Assays of Intratumoral Heterogeneity May Predict RCCs Likely to Respond to PD-1 Blockade

January 21, 2021
Hannah Slater

“Our results suggest that low [intertumoral heterogeneity] is associated with increased response to anti–PD-1 immunotherapy in renal cell carcinoma through increased immune activity involving more neoantigens and less frequent immune evasion,” wrote the study authors, led by Xia Ran.

Data from a study published in Therapeutic Advances in Medical Oncology suggest that assays determining intratumor heterogeneity (ITH) could be helpful in determining which patients with renal cell carcinoma (RCC) are more likely to respond to PD-1 blockade.

Moving forward, the investigators suggested that understanding the mechanism by which ITH impacts response to PD-1 inhibitors may provide insights into how ITH could affect cancer therapy and patient survival, and aid in the development of predictive biomarkers for response to immune checkpoint therapy (ICT).

“A key unanswered question in RCC is whether and which genomic metrics are correlated with clinical benefit of ICT,” wrote the study authors who were led by Xia Ran. “Our results suggest that low ITH is associated with increased response to anti–PD-1 immunotherapy in RCC through increased immune activity involving more neoantigens and less frequent immune evasion.”

Among patients with clear cell RCC (ccRCC; n = 336) and papillary RCC (pRCC; n = 280) taken from The Cancer Genome Atlas, investigators quantified ITH using mutant-allele tumor heterogeneity (MATH). An independent cohort of 152 patients with ccRCC was used to validate the findings. Additionally, to assess the relationship between ITH and response to anti–PD-1 immunotherapy, 35 patients with metastatic ccRCC from a clinical trial of anti­–PD-1 therapy were evaluated with results validated across 3 equal-size simulated data sets (n = 60) generated by random sampling with replacement based on the trial cohort.

Of those with ccRCC, low ITH was found to be associated with response to anti­–PD-1 immunotherapy through increased immune activity involving more neoantigens, elevated expression of human lymphocyte antigen class 1 genes, and greater abundance of dendritic cells. Moreover, the investigators also revealed that among patients with ccRCC, the association between the level of ITH and response to PD-1 blockade was independent of PBRM1 mutation status and that taking both factors into consideration resulted in better performance when compared with the individual predictors in determining prognosis with anti–PD-1 immunotherapy.

In patients with pRCC, increased immune activity was greater in patient with low-ITH status, which included greater neoantigen counts, increased amounts of monocytes, and decreased expression of PD-L1 and PD-L2.

“In this study, we quantified ITH using MATH based on the allele frequencies of somatic mutations,” the authors noted. “Admittedly, there are other well-designed tools (eg PyClone, EXPANDS, and ABSOLUTE) quantifying ITH based on not only somatic mutations, but also other metrics such as copy number estimates and loss of heterozygosity. While taking more parameters into account may improve the accuracy of ITH quantification, it also means more complex analyses and longer run time, which is not conducive to large-scale clinical application.”

Ultimately, based on their findings, the investigators indicated MATH may be a quick and accurate measurement of ITH in RCC. However, it was also suggested that the cutpoint of MATH scores for ccRCC and pRCC will need further preclinical and prospective clinical validation in order to be used for large-scale clinical application.

Reference:

Ran X, Xiao J, Zhang Y, et al. Low intratumor heterogeneity correlates with increased response to PD-1 blockade in renal cell carcinoma. Ther Adv Med Oncol. 2020;12:1-17. doi:10.1177/1758835920977117