One of the major breakthroughs in cancer treatment is CAR-T technology, which involves genetically modifying a patient’s own immune cells so they can recognize and attack cancer. But while the innovation has benefited patients with certain blood malignancies, progress in solid tumors remains limited.
Now, scientists at McMaster University and the University of Toronto have developed a CAR-T therapy for the aggressive brain cancer glioblastoma. It helped reduce tumor burden and improved survival in mouse models, according to a new study published in the journal Cell Stem Cell.
The researchers were so encouraged by the findings that they launched a startup called Empirica Therapeutics, which aims to bring the CAR-T drug into clinical trials in recurrent glioblastoma patients by 2022.
For each CAR-T construct, T cells are modified to produce a special structure called a chimeric antigen receptor (CAR) that gives the cells the ability to recognize a specific protein on cancer cells. The two FDA-approved CAR-Ts, Novartis’ Kymriah and Gilead Sciences’ Yescarta, are directed toward CD19. The CAR-T cell Empirica is developing targets CD133, also known as prominin-1.
In a 2003 Cancer Research study, a McMaster University team identified a group of neural stem cells from human brain tumors that bear CD133 on their surface. They found these CD133-expressing cells could differentiate into cells identical to the original tumor, suggesting these stem cells are necessary for glioblastoma tumor growth.
For the current study, the team tested three types of treatments in lab dishes and in mice. The first was a human IgG antibody that binds to CD133 on glioblastoma cells. The second was a bispecific T-cell engager antibody (BiTE), which can recruit cytotoxic T cells to kill tumor cells. The third was the CAR-T, known at Empirica as eCAR-133.
“We found that the CAR-T therapy had enhanced activity compared to the other two therapeutics in preclinical models of human glioblastoma,” Parvez Vora, the study’s first author and director of preclinical development at Empirica, said in a statement.
Moreover, the CAR-T drug didn’t induce any acute systemic toxicity in mice, showing it wouldn’t disrupt hematopoiesis, a vital process in the human body that leads to the formation of blood cells, Vora said.
The potent clinical responses from CAR-T cells in blood cancers have sparked interest in exploring the approach in solid tumors, including hard-to-treat glioblastoma. A research team at City of Hope recently designed a novel CAR based on chlorotoxin, a toxin found in scorpion venom, and recorded promising results of the CAR-T cells in mice with glioblastoma xenografts.
There are many obstacles ahead. For one thing, the glioblastoma tumor microenvironment is notoriously immunosuppressive, which could dampen CAR-T cells’ activity once they arrive at the tumor site.
Besides CD133, other glioblastoma CAR-T targets that have been floated include IL-13Ra2 from City of Hope researchers, CSPG4 from a team at the University of North Carolina, NKG2DL and EGFRvIII, among others. One possibility could be a combo of CAR-T and BiTE technologies. Last year, a team led by Massachusetts General Hospital designed a CAR-T that also expressed BiTE to activate bystander T cells against tumors. The CAR-T/BiTE cells eliminated tumors in mouse models of glioblastoma.
The Empirica scientists are also exploring combination strategies for their CD133-targeting CAR-T to treat glioblastoma. "We hope that our work will now advance the development of really new and promising treatment options for these patients," said co-author Sheila Singh, professor in the department of surgery at McMaster and CEO of the startup.