CAR T-cell therapy before surgery boosts glioblastoma control in mice

A CAR T-cell therapy targeting glioblastoma improved tumor control and survival in mice when given before surgery rather than afterward, according to a new study.

The study, which involved experiments in mice and human glioblastoma tissue grown outside the body, suggests that surgery triggers changes in the cellular environment that surrounds glioblastoma tumors. These changes can create a more immune-suppressive environment that may weaken the activity of CAR T cells given after surgery.

An early-access version of the study, “Perioperative myeloid cell remodeling shapes CAR-T cell efficacy in glioblastoma,” was published in Nature Communications.

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Surgery remains the first step in standard glioblastoma treatment

Glioblastoma is an aggressive form of glioma, a group of tumors that develop from glial cells, which normally support nerve cells in the brain. Standard treatment for glioblastoma usually begins with surgery to remove as much of the tumor as possible. Other treatments may then be given to kill remaining cancer cells and reduce the risk of the tumor growing back.

T cells are a type of immune cell that can fight and kill cancer cells. With CAR T-cell therapy, these cells are collected from a patient and then engineered to express a human-made chimeric antigen receptor (CAR), which directs the T cells to attack a specific target.

CAR T-cell therapies have shown substantial anticancer effects for some types of cancer, including various forms of blood cancer. But they have shown limited effectiveness in glioblastoma. In clinical studies, patients have generally received CAR T-cell therapy after undergoing surgery, the usual first step in glioblastoma treatment.

Although surgery is usually the first step in glioblastoma treatment, it remains unclear exactly how the procedure changes the tumor and its surrounding environment, and how those changes may affect treatments given afterward. To investigate, scientists conducted a series of tests using two mouse models of glioblastoma to assess how the tumor environment changes following surgery.

“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. 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,” Denis Migliorini, MD, co-author of the study at the University of Geneva, said in a university news story.

The researchers found that surgery triggered substantial changes in myeloid cells, immune cells that are abundant in the tumor environment. Specifically, surgery was followed by an increase in myeloid cells expressing a protein called TREM2. Later, T cells showed increased signs associated with exhaustion, a state in which prolonged stimulation can impair their ability to mount an effective immune response.

These experiments suggest that surgery itself changes the tumor microenvironment in ways that may make CAR T-cell therapy less effective when given afterward.

Pre-surgery CAR T-cell treatment improves survival in mice

Building on the results, the researchers conducted a series of tests using CAR T cells targeting a glioblastoma marker called GD2. In both mouse models, giving the cells three days before surgery improved tumor control and survival compared with giving them after surgery. CAR T cells given before surgery also showed better-preserved effector function and fewer signs of exhaustion inside the tumor.

“We identify the timing of CAR-T cell administration as a critical determinant of therapeutic outcome, with [pre-surgery] outperforming [post-surgery] treatment by preserving CAR-T cell effector function in mice,” the researchers concluded.

In one of the mouse models, the researchers also found that survival could be extended by combining two different CAR T-cell therapies after surgery: one targeting the cancer marker GD2, and another targeting TREM2, which is expressed by myeloid cells in the tumor environment. However, this benefit was not seen when the combination was given before surgery.

Collectively, these data indicate that glioblastoma surgery can alter the tumor environment in ways that may reduce the effectiveness of CAR T-cell treatment given afterward. The results suggest that GD2-targeting CAR T-cell treatment may be more effective when administered before surgery, and that directly targeting cells in the tumor microenvironment may also enhance treatment in certain settings.

The researchers cautioned that the human tissue model does not fully reproduce the post-surgery environment in patients. The researchers are currently working to start a Phase 1 clinical trial in patients, which is expected to open next year. The initial trial is planned to test CAR T-cell therapy after surgery and radio-chemotherapy, with the possibility of later modifying the protocol to test treatment before surgery.

“This trial primarily aims to demonstrate the safety of CAR-T cells after surgery and radio-chemotherapy,” Migliorini said. “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.”

Migliorini is an inventor on patents related to CAR T-cell therapy and a scientific co-founder and consultant for Cellula Therapeutics, according to disclosures in the study.