Key discovery in understanding successes and failures of immunotherapy

Key discovery in understanding successes and failures of immunotherapy
Key discovery in understanding successes and failures of immunotherapy

A key discovery has advanced the understanding of why some patients respond to ipilimumab, an immunotherapy drug, while others do not. The report, published in the New England Journal of Medicine (2014;371[23]:2189-2199), indicated that patients who respond to ipilimumab have cancer cells that carry a high number of gene mutations. Some of these mutations make tumors more visible to the immune system, and therefore easier to fight.

"We are learning that there are few treatments that don't have some footprint in the cancer genome," said lead researcher Timothy Chan, MD, PhD, vice chair of Radiation Oncology at Memorial Sloan Kettering Cancer Center in New York, New York. "For the first time, it might be feasible to develop a reliable diagnostic test to help guide treatment decisions by predicting who will respond."

Clinical trials of ipilimumab (Yervoy) have produced practice-changing results for many types of cancer. The drug works by blocking the protein CTLA-4, boosting the body's natural immune defense against tumors. Normally, CTLA-4 keeps the tumor-fighting activity of the immune system's T cells in check. In the presence of the drug, T cells are unleashed and their inherent ability to recognize and destroy cancer cells is enhanced.

For some patients, the drug shrinks tumors and significantly prolongs lives. Over the past decade, immunotherapy has signaled a scientific game changer. "We've spent much time and effort studying how to target the tumor. And we've only recently understood how to have the patient's immune defenses mobilized to treat the tumor. Immunotherapy is by definition how that happens," said co-author Jedd Wolchok, MD, PhD, also of Memorial Sloan Kettering.

But the approach does not help everyone. In fact, about 80% of people with melanoma get little or no benefit from ipilimumab. Thus far, doctors have had no way of predicting which patients are more likely to respond to the drug. This new study brings the team one step closer to finding an answer.

The team collected tumor samples from 64 patients with melanoma who had been treated with ipilimumab or tremelimumab, an experimental drug that works in a similar way. The tumors were analyzed by whole-exome sequencing, a method that deciphers DNA changes across all parts of the genome that code for protein. About half of the tumors analyzed came from patients for whom the treatment had been successful and the other half from people who derived little or no benefit from it.

The tumors that responded to the drug were found to have a higher mutational burden, or overall number of DNA changes. However, not all patients with a high mutational burden responded to the drug.

"This made us ask, 'What is the immune system seeing?" said Wolchok. "What is it about the mutational landscape of a tumor that helps the immune system recognize and attack it?"

Using sophisticated computational tools, the researchers were able to explore their data through the lens of immunology. They found that drug-responsive tumors share a certain type of mutation that makes cancer cells express new antigens, which are the substances that T cells can detect and recognize as foreign to the body.

Eventually, these findings could translate into a diagnostic test to detect the mutations in melanoma patients.

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