It’s reasonable to assume immunotherapies such as PD-1 inhibitors, which unleash the body’s own immune system to target and destroy cancer, work best in “hot” tumors that are flooded with immune cells in their microenvironment. But a new study by scientists at the Dana-Farber Cancer Institute found that is not the case in kidney cancer.
The researchers discovered that in advanced clear cell renal cell carcinoma (ccRCC)—the most common form of kidney cancer—tumors that were infiltrated with large numbers of CD8 T cells were less likely to respond to Bristol Myers Squibb’s PD-1 inhibitor Opdivo than “cold” tumors were.
The findings, presented at the American Society of Clinical Oncology virtual event and published in Nature Medicine, provide critical insights that may help predict which patients are more likely to benefit from immuno-oncology agents, the researchers argued.
The Dana-Faber scientists examined 592 tumors collected from three Opdivo kidney cancer clinical trials in an attempt to draw a correlation between patient outcomes and immune and genomic biomarkers. They discovered that kidney cancer deviates from several well-known tenets of cancer treatment. Normally, tumors containing a large number of neoantigens—proteins formed as a result of tumor mutations and therefore new to the immune system—are often more susceptible to immunotherapy. But that didn’t affect ccRCC responsiveness to Opdivo, the team found.
Perhaps most surprisingly, hot tumors with high levels of CD8 T cells didn’t respond well to Opdivo, either. But why?
The researchers found that these hot tumors were depleted of mutated PBRM1 genes, which are often associated with improved survival from PD-1 blockade. Instead, they had more of an unfavorable genetic feature—the loss of a chromosomal segment called 9p21.3. When found within hot tumors, deletion of 9p21.3 was associated with worse clinical benefit and survival after PD-1 treatment.
“We believe that these two factors may explain why CD8 T cell infiltration of the tumors did not make them responsive to checkpoint blocker therapy, while other types of cancer that exhibited CD8 T cell infiltration but did not have those chromosomal changes did respond,” explained co-author Sachet Shukla, Ph.D., chief of the computational group at the Dana-Farber Translational Immunogenomics Laboratory, in a statement.
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The Dana-Farber study offers clues to mechanisms that contribute to response and resistance to PD-1 drugs in ccRCC and possibly other types of tumors as well, the researchers suggested. It can help identify patients most suitable for these immuno-oncology drugs and provide “fundamental information to aid in development of rational combination therapies to overcome resistance in the future,” said study co-author Toni Choueiri, M.D., director of the Lank Center for Genitourinary Oncology at Dana-Farber.
The presence of high numbers of tumor-infiltrating immune cells is often linked to better immunotherapy treatment outcomes. That’s why scientists are constantly looking for ways to turn cold tumors hot. In October, a Yale University team described a method for using gene-editing system CRISPR to make tough-to-spot tumors more visible to the immune system.
Another approach aimed at improving immuno-oncology in kidney cancer involves combining immune-boosting treatments. A combo of BMS' Yervoy with Opdivo was approved for first-line treatment of kidney cancer in 2018. In February of this year, the company unveiled new data showing 56% of patients taking the combo in a trial were still alive at 42 months, versus 47% of patients taking Pfizer's Sutent alone.