David A. Braun, MD, PhD from Dana Farber discusses an ASCO 2020 abstract entitled Immunogenomic characterization of advanced clear cell renal cell carcinoma treated with PD-1 blockade
The treatment of many advanced malignancies, including clear cell renal cell carcinoma (ccRCC), has modified immune control point inhibitors targeting the PD-1 pathway, but the PD-1 response drivers and resistors remain incompletely elucidated. In addition, the widespread paradigm in solid tumor immunology that pre-existing infiltration of CD8 + T cells in combination with large numbers of nonsynonymous mutations (which may be viewed as neoantigens in the sense of various HLA class I alleles) drives response to PD-1 blockade has not been thoroughly studied in ccRCC.
We examined 592 tumors obtained from advanced ccRCC patients participating in prospective clinical trials (CheckMate 009, CheckMate 010, CheckMate 025) of PD-1 blockade treatment (n = 362) or mTOR inhibition (as control arm; n = 230) of complete exome (n = 454) and RNA sequencing (n = 311), integrated with CD8 immunofluorescence analysis (n = 219), to detect immunogenomic determinants of therapy. Wilcoxon rank-sum test was used to compare somatic alteration burden between clinical benefit (CB) v.s no CB (NCB); Fisher 's exact test was used to compare mutations and copy number alteration by infiltration status; and Cox PH model determined hazard ratio (HR) for progression-free (PFS) and overall survival (OS) endpoints. All the measurements were at a degree of significance of p < 0.05.
Conventional genomic markers (tumor mutation burden, p = 0.81; neoantigen load, p = 0.47 for CB vs. NCB) and degree of penetration of CD8 + T cells (p = 0.88 for PFS; p = 0.65 for OS) were not associated with PD-1 blockade clinical response or altered survival. These advanced ccRCC tumors were heavily infiltrated with CD8 + T cells, with just 22% having an immune desert phenotype and 5% having an immune-excluded phenotype. Our study showed that CD8 + T cell infiltrated tumors are depleted from clinically beneficial PBRM1 mutations (p = 0.013) and enriched with unfavorable 9p21.3 (p < 0.001) chromosomal losses relative to non-infiltrated tumours. In the case of infiltrated tumors, del(9p21.3) was associated with a lower CB rate (36% (9/25) for del(9p21.3) vs. 88% (7/8) for wildlife at that locus, p = 0.017) and a lower PD-1 blockade rate (HR = 2.38, p = 0.01 for PFS; HR = 2.44, p = 0.01 for OS).
These data show how therapeutic effectiveness in advanced ccRCC is impaired by the possible association of immunophenotypes with somatic mutations and chromosomal alterations.