By analyzing tumors from patients treated with immunotherapy for advanced kidney cancer in three clinical trials, scientists have identified several features of the tumors that influence their response to immune checkpoint inhibitors. The research was presented during the ASCO20 Virtual Scientific Program (Abstract 5010) and published simultaneously by Braun et al in Nature Medicine.
The researchers say the study provides important clues about kidney cancer genetics and their interaction with the immune system that may prove to be vital in the ability to predict which patients are likely to benefit from immunotherapy. The study showed that features that are typically linked to immunotherapy response or resistance in other types of cancer don't work the same way in advanced clear cell renal cell cancer.
David Braun, MD, PhD
“Kidney cancer breaks all those rules,” said first study author David Braun, MD, PhD, a kidney cancer specialist at Dana-Farber Cancer Institute.
Clear Cell Renal Cell Carcinoma Characteristics
Clear cell renal cell carcinoma is the most common form of kidney cancer. There are about 74,000 new cases of kidney cancer in the United States each year and about 15,000 deaths. Checkpoint inhibitors such as pembrolizumab and nivolumab—programmed cell death protein 1 (PD-1) inhibitors—are often used to treat patients with advanced kidney cancer, who generally don’t respond to standard chemotherapy.
In cancers such as melanoma and lung cancer, checkpoint inhibitors tend to be more effective against tumors with a high mutational burden. Advanced clear cell renal cell carcinoma, by contrast, has a moderate number of mutations yet is relatively responsive to checkpoint inhibitors.
Another puzzling difference is that in melanoma and some other cancers, tumors that are infiltrated with large numbers of immune CD8 T-cells, creating a “hot” environment within the tumor, respond better to PD-1 blockade. However, the reverse is true in advanced kidney cancer—high infiltration by CD8 T-cells is associated with a worse outcome.
Methods
In this study, the scientists analyzed 592 tumors collected from patients with advanced kidney cancer who were enrolled in clinical trials of PD-1 inhibitors. They used whole-exome and RNA sequencing and other methods to uncover genomic changes, and tracked the patients’ progression-free survival and overall survival.
The study was aimed at determining what features of advanced kidney cancer cells were associated with response or resistance to PD-1 inhibitors. In analyzing the tumors, the investigators looked for biomarkers in the genomes of the kidney cancer cells that might be correlated with patient outcomes.
Results
Dr. Braun said that some of the most interesting findings were characteristics of the kidney tumors that—unlike with other types of cancer—did not influence responsiveness to PD-1 inhibitors. For example, kidney tumors containing a large number of neoantigens—proteins made by cancer-related DNA mutations that may make tumors more responsive to immunotherapy—did not show increased response to checkpoint inhibitors. Also, even though the kidney tumors were heavily infiltrated by CD8 immune T-cells, this led to no difference in outcome for these patients.
“To our surprise, the immunologically ‘hot’ tumors did not respond any better than the ‘cold’ tumors,” said Dr. Braun.
“To our surprise, the immunologically ‘hot’ tumors did not respond any better than the ‘cold’ tumors."— David Braun, MD, PhD
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Another factor that affects responsiveness in some types of cancer—the specific HLA molecules inherited by individuals that present antigens to the immune system—didn't affect the immune response in advanced kidney tumors.
“That surprised us,” said coauthor Catherine J. Wu, MD, Chief of Division of Stem Cell Transplantation and Cellular Therapies. “We reasonably hypothesized that the potential of the patient's immune system to present and react to a greater diversity of antigens may be associated with better outcomes, but clearly kidney cancer does not fit the standard mold,” she noted.
“However, we did uncover some factors that may explain the unexpected observations,” added coauthor Sachet Shukla, PhD, who leads the computational group at the Dana-Farber Translational Immunogenomics Laboratory. The study uncovered the finding that advanced kidney tumors heavily infiltrated with CD8 T-cells did not respond well to immune checkpoint blockers even though they were immunologically “hot” tumors. The scientists, with their comprehensive analysis of changes in the kidney tumors' genomes, found that the tumors were depleted of mutated PBRM1 genes—which are correlated with improved survival with PD-1 blockade therapy—and also had an abundance of deletions of a chromosomal segment known as 9p21.3, which is associated with worse outcomes with PD-1 blockade.
“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 Dr. Shukla.
“The current study provides critical insights into immunogenomic mechanisms contributing to response and resistance to immunotherapy in clear cell renal cell cancer."— Toni Choueiri, MD
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“The current study provides critical insights into immunogenomic mechanisms contributing to response and resistance to immunotherapy in clear cell renal cell cancer,” said senior author Toni Choueiri, MD, Director of the Lank Center for Genitourinary Oncology and the Jerome and Nancy Kohlberg Professor of Medicine at Harvard Medical School. “The detailed clinical, genomic, transcriptomic, and immunopathology data produced by this study will serve as a valuable resource for the cancer immunology community. This work, therefore, will be important for ongoing research in precision medicine and immuno-oncology, helping to identify which patients are likely to respond to current therapies, and providing fundamental information to aid in development of rational combination therapies to overcome resistance in the future.”
Disclosure: The research was supported in part by Dana-Farber/Harvard Cancer Center Kidney Cancer SPORE (P50-CA101942-12) and program, DOD CDMRP (W81XWH-18-1-0480), and in part by Bristol-Myers Squibb. For full disclosures of the study authors, visit coi.asco.org or nature.com.
