With survival at barely 5% at five years, glioblastoma remains one of the deadliest brain cancers. The first line treatment consists of surgery to remove as much tumour tissue as possible. A team from the University of Geneva (UNIGE) and the Geneva University Hospitals (HUG) has now shown that this operation triggers a tissue-repair process that makes the residual tumour even harder to combat. By administering lab-engineered immune cells — CAR-T cells — to mice before rather than after surgery, the team achieved unprecedented durable tumour control. This research, with significant clinical implications, is published in the journal Nature Communications.

CAR-T cell therapies consist in collecting a patient’s own immune cells, engineering them in the laboratory so they can recognise engage and eliminate tumour cells.

Until now, clinical trials testing CAR-T cells against glioblastoma have aimed to administer them after surgery, the first-line intervention. "However, the surgical procedure itself is not neutral, neither for the immune system nor for the tumour microenvironment, which will seek to defend the tumour against this assault," explains Denis Migliorini, associate professor in the Department of Medicine and at the Translational Research Centre in Onco-Haematology (CRTOH) of the UNIGE Faculty of Medicine, and Head of the HUG Neuro-oncology Unit, who led the research. "We therefore wanted to investigate on the one hand, whether administering CAR-T cells before surgery changed treatment efficacy, and on the other, whether we could identify the most effective markers of immunosuppression."

A scar that protects the tumour

Using two mouse models replicating closely the human disease, the scientists analysed the immune mechanisms at work in the tumour microenvironment with and without surgery, as well as their impact on tumour recurrence. "The tissue-repair mechanism that sets in after surgery leads to the overexpression of the TREM2 protein, a marker of immunosuppressive macrophages, that is very strongly expressed in the tumour microenvironment. This protein reflects their level of activity and their ability to dampen the antitumour immune response," explains Martin Pédard, senior research and teaching assistant in Denis Migliorini's team. "Thus, TREM2, already overexpressed in the tumour before surgery, further increases in response to the surgically induced wound and triggers a massive macrophage response that neutralises the immune cells fighting the cancer."

So, could the infusion of CAR-T cells before rather than after surgery help avoid this hostile post-operative environment? The team set out to test this hypothesis. They also developed CAR-T cells specifically targeting TREM2 and deposited directly into the cavity during surgery in a mouse model. Combined with another type of CAR-T cell targeting tumour cells via the specific marker GD2, these cells were able to neutralise the immunity-suppressing macrophages.

Unprecedented control over the tumour

Administered before rather than after surgery, GD2-targeting CAR-T cells retained their ability to attack the tumour and achieved far better disease control. Combined with the TREM2-targeting CAR-T cells delivered into the resection cavity, they further extended survival. "CAR-T cells shift the tumour towards an environment more favourable to the immune response, with more molecules promoting inflammation and tumour cell death," describes Denis Migliorini. The team then confirmed these observations in human tissue. Using a platform developed with the HUG neurosurgery and neuropathology divisions, they were able to culture tumour samples taken directly in the operating theatre and reproduce, in this tissue, the effect observed in mice.

Towards clinical trials

These results could influence the design of future clinical trials. The Geneva team plans to open a first in human phase 1 trial, next year for newly diagnosed patients. "This trial primarily aims to demonstrate the safety of CAR-T cells after surgery and radio-chemotherapy," specifies Denis Migliorini. "Based on our data, we will then be able to modify the protocol to include a trial in which CAR-T treatments would be administered before surgery."