Researchers gain insight into factors influencing immunotherapy response in kidney cancer
Tumor mutational burden is considered a hallmark indicator of a tumor’s potential for response to immunotherapy.
PD-1 checkpoint inhibitors such as pembrolizumab (Keytruda, Merck) and nivolumab (Opdivo, Bristol-Myers Squibb) have been shown to be more effective in treating tumors with high mutational burden. However, despite having only a moderate number of mutations, advanced clear cell renal cell cancer is relatively responsive to PD-1 blockade.
A study at Dana-Farber Cancer Institute sought to identify characteristics of advanced kidney tumors that influence their response to PD-1 inhibitors.
The results surprised researchers.
“The features that oncologists associate with response to immune therapy, like high tumor mutational burden or a high level of infiltrating T cells, were not associated with better response or better survival in this cohort,” David Braun, MD, PhD, a Dana-Farber kidney cancer specialist and first author of the study, said in an interview with Healio. “So, we can’t just take the lessons learned from other tumor types and think it will directly apply to kidney cancer. They are just not predictive.”
Braun spoke with Healio about the study, presented during this year’s ASCO20 Virtual Scientific Program and published simultaneously in Nature Medicine, and its potential implications for treatment of this common form of kidney cancer.
Question: What are the typical characteristics of tumors that respond to immunotherapy?
Answer: The classic paradigm for a tumor that will respond to immunotherapy is a tumor with a lot of mutations. These mutations create new antigens, neoantigens, that can be recognized by the immune system. Kidney cancer is different. It’s not a high mutation-load cancer, and so it doesn’t quite fit the mold.
Q: What was the purpose of this study?
A: Immune therapy has entered the front line for the treatment of advanced kidney cancer and has changed the lives of many patients with this disease. However, most patients ultimately will develop resistance and will relapse and progress. My interests lie in understanding why certain patients respond to this therapy and others don’t. This will hopefully enable better patient selection. More importantly, it will give us insight into the mechanisms of resistance to this treatment so that we can rationally design new combinations of therapies and improve the response for future patients.
Q: What did the study reveal?
A: In this study, some of the negative results were the most surprising and informative. Factors such as high tumor mutational burden or a high level of infiltrating T cells were found not to be predictive. One potential explanation for this finding is that tumors that are highly infiltrated with T cells appear to have different genomic profiles. Specifically, they have chromosomal changes that make them more likely to be aggressive tumors.
Q: What did you learn in terms of how to overcome the mechanisms of resistance you mentioned?
A: This is a work in progress, and this study provides an initial roadmap to investigate mechanisms of resistance. Of equal importance, we’ve learned that we can’t simply look at one factor in isolation anymore. Looking only at mutations in a tumor, or only the infiltration of T cells at this bulk genomic level is not an effective approach for such a complex process like antitumor immunity. We need to integrate pieces of data and take a deep dive into these different cell types. I think that’s a lesson learned, and hopefully our study will provide a framework for that approach.
Q: What will your next steps be for studying immunotherapy in kidney cancer?
A: One step will be to directly validate our findings so far. When we did this study, the patients received therapy in the second line or third line, which is where these drugs originally were approved. Now, PD-1 blockade is part of the standard of care for first-line therapy. The next step is seeing whether these findings are also true in the first-line setting, because that’s going to be most relevant to our patients today.
Further, although the analysis we performed used modern immunogenomic approaches, they still have a fundamental problem. Basically, we take the tumor out, put it into a blender, extract the DNA and RNA and try to piece together what would happen. We don’t have an idea of what the individual cells are doing. A tumor is a complex ecosystem where there are immune cells, tumor cells and stromal cells. Having a cell-by-cell understanding of what’s going on is going to be critical to understanding response and resistance, and this will require analysis at the single-cell level.
So, although we have some leads, we have not yet identified any clinical biomarkers. There are indications of important biology that need to be followed up and understood. Hopefully, that will lead to biomarkers and beyond that, to better treatment for our patients.
For more information:
David Braun, MD, PhD, can be reached at 450 Brookline Ave., Boston, MA 02215; email: firstname.lastname@example.org.