Aug 18: A new Phase I clinical trial has found that an emerging immunotherapy is promising for the treatment of recurrent glioblastoma, a highly aggressive and fatal brain cancer.
Chimeric antigen receptor Tcell therapy is a form of immunotherapy that modifies an individual’s own T cells (a type of immune cell) so that they are better able to recognize and destroy cancer cells. The new clinical trial, the results of which were published Aug. 6 in Nature Medicine, focuses on a form of CAR-T therapy that trains these immune cells to target a protein known as B7-H3, which is highly prevalent in most glioblastomas.
To determine the safety of B7-H3-targeting CAR-T cell therapy, a team of researchers tested three doses of the treatment in a small cohort of patients whose cancer was not responsive to standard therapies. They found that participants tolerated the therapy well and identified a recommended dose for future research.
Furthermore, the researchers observed that in over half of the participants, the tumors stopped growing or reduced in size for as long as three years post-treatment—including one participant whose cancer has remained to this day in complete remission. B7-H3-targeting CAR-T cell therapy could bring new hope to patients living with treatment-resistant recurrent glioblastomas who currently have few, if any, options, the team says.
“We are excited about figuring out how to treat currently untreatable cancers,” says Lieping Chen, MD, PhD, United Technologies Corporation Professor in Cancer Research and professor of immunobiology and of medicine at Yale School of Medicine and one of the study’s co-principal investigators.
Collaborators on the study included a neurosurgical team at Beijing Tiantan Hospital led by Nan Ji, MD, and a team led by Gangxiong Huang, MD, at Tcelltech, a biotech company preparing clinical grade CAR-T cells.
A protein upregulated in cancers
The standard therapy for glioblastoma is a combination of surgery and chemotherapy. In the majority of cases, however, the cancer returns, often in an even more aggressive and treatment-resistant form. Due to the lack of treatment options, the median life expectancy for patients with recurrent glioblastoma is less than a year.
Chen’s laboratory first identified back in 2001 that the protein B7-H3 is highly upregulated in cancer cells, especially solid tumors such as colorectal, lung, and breast cancers. It’s still unclear to scientists why this molecule is so prevalent in tumors and not in healthy tissues. But since its discovery, researchers have been exploring it as a target for new cancer therapies. Ongoing trials, for example, are studying the efficacy of B7-H3 as a target for antibody-drug conjugates, a cancer treatment in which antibodies bind to proteins on cancer cells to more directly deliver chemotherapy drugs.
The majority of glioblastomas also express B7-H3. But brain cancers are especially challenging to treat because many emerging therapies such as antibody-drug conjugates can’t pass through the blood-brain barrier. Thus, these therapies have had minimal success in treating glioblastomas, previous research shows.
Modifying T cells to target B7-H3
Clinicians most commonly use CAR-T cell therapy to treat blood cancers. But in the new Phase I trial, Chen’s team designed a form of CAR-T cell therapy that targets B7-H3 and studied its effects in 15 patients with recurrent glioblastoma that had not responded to available therapies.
First, the scientists biopsied the tumors to make sure they expressed B7-H3. Then, they drew blood from all of the participants and used a process called leukophoresis to enrich their T cells. In order to “educate” the T cells to target B7-H3, they added a gene into the immune cells that produces a protein that binds to B7-H3. This enabled the modified immune cells, called CAR-T cells, to recognize B7-H3 and attack the cancerous cells after being returned to the patients.
“One of the advantages of this kind of therapy is that it’s quite safe because we use the patient’s own material,” says Chen, a member of Yale Cancer Center. “We do a little engineering on the cells and put them back.”
The researchers studied the effects of the therapy at three different dose levels. To get around the blood-brain barrier, the team injected the cells directly into the tumor site on the brain through a catheter. Because some clinicians use catheters to more easily and directly administer cancer drugs, some participants already had one placed from previous treatments.
CAR-T cell therapy shows promising initial efficacy
The trial found that in most participants, B7-H3-targeting CAR-T cell therapy was associated with manageable side effects such as fever, vomiting, and itchy skin. Three participants experienced more serious side effects including increased intracranial pressure and epilepsy, but these adverse events were manageable with clinical intervention. Because severe side effects were most often associated with the highest dose level, the researchers are recommending the second dose level for this therapy going forward.
While the primary goal of the trial was to evaluate the safety of the CAR-T cell therapy, the researchers also monitored cancer growth post-treatment. In eight of the participants, the cancer had stabilized or even reduced in size. Notably, one patient experienced complete remission of the cancer.
“We’re seeing tumors get smaller in patients who have had no other option,” Chen says. “For a Phase I trial, it is very encouraging to already be seeing clinical effects.”
The researchers are now further studying the efficacy of this therapy in a Phase II clinical trial, where they hope to recruit even more patients with recurrent glioblastoma. They are also exploring ways to further engineer CAR-T cells to improve the therapy so that it is more effective in killing cancerous cells and that its effects last longer. They plan to study this second-generation therapy over the next several months.
“Hopefully this will bring even more benefits to patients,” Chen says.
