An Immune-Suppressing Target for Glioblastoma?

The discovery of immune-oncology, which harnesses the body’s own immune system to fight cancer, has brought hope where there was none in diseases like metastatic melanoma and advanced lung cancer. Still, leaders in immuno-oncology recognized that their breakthrough treatments—checkpoint inhibitors—didn’t work in every cancer. And they’ve wanted to know how to change that.

Perhaps the most stubborn outlier has been glioblastoma, the aggressive form of brain cancer that claimed the life of Senator John McCain. In the past year, some signs of hope led researchers to believe they were making progress in this most difficult and deadly of cancers.

Now, a team at The University of Texas MD Anderson Cancer Center in Houston led by original pioneers in the field have published a paper in Nature Medicine that discusses an immune-suppressing enzyme that was strongly present in glioblastoma but not in 5 other tumor types the team studied.

The team combined anti-programmed death-1 (PD-1) and anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) in mice bred to knock out the enzyme, CD73. They found the combination stifled tumor growth, and led to increased survival.

“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,” Padmanee Sharma, MD, PhD, professor or Genitourinary Medical Oncology and Immunology at MD Anderson, said in a statement. Sharma, who is senior author on the research letter in Nature Medicine, worked on the original early trials with ipilimumab that led to the award of the 2018 Nobel Prize in Medicine or Physiology for James P. Allison, PhD, the MD Anderson immunologist who is also an author on the letter.

The paper in Nature Medicine identifies a subset of cells called macrophages—which can aid immune system responses—that had high levels of the CD73 enzyme. The work exemplifies current research that looks not just at the type of cancer but at the common links of the drivers across different cancers. “By studying the immune microenvironments across tumor types, we’ve identified a rational combination therapy for glioblastoma,” first author Sangeeta Goswami, MD, PhD, assistant professor in Genitourinary Medical Oncology, said.

The approach of “reverse translation” calls on scientists to examine human tumors across multiple cancers to derive insights, which are then used to generate hypotheses to be tested on animal models—the inverse of the usual method. In this case, the team examined 94 human tumors from glioblastoma, lung cancer, kidney, prostate, and colorectal cancer to study clusters of immune cells.

This process revealed a concentration of immune cells among the glioblastoma tumors the expressed CD68, a marker for macrophages, along with CD73 and other immune-inhibiting molecules. They confirmed these findings in additional glioblastoma tumors. RNA sequencing revealed an immunosuppressive gene expression signature linked to the CD73 macrophages.

Their presence, the authors speculated, was likely the reason that immunotherapy designed to trigger T-cell responses has not worked in glioblastoma. But to test this theory, they used the CD73 knockout mice.

“We found that the absence of CD73 improved survival in a murine model of glioblastoma multiforme treated with anti-CTLA-4 and anti-PD-1,” they wrote in Nature Medicine.

Now, the task ahead is to design a clinical trial that brings together the combination checkpoint inhibitors with a therapy to target CD73. And more than one company is working on this. Among them: investigators presented data on an agent known as CPI-006 (Corvus Pharmaceuticals) at the annual meeting for the Society of the Immunotherapy of Cancer in November. Another company working on a CD73 target, Surface Oncology, announced $25 million in financing in late November.

Reference

Goswami S, Walle T, Cornish AE, et al. Immune profiling of human tumors identifies CD73 as a combinatorial target in glioblastoma [published December 23, 2019]. Nature Med. DOI: doi.org/10.1038/s41591-019-0694-x.