What a Year It Was! A Look Back at Research Progress in 2017

I want to wish everyone a Happy New Year! Hope your 2018 is off to a great start.

Over the holidays, the journal Science published its annual, end-of-the-year list of research breakthroughs, from anthropology to zoology. I always look forward to seeing the list and reflecting on some of the stunning advances reported in the past 12 months. Last year was no exception. Science’s 2017 Breakthrough of the Year, as chosen by its editors, was in the field of astrophysics. Scientists were able to witness the effects of the collision of two neutron stars—large stars with collapsed inner cores—smacking into each other 130 million light years away. How cool is that!

Numbered prominently among the nine other breakthroughs were five from biomedicine: gene therapy, gene editing, cancer immunotherapy, cryo-EM, and biology preprints. All involved varying degrees of NIH support, and all drew great interest from readers. In fact, three of the top four vote-getters in the “People’s Choice” category came from biomedicine. That includes the People’s 2017 Breakthrough of the Year: gene therapy success. And so, in what has become a Director’s Blog tradition, I’ll kick off our new year of posts by taking a closer look at these biomedical breakthroughs—starting with the little girl in the collage above, and moving clockwise around the images:

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Precision Oncology: Gene Changes Predict Immunotherapy Response

Cancer Immunotherapy

Caption: Adapted from scanning electron micrograph of cytotoxic T cells (red) attacking a cancer cell (white).
Credits: Rita Elena Serda, Baylor College of Medicine; Jill George, NIH

There’s been tremendous excitement in the cancer community recently about the life-saving potential of immunotherapy. In this treatment strategy, a patient’s own immune system is enlisted to control and, in some cases, even cure the cancer. But despite many dramatic stories of response, immunotherapy doesn’t work for everyone. A major challenge has been figuring out how to identify with greater precision which patients are most likely to benefit from this new approach, and how to use that information to develop strategies to expand immunotherapy’s potential.

A couple of years ago, I wrote about early progress on this front, highlighting a small study in which NIH-funded researchers were able to predict which people with colorectal and other types of cancer would benefit from an immunotherapy drug called pembrolizumab (Keytruda®). The key seemed to be that tumors with defects affecting the “mismatch repair” pathway were more likely to benefit. Mismatch repair is involved in fixing small glitches that occur when DNA is copied during cell division. If a tumor is deficient in mismatch repair, it contains many more DNA mutations than other tumors—and, as it turns out, immunotherapy appears to be most effective against tumors with many mutations.

Now, I’m pleased to report more promising news from that clinical trial of pembrolizumab, which was expanded to include 86 adults with 12 different types of mismatch repair-deficient cancers that had been previously treated with at least one type of standard therapy [1]. After a year of biweekly infusions, more than half of the patients had their tumors shrink by at least 30 percent—and, even better, 18 had their tumors completely disappear!

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A Surprising Match: Cancer Immunotherapy and Mismatch Repair

Anti-PD-1 Immunotherapy

How Anti-PD-1 Immunotherapy Works. Before immunotherapy (top), the tumor cell’s PD-1 ligand, or PD-L1, molecule (red) binds to a type of white blood cell called a T-cell in a way that enables the tumor cell to evade destruction by the immune system. During immunotherapy (bottom), an anti-PD-1 inhibitor drug (bright green) blocks PD-L1 binding, enabling the T cell to target the tumor cell for destruction.
Credit: NIH

Mismatch repair genes have long been a source of fascination to basic biologists. Normally, these genes serve to fix the small glitches that occur when DNA is copied as cells divide. Most of the original work was done in bacteria, with no expectation of medical relevance. But, as often happens, basic science studies can provide a profoundly important foundation for advances in human health. The relevance of mismatch repair to cancer was dramatically revealed in 1993, when teams led by Bert Vogelstein of Johns Hopkins University School of Medicine, Baltimore, and Richard Kolodner, then of Harvard Medical School, Boston, discovered that mutations in human mismatch repair genes play a key role in the development of certain forms of colorectal cancer [1, 2].

That discovery has led to the ability to identify individuals who have inherited misspellings in these mismatch repair genes and are at high risk for colorectal cancer, providing an opportunity to personalize screening by starting colonoscopy at a very early age and, thereby, saving many lives. But now a new consequence of this work has appeared. Vogelstein and his colleagues report that mismatch repair research may help fight cancer in a way that few would have foreseen two decades ago: predicting which cancer patients are most likely to respond to a new class of immunotherapy drugs, called anti-programmed death 1 (PD-1) inhibitors.

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