New Study Reveals that Patient Genetics Can Influence Response to Immune Checkpoint Blockade Therapy

Bottom line: Patient-specific HLA genotype influences response to immune checkpoint inhibitors.

Journal: “Patient HLA genotype influences cancer response to checkpoint blockade immunotherapy” appears in the December 7, 2017, issue of Science.

Authors: The senior author was Timothy A. Chan, MD, PhD, Director, Immunogenomics and Precision Oncology Platform. MSK’s Diego Chowell served as a first author and MSK’s  Luc Morris, Vladimir Makarov, Fengshen Kuo, Sviatoslav Kendall, Nadeem Riaz, David Hyman, Ahmet Zehir, David Solit, Michael Berger, and Robert Samstein were middle author collaborators. Co-senior author was Naiyer Rizvi, MD, of Columbia University Medical Center.

Findings: In the largest-ever genetic analysis of people being treated with checkpoint inhibitors, researchers looked at 1,535 patients who received several checkpoint inhibitors for a number of different cancers at many different hospitals. Researchers found that people who had a greater diversity and more variation in their human leukocyte antigen (HLA) genes responded much better to immunotherapy compared with those who had less diversity.

The researchers looked not only at genetic changes inside the tumor tissue, which many other studies have done, but also at certain genes that people are born with (germline genes). Specifically, they looked at genes that make up the HLA system. These genes are important for regulating the immune system. The HLA system is used to match recipients and donors for stem cell and bone marrow transplants. HLA genes teach immune cells called T cells to recognize what is “self” and what is not. For transplants, the goal is for the donor’s HLA system to be similar enough to the recipient’s that donated T cells will not attack the recipient’s tissues. But in the case of cancer, the goal is also to boost the T cells’ ability to destroy tumor cells.  These findings make it very clear that knowing the genotype of patients as well as the mutations in tumors is critical for determining who benefits from immune checkpoint agents.

The MSK-IMPACT test, which recently received authorization from the US Food and Drug Administration, already analyzes the HLA genes in patients’ blood samples, so MSK care teams can start implementing these new findings right away. Other tests that look at tumor genomes don’t include HLA analysis. 

Corresponding author comments: “Just as tumors with a greater number of genetic changes are more recognizable to immune cells, having more-diverse HLA genes means the immune system has a greater ability to recognize what doesn’t belong inside the body,” said senior study author, Timothy A. Chan, MD, PhD. “Our findings will need to be validated in other studies, but because we included such a large and diverse number of patients, we have made a lot of progress towards using this in the clinic.”

“While the HLA genes that people are born with can’t be changed, learning more about how the immune system recognizes novel proteins can help with the development of new cancer treatments, such as vaccines that could be used on their own or in combination with checkpoint inhibitors,” said Dr. Chan.

Funding: This study was funded by the National Institutes of Health and the National Cancer Institute (grants P30 CA008748, NIH K08 DE024774, and 1R01CA205426), the Damon Runyon Cancer Research Foundation, the Pershing Square Sohn Cancer Research Alliance, the STARR Cancer Consortium, and Stand Up 2 Cancer.