Proliferative potential and response to nivolumab in clear cell renal cell carcinoma patients

Abstract

Background: Biomarkers predicting immunotherapy response in metastatic renal cell cancer (mRCC) are lacking. PD-L1 immunohistochemistry is a complementary diagnostic for immune checkpoint inhibitors (ICIs) in mRCC, but has shown minimal clinical utility and is not used in routine clinical practice. Methods: Tumor specimens from 56 patients with mRCC who received nivolumab were evaluated for PD-L1, cell proliferation (targeted RNA-seq), and outcome. Results: For 56 patients treated with nivolumab as a standard of care, there were 2 complete responses and 8 partial responses for a response rate of 17.9%. Dividing cell proliferation into tertiles, derived from the mean expression of 10 proliferation-associated genes in a reference set of tumors, poorly proliferative tumors (62.5%) were more common than moderately (30.4%) or highly proliferative (8.9%) counterparts. Moderately proliferative tumors were enriched for PD-L1 positive (41.2%), compared to poorly proliferative counterparts (11.4%). Objective response for moderately proliferative (29.4%) tumors was higher than that of poorly (11.4%) proliferative counterparts, but not statistically significant (p = .11). When cell proliferation and negative PD-L1 tumor proportion scores were combined statistically significant results were achieved (p = .048), showing that patients with poorly proliferative and PD-L1 negative tumors have a very low response rate (6.5%) compared to moderately proliferative PD-L1 negative tumors (30%). Conclusions: Cell proliferation has value in predicting response to nivolumab in clear cell mRCC patients, especially when combined with PD-L1 expression. Further studies which include the addition of progressionfree survival (PFS) along with sufficiently powered subgroups are required to further support these findings.

RB1 and TP53 co-mutations correlate strongly with genomic biomarkers of response to immunity checkpoint inhibitors in urothelial bladder cancer

“…A recent study on clear cell renal carcinoma treated with nivolumab identified the proliferative ability, measured by the mean expression rank value of 10 proliferation related genes, as a response predictor in these patients. Patients with a lower proliferation rate had poorer responses [ 28 ]. Furthermore, a recent phase II basket trial of dual blockade with ipilimumab (anti-CTLA4) and nivolumab (anti-PD1) in nonpancreatic neuroendocrine tumors showed an impressive 44% response rate (8 out of 18 patients) in high grade tumors versus 0% (0 out of 14 patients) in low or intermediate grade tumors [ 29 ].…”

Novel Therapies for Tongue Squamous Cell Carcinoma Patients with High-Grade Tumors

“…However, the disadvantages of these prevalent biomarkers suggested that novel robust biomarkers are needed. A previous study found that 10 cell proliferation genes, including BUB1, CCNB2, and CDK1, could act as indicators for response to immune checkpoint inhibitors in PD-L1 negative renal cell carcinoma [ 43 ]. In the present study, the six hub proteins were found to be negatively correlated with most immune cell types such as CD4 T cell, B cell, and CD8 T cell ( Figure 3 ).…”

Tumor Inflammation, Obesity, and Proliferative Status as Biomarkers in Gastroesophageal Adenocarcinoma

“…In obese patients, several factors work together to result in T-cell dysfunction, ultimately leading to an exhausted T-cell phenotype [20]. Our previous work in a metastatic GEAC population showed that overweight individuals (BMI ≥ 25) were more likely to express PD-L1 in their TME than normal-weight individuals [21]. In addition, many other immune suppressive markers, such as FOXP3 and IDO1, were found to be upregulated in the obese group.…”