How Cancers Evolve Drug Resistance

Researchers unravel the sophisticated ways cancers evade treatments, including immunotherapies, designed to destroy them

Anna Azvolinsky, The Scientist

Receiving three separate courses of a new class of anticancer immunotherapy agents is not typical for a cancer patient, yet that is what retired Major League Baseball administrator Bill Murray, now 79, endured to treat his melanoma. “When I was told that I might be dying from melanoma, I thought I might as well go for it,” says Murray. In 2011, Murray was given a round of a peptide-based vaccine plus nivolumab (Opdivo), a monoclonal antibody that targets the programmed cell death protein 1 (PD-1) displayed on the surface of T cells, as part of a clinical trial at the Moffitt Cancer Center in Florida. Unfortunately, this two-pronged attack—lasting 12 weeks—didn’t work.

PD-1 is a signaling receptor on activated T cells that functions as an immune checkpoint, tamping down T cell activity when it detects its counterpart, PD-L1, on a tumor cell’s surface. Blocking PD-1 was intended to keep Murray’s T cells actively fighting the cancer. Because his tumors did not completely go away, Murray’s doctor gave him ipilimumab (Yervoy), then a newly approved antibody, which binds cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), also expressed on the same T cells that express PD-1. Ipilimumab also serves as a checkpoint blockade releasing the checkpoint’s break on the immune cells, allowing active T cells to attack cancer. Murray’s tumors began to shrink after 12 weeks of treatment. After several more months, ipilimumab “essentially made his disease disappear,” says Murray’s oncologist Jeffrey Weber, now at New York University.

Five years later, Murray’s cancer resurfaced. Weber decided to use the most powerful immune checkpoint inhibitor regimen on the market: a combination of nivolumab plus ipilimumab that was approved by the US Food and Drug Administration (FDA) in January 2016. Over the last nine months of 2016, Murray received four doses of the combo, and he will continue to receive nivolumab maintenance therapy for a total of 12 months.
So far, Murray says he is feeling fine, and he even flew from New York to Florida to spend the winter. But he will have to be regularly monitored for cancer over the coming years; there are never any guarantees that tumors won’t return. While immunotherapies provide a better chance for a long-term and durable response, Murray’s story highlights that even this new class of cancer treatments is susceptible to drug resistance, a problem that has plagued the field since the first chemotherapies were used in the United States in the 1940s.

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