Determinants of Resistance to Nivolumab in Advanced Kidney Cancer

At the American Society of Clinical Oncology (ASCO) annual meeting, a study was presented that sought to evaluate why advanced renal cell carcinoma (RCC) patients receiving initial treatment with single-agent nivolumab (Opdivo) develop resistance to the PD-1 inhibitor.

In this exclusive MedPage Today video, investigator David A. Braun, MD, PhD, of the Center of Molecular and Cellular Oncology at Yale Cancer Center in New Haven, Connecticut, discusses findings from the genomic and transcriptomic analysis and explains the next steps for the research.

Following is a transcript of his remarks:

This was the scientific analysis of a clinical trial testing the antibody nivolumab in kidney cancer. This is a classic immunotherapy drug that we use in kidney cancer, and the goal was really to try to understand, can we use some advanced genomic techniques — like single-cell RNA sequencing — to really try to understand what are things that might impact response to this therapy, either positively or negatively.

So we performed single-cell RNA sequencing on a subset of patients that were part of this trial. And really, the goal was to ask, can we find any particular cell types within their tumors — individual cell types, cell states, or even cell-cell interactions — that might lead tumors to be more responsive, or unfortunately, more resistant to the therapy.

And so when we performed this analysis we actually, interestingly, identified a particular T-cell population. We think of T cells as sort of good soldiers for the immune system — really helpful and positive for antitumor responses. But this particular T-cell population — it was marked by expression of a gene called SLAMF7 — was associated with resistance to nivolumab. So those patients that had high levels of this T-cell population had, unfortunately, higher rates of progressive disease and worse outcomes — worse progression-free and overall survival.

And so our work was really a discovery effort to see what within the tumor might impact response. But we’re now going through multiple steps of validation. Now that we’ve honed in on this particular T-cell population, we have to ask, is this really true? Is this something we see not just in this small cohort of patients, but in other clinical trials as well? And that work is ongoing. And then is it really functional? Meaning is this just a marker of resistance to a particular type of therapy, or is this potentially a therapeutic target where we might be able to, not just identify, but actually hit it with a new type of therapy that might allow us to overcome resistance in a rational way? And those are the two next-step areas of this work.