Drugs that block the immune checkpoints PD-1 and CTLA-4 have transformed the treatment of many tumor types, but not glioblastoma, which accounts for about 17% of all brain tumors and is particularly difficult to beat.
Researchers at the University of Texas MD Anderson Cancer Center say they’ve figured out one reason glioblastoma tumors are resistant to checkpoint blockers—and they’ve come up with a combination treatment that could help address the problem.
The MD Anderson team identified a particular macrophage, a type of white blood cell, that makes an immune-suppressing enzyme called CD73. They analyzed five tumor types and discovered that CD73 macrophages were particularly abundant in glioblastoma. Knocking out CD73 in mouse models of glioblastoma increased survival, and when those mice were treated with PD-1 and CTLA-4 inhibitors, they lived even longer, the researchers reported in the journal Nature Medicine.
What’s particularly interesting about this finding is that several companies are already developing drugs targeting CD73 in cancer. They include Surface Oncology, a 2015 Fierce 15 selection, which raised $35 million and teamed up with Novartis before going public in 2018. ORIC Pharmaceuticals, which is also working on a CD73 inhibitor, has an A-list set of investors and pulled in $55 million in a series D funding earlier this year.
The MD Anderson researchers fingered CD73 as a promising target in glioblastoma using a process called “reverse translation.” Rather than using human cancer cells and animal models to test hypotheses, they analyzed glioblastoma tumors to generate hypotheses. In this case, they studied immune cells from 94 samples of human glioblastoma, as well as lung, kidney, prostate and colon tumors.
Among the 13 glioblastoma tumors they studied, the researchers found a cluster of macrophages expressing high levels of CD73 and other immune-inhibiting substances.
They went on to identify a gene signature for CD73 macrophages and to compare that to 525 glioblastoma samples in the Cancer Genome Atlas. Sure enough, the gene signature for high CD73-expressing macrophages correlated with decreased survival.
So, the MD Anderson team analyzed five glioblastoma tumors from patients that had been treated with Merck’s blockbuster PD-1 inhibitor Keytruda and seven from patients who did not receive PD-1-blocking drugs. They discovered clusters of CD73-expressing macrophages that persisted in spite of the immuno-oncology treatment.
In mouse models of glioblastoma, simply eliminating CD73 was enough to slow tumor growth and increase survival, the MD Anderson team reported. But when they treated the CD73-knockout mice with PD-1 inhibitors or a combination of PD-1 and CTLA-4 blockers, survival improved.
"We're working with pharmaceutical companies that are developing agents to target CD73 to move forward with a glioblastoma clinical trial in combination with anti-PD-1 and anti-CTLA-4 checkpoint inhibitors," said Padmanee Sharma, M.D., Ph.D., professor of genitourinary medical oncology and immunology, in a statement.