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Successful Treatment of HIV-Associated Kaposi Sarcoma with Immune Checkpoint Blockade.

ABSTRACT: Kaposi sarcoma (KS) is an incurable, human immunodeficiency virus (HIV)-associated malignancy. We reviewed 320 immunotherapy-treated patient records. Seventeen had HIV-associated malignancies, including nine men with KS. Median viral load was 20 copies/mL (range, undetectable to 549,704) and median CD4 count was 256 cells/?L (range, 10-603). Eight patients received nivolumab and one received pembrolizumab. Six patients (67%) achieved partial (N = 5) or complete remission (N = 1). No drug-related grade >2 toxicities occurred. In seven patients, CD4 counts increased (P = 0.09). Tissue and/or blood-derived circulating tumor DNA (ctDNA) was evaluated by next-generation sequencing. Four evaluable patients each showed anomalies in distinct genes: TP53, KRAS, TLL2, PTPN6 (tissue and/or ctDNA), and NF1 (ctDNA). Tumor mutational burden was low, and PD-L1 immunohistochemistry was negative (three and four assessable patients, respectively). Responders included patients with low CD4 counts, high HIV load, and/or visceral disease. In summary, checkpoint blockade demonstrated significant antitumor activity and low toxicity in patients with HIV-associated KS. Cancer Immunol Res; 6(10); 1129-35. ©2018 AACR.

SUBMITTER: Galanina N

PROVIDER: S-EPMC6248326 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Project description:Intra-host tumor virus variants may influence the pathogenesis and treatment responses of some virally-associated cancers. However, the intra-host variability of Kaposi sarcoma-associated herpesvirus (KSHV), the etiologic agent of Kaposi sarcoma (KS), has to date been explored with sequencing technologies that possibly introduce more errors than that which occurs in the viral population, and these studies have only studied variable regions. Here, full-length KSHV genomes in tumors and/or oral swabs from 9 Ugandan adults with HIV-associated KS were characterized. Furthermore, we used deep, short-read sequencing using duplex unique molecular identifiers (dUMI)-random double-stranded oligonucleotides that barcode individual DNA molecules before library amplification. This allowed suppression of PCR and sequencing errors to ~10-9/base as well as afforded accurate determination of KSHV genome numbers sequenced in each sample. KSHV genomes were assembled de novo, and rearrangements observed were confirmed by PCR and Sanger sequencing. 131-kb KSHV genome sequences, excluding major repeat regions, were successfully obtained from 23 clinical specimens, averaging 2.3x104 reads/base. Strikingly, KSHV genomes were virtually identical within individuals at the point mutational level. The intra-host heterogeneity that was observed was confined to tumor-associated KSHV mutations and genome rearrangements, all impacting protein-coding sequences. Although it is unclear whether these changes were important to tumorigenesis or occurred as a result of genomic instability in tumors, similar changes were observed across individuals. These included inactivation of the K8.1 gene in tumors of 3 individuals and retention of a region around the first major internal repeat (IR1) in all instances of genomic deletions and rearrangements. Notably, the same breakpoint junctions were found in distinct tumors within single individuals, suggesting metastatic spread of rearranged KSHV genomes. These findings define KSHV intra-host heterogeneity in vivo with greater precision than has been possible in the past and suggest the possibility that aberrant KSHV genomes may contribute to aspects of KS tumorigenesis. Furthermore, study of KSHV with use of dUMI provides a proof of concept for utilizing this technique for detailed study of other virus populations in vivo.

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Successful Treatment of HIV-Associated Kaposi Sarcoma with Immune Checkpoint Blockade.

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