ICI has improved outcomes in advanced melanoma with often durable response. Mixed responders are an interesting subgroup of responding patients (pts) to identify mechansims of resistance to ICI.
Stage IV melanoma pts treated with ICI achieving mixed response were retrospectively screened for available samples containing sufficient tumor at at least 2 time-points. Included pts were divided among groups based on sample characteristics: regressive and progressive lesion at same site (group A, n=1), regressive and new lesion at other site (group B, n=2), and regressive and progressive lesion at different sites (group C, n=3). Of these pts, matched CD8+ IHC stainings (4 pts) plus RNAseq (5 pts) and DNAseq (3 pts) were performed.
The table gives an overview of patients and their tumor lesions. The progressive vs regressive lesion of pt 1 (group A) had more CD8+ cells/mm2 but a decrease of RNAseq T cell expression and a decreased IFNy score [Table]. Unlike group A, both pts in group B had increased IFNγ scores in their new progressive vs regressive lesion. However, pt 2 had less CD8+ cells/mm2 and stable RNAseq T cell expression, while pt 3 had more CD8+ cells/mm2 and increased RNAseq T cel expression in the progressive lesion. Pts 4 and 5 (group C) had increased IFNγ scores as well, but lower RNAseq T cell expression in the progressive vs regressive lesions. Mutational profiles, based on DNA base changes, of pt 5 and 6 (group C) differed slightly between both lesions (14% and 4%, resp.) but tumor mutional burden (TMB) was much higher in the progressive lesions (540% and 429% increase, resp.). Pt 2 (group B) had similar mutational profiles between the lesions (2% difference) but a 35% decrease in TMB.
Patient group Patient Regressive lesion CD8+ cells/mm2 IFNγ score TMB level Progressive lesion CD8+ cells/mm2 IFNγ score TMB level A 1 Lymph node 314 0.64 - Lymph node 842 -1.30 - B 2 Cutis 1742 0.05 742 Adrenal gland 1629 0.53 482 B 3 Liver 225 -2.16 Cutis 521 -0.23 C 4 Cutis - 0.15 717 Cutis 1094 0.88 4588 C 5 Lymph node 172 -1.15 - Gall bladder 250 1.22 - C 6 Lymph node - - 169 Cutis - -0.39 894
Progressive lesions at a different site have greatly increased TMB, while the newly emerged lesion showed decrease in TMB. In both groups, mutational profile showed only a moderate change between regressive and progressive lesions.
The authors.
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C.U. Blank: Financial Interests, Institutional, Advisory Board: BMS, MSD, Roche, Novartis, GSK, AZ, Pfizer, Lilly, GenMab, Pierre Fabre; Financial Interests, Personal, Expert Testimony: Third Rock Ventures; Financial Interests, Personal, Stocks/Shares: Immagene; Financial Interests, Personal, Stocks/Shares, intention to develop IFN signature algorithm: NewCo, no name yet; Financial Interests, Institutional, Invited Speaker: BMS, Novartis, NanoString, 4SC; Other, Personal, Other, pending patent: WO 2021/177822 A1. All other authors have declared no conflicts of interest.