation.
The human tissue experiments supported the finding that resection induces TREM2-positive myeloid cells, but treatment efficacy was tested only in male mice. The authors also note that mouse models do not fully reproduce the complexity of the human glioblastoma immune environment.
The Geneva team plans to begin a phase I trial in newly diagnosed patients, initially testing CAR T cells after surgery and chemoradiotherapy. Migliorini said the protocol could later be modified to evaluate treatment before surgery.
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