Haydn Kissick: Cabozantinib as a neoadjuvant therapy for patients with clear cell RCC
Haydn Kissick, Assistant Professor at Emory University, shared a post on X:
“Check out our new paper, studying the effects of cabozantinib as a neoadjuvant therapy for patients with clear cell renal cell carcinoma.
To my surprise, large effect on T cell infiltration in tumors post-therapy, thread below.
Patients with advanced ccRCC received 12 weeks of Cabozantinib followed by nephrectomy. All patients had a reduction in tumor size over the 12 weeks, 6/17 had an objective PR in that time. 2 patients downgraded from full to partial nephrectomy, 1 unresectable -> resectable.
Changes in cfDNA over the course of the treatment were associated with the overall reduction in tumor size, suggesting this could be a marker to investigate in future trials. Blood markers including VEGF and cMet increased while on treatment and could also be investigated.
Now what I actually know about..
I was surprised to see some patients showing new CD8 T cell activation. HLA-DR/CD38 are the same we see in PD1 treated patients. It wasn’t quite significant, but there are clearly patients that have a T cell response early.
Most consistent feature of the immune response in blood was big decline in classical monocytes. We didn’t measure MDSCs because of the method we froze blood samples, but this seems in line with several studies suggesting Cabzantinib inhibits myeloid cell generation.
Having baseline biopsy and surgical specimens, we could look at how the immune response changed in tumors. Every patient had an increase in CD8 T cells in their tumor compared to their biopsy baseline and disease matched controls by IF. Same result by FACS.
Most interesting to me was that the immune niches we previously described where TCF1+ stem-like CD8 T cells are located in tumors, were all greatly increased in treated patients. We believe these niches are required to both generate a T cell response, and respond to PD1.
Interestingly, the patients who had the highest decline in tumor size (PR) had a much higher level of these niches in their tumor.
Overall, very interesting to me as an immunologist. Generally ~50% of kidney tumors have very poor immune infiltration, but after Cabozantinib treatment, 100% of patients looked like the top quartile of all patients we have looked at.
Across many cancer types, PD1 blockade is much less effective in low T cell tumors, so cabo might be a drug that can turn cold tumors hot, something we have been looking for for a long time. Mouse experiments are ongoing and building on lots of prior research on this topic.
Most thankful to Baohan Vo, the scientist who led all the research and kept the team running strongly, my 2 good friends
Mehmet Asim Bilen and Viraj Master who are exceptional people who run these difficult neo-adjuvant trials, and Winship Cancer Institute of Emory University and Nature Cancer for their support.”
Authors: Mehmet A. Bilen et al.
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