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Under the Microscope: Treating “Invisible” Tumors

Immunotherapies—which use the body’s own immune system to find and destroy cancer—have demonstrated some exciting successes. But what if the immune system can’t even find the cancer?

Medulloblastoma is the most common malignant pediatric brain tumor, affecting between 250 and 500 children in the U.S. annually and accounting for 20 percent of all childhood brain tumors. While new immunotherapies could bring hope to many children and their families, many of these patients have a mutation that enables the tumor to hide from the body’s immune system, making any immunotherapy completely ineffective.

“In general, tumors try to avoid being recognized and attacked by the immune system,” explains Robert Wechsler-Reya, Ph.D., director of the Tumor Initiation and Maintenance Program at the Sanford Burnham Prebys Medical Discovery Institute in La Jolla, California. “Tumors with this mutation can remove a key protein from their surface that is critical for immune system recognition.”

With a V Foundation designated grant, Wechsler-Reya and his team are exploring ways to fight tumors with the mutation, which affects a gene called TP53.

Children whose tumors have the TP53 mutation have an extremely poor prognosis. The standard treatment protocol for medulloblastoma includes surgery to remove the tumor followed by radiation and intensive chemotherapy to eradicate any tumor cells that remain. Immunotherapy could replace or supplement parts of this intense regimen, but only if the immune system can locate the tumor.

 

Making the tumors visible

Wechsler-Reya and his team first observed the effects of the mutation on susceptibility to the immune system when they compared different animal models of medulloblastoma that they had developed in the lab. The immune system rejected models that had normal TP53. However, those that had the mutant form of the gene were accepted, because the immune system couldn’t see them.

If removing a protein renders tumor cells invisible, is there a way to add that protein back and make them visible again? The team tested multiple treatments that they suspected might affect tumor visibility. They observed that one, TNF (tumor necrosis factor), was able to “unmask” the tumor, allowing the immune system to see it and fight it. The body normally makes TNF in times of inflammation or infection.

In experiments in cell cultures, they discovered that a very low dose of TNF could make tumor cells turn on the missing protein, making them recognizable by the immune system. And in mice with medulloblastoma tumors, combining TNF with standard immunotherapy resulted in destruction of the tumors and a marked increase in animal survival.

The team’s next step, in partnership with the Pacific Pediatric Neuro-Oncology Consortium, is to test whether TNF can enhance the effects of immunotherapy in medulloblastoma patients. If all goes well, they hope to launch clinical trials sometime next year.

“Our studies are one example of how you can take an observation that looks promising in the lab and really make it pay off for patients,” said Wechsler-Reya.

 

Thinking big

Not only are these results hopeful for children with medulloblastoma and their families, but they may also be generalizable to other cancers. Laboratory experiments are now underway to test whether TNF can boost immunotherapies for other types of brain tumors, as well as for cancers outside the nervous system. TNF may not work for every cancer, so it will be critical to identify the diseases for which it is most effective.

It’s also possible to learn from studies where TNF doesn’t unmask tumors. If applying TNF is ineffective, there might be another mechanism hiding the tumor from the immune system. Identifying that mechanism will be the first step in overcoming it and treating those cancers.

More studies will also help to deepen our understanding of immunotherapy’s potential. Despite its successes, a majority of patients do not respond to immunotherapy treatments. It’s critical to understand why the immune system does not attack a tumor before we can instruct it to do so.

Wechsler-Reya credits the V Foundation with recognizing the promise in his team’s early findings and helping to speed their discoveries. “This work simply could not have been done without their support,” says Wechsler-Reya. “It’s hard to even capture how important it has been, and we are grateful.”