Glioblastoma is an extremely aggressive type of brain cancer and is the most common type of primary malignant brain tumor in adults. There is currently no cure for it and, due to its fast-growing nature and location, it is very difficult to treat. But could CAR-T cell therapy – which has been so groundbreaking in treating blood cancers – be the best hope for successfully treating, and perhaps even curing, glioblastoma?
The mainstay of treatment for glioblastoma is surgery, followed by radiation therapy and chemotherapy. However, location is always a critical factor when it comes to the successful treatment of cancer, and in glioblastoma, complete surgical resection is nearly impossible.
Even when it seems as though the tumor has been eradicated, there is a very high chance that it will return. Often cancerous cells are left around the edges of where the tumor has been removed because it is difficult for surgeons to tell where the tumor actually ends and where the healthy cells begin.
CAR-T cell therapy is currently being tested in preclinical and clinical studies as an experimental new way to treat glioblastoma. When it comes to solid tumors, these therapies have struggled to live up to the success they showed in blood cancers. But many studies are beginning to focus on two-pronged approaches, either using CAR-T therapy along with another type of treatment, or CAR-T therapies that target more than one antigen.
Some of these approaches have shown success in mouse models with glioblastoma and, just recently, there have even been CAR-T studies that have shown initial success in humans.
New strategy discovered: vaccine could enable CAR-T cell therapy to eradicate glioblastoma and other solid tumors
One major reason for the lack of success in using CAR-T cell therapies to treat solid tumors is that the T cells only target one antigen. The issue here is that, if some of the tumor cells do not express that antigen, they can essentially evade the T cells’ attack on them.
But a new strategy was developed in 2019, by researchers at the Massachusetts Institute of Technology (MIT) that could overcome that obstacle.
In a study, the researchers enhanced CAR-T cells’ effectiveness against glioblastoma by delivering a vaccine to mice shortly after the engineered T cells were administered. This vaccine, which carried the same antigen targeted by the CAR-T cells, was taken up by immune cells in the lymph nodes, where the CAR-T cells were exposed to it. Not only did this vaccine boost help the engineered CAR-T cells attack tumors, but it also helped to generate host T cells that target other tumor antigens.
Using this approach, the researchers found that they could completely eliminate solid tumors in 60 percent of the animals that were given CAR-T cell therapy along with the booster vaccination, while engineered T cells on their own had almost no effect.
Meanwhile, in a new study conducted this year, the same MIT researchers wanted to explore how the additional T cell response becomes activated. They used the same type of CAR-T cells from their 2019 study and the same vaccine. The mice in the study were given two doses of the vaccine, one week apart.
The researchers found that in these mice, metabolic changes occurred in the CAR-T cells that increased their production of interferon gamma – a cytokine that helps stimulate a strong immune response. This is what helps the T cells to overcome the immunosuppressive environment of the tumor. As the CAR-T cells killed tumor cells expressing the target antigen, host T cells then encountered other antigens from those tumor cells, in turn stimulating the host T cells to target those antigens and help destroy tumor cells.
The researchers also tested their approach in mice with tumors that had different levels of the target antigen. They found that even in tumors where only 50 percent of the tumor cells expressed the target antigen, about 25 percent of the tumors could still be eradicated through a combination of CAR-T cells and host T cells.
In this particular study, the researchers focused on glioblastoma and melanoma, but they believe it could potentially be used to combat other types of cancer as well. The technology used in the study has now been licensed to Elicio Therapeutics, which is working on developing it for potential testing in patients.
CAR-T cells paired with fibrin gel help stop glioblastoma recurrence in mice
In 2021, researchers from the University of North Carolina Lineberger Comprehensive Cancer Center paired a newly developed fibrin gel with CAR-T therapy, delivering it to mice with glioblastoma who had just had surgery to have their tumors removed. The CAR-T cells and gel were specifically placed to fill in the area where the tumor had been removed from.
Although previous studies had shown that administering T cells alone produced limited benefit, the addition of the fibrin gel in this study aided CAR-T cell distribution in the brain by acclimating the T cells to the post-surgical wound environment, while also stopping the tumor from recurring.
To develop the gel, the researchers used concentrations of human fibrinogen, a protein produced by the liver, which was transformed into fibrin with enzymes, before being mixed with CAR-T cells and placed in the post-surgical brain area. The gel then created web-like fibrin scaffolds in the brain, in which the CAR-T cells uniformly entangled themselves into the pores of scaffolds.
The result of this was that nine out of 14 (64%) mice that received the combination of fibrin gel and CAR-T cells were tumor-free 94 days after treatment, compared to only two out of 10 (20%) mice that only received the T cells on their own.
The researchers said if these findings can be replicated in human studies, it would result in a great improvement in current treatment rates for glioblastoma – which, as mentioned previously, often returns, even after surgical resection.
In January 2023, a new study was conducted that built its work on these findings. In a paper published in Science Advances, researchers from the University of Pennsylvania told of how they added CAR-T cells to a gel designed to prevent bleeding post-surgery. When they applied the gel to the surgical wounds of 20 mice right after they had various hard-to-treat solid tumors resected, it prevented recurrence in 19 of them without interfering with healing.
This therapy is now set to be tested in humans with locally advanced breast cancer, according to a Penn Medicine press release.
Although it is not specifically being tested in patients with glioblastoma at this moment in time, it could ultimately still offer hope for treatment outcomes for solid tumors in general – including brain cancer – if it advances through clinical trials.
Clinical success: two CAR-T cell therapies infused into brain shrink tumors in matter of days
As reported in Endpoints news in November, two groups of researchers – one from the University of Pennsylvania and the other from the Mass General Cancer Center – said that their experimental CAR-T therapies had shrunk tumors in patients with glioblastoma just one to three days after receiving the therapies. In both of these ongoing phase 1 studies, the patients received a single infusion of the engineered T cells directly into their heads.
Both groups of researchers designed their CAR-T cell therapies to land a ‘one-two punch’ against glioblastoma in order to attack as much of the tumor as possible. The University of Pennsylvania’s engineered cells include two CAR molecules that target two proteins with a strong connection to glioblastoma, known as EGFR and IL13Ra2. Meanwhile, the Mass General Cancer Center’s therapy uses a CAR that targets a common mutant form of EGFR called EGFRvIII, using it as a homing beacon to attract the engineered cells to attack the cancer. The cells then release a bispecific antibody that targets regular EGFR, recruiting more immune cells to attack the rest of the tumor.
The three patients in the University of Pennsylvania’s study were on their third recurrence of glioblastoma, and had multiple tumors throughout their brains. After receiving the experimental treatment, all three patients are still alive, and two are stable roughly five and three months post-treatment. Two of the three patients in the Mass General Cancer Center’s study are still stable, one for four months so far. However, the third patient’s cancer has resurged.
A one-two punch against glioblastoma: overcoming the challenges of solid tumors
Solid tumors like glioblastoma are notoriously difficult to treat. As mentioned before, CAR-T cell therapies may have been a revolutionary success when it comes to treating blood cancers, but even they are struggling to do the job with solid tumors.
However, all is not lost. As can be seen from the aforementioned studies, whether they be preclinical or clinical, scientists are starting to come up with smart, two-pronged approaches for treating solid tumors, which make use of and enhance the ability of CAR-T cell therapies to target tumor antigens.
Ultimately, this is likely to lead to more successful clinical trials evaluating the use of CAR-T therapy for solid tumors in the future, one day potentially offering a curative option for patients with glioblastoma.
New technologies related to glioblastoma
- Chimeric Antigen Receptor T cell Therapy for GBM – CLM-103 – CellabMED
- Irreversible S1PR2 Antagonists for the Treatment of Inflammation and Fibrosis – Cornell University
- Therapeutic Targeting of TGFb1 – UNIL-CHUV Lausanne