Use of plasma ctDNA as a potential biomarker for longitudinal monitoring of a patient with metastatic high-risk upper tract urothelial carcinoma receiving pembrolizumab and personalized neoepitope-derived multipeptide vaccinations: a case report

Abstract

Upper tract urothelial carcinoma (UTUC) is often diagnosed late and exhibits poor prognosis. Only limited data are available concerning therapeutic regimes and potential biomarkers for disease monitoring. Standard therapies often provide only insufficient treatment options. Hence, immunotherapies and complementary approaches, such as personalized neoepitope-derived multipeptide vaccine (PNMV), come into focus. In this context, genetic analysis of tumor tissue by whole exome sequencing represents an essential diagnostic step in order to calculate tumor mutational burden (TMB) and to reveal tumor-specific neoantigens. Furthermore, disease progression is essential to be monitored. Longitudinal screening of individually known mutations in plasma circulating tumor DNA (ctDNA) by the use of next-generation sequencing and digital droplet PCR (ddPCR) might be a promising method to fill this gap.Here, we present the case of a 55-year-old man who was diagnosed with high-risk metastatic UTUC in 2015. After initial surgery and palliative chemotherapy, he developed recurrence of the tumor. Genetic analysis revealed a high TMB of 41.2 mutations per megabase suggesting a potential success of immunotherapy. Therefore, in 2016, off-label treatment with the checkpoint-inhibitor pembrolizumab was started leading to strong regression of the disease. This therapy was then discontinued due to side effects and treatment with a previously produced PNMV was started that induced strong T cell responses. During both treatments, plasma Liquid Biopsies (pLBs) were performed to measure the number of mutated molecules per mL plasma (MM/mL) of a known tumor-specific variant in the MLH1 gene by ddPCR for longitudinal monitoring. Under treatment, MM/mL was constantly zero. A few months after all therapies had been discontinued, an increase of MM/mL was detected that persisted in the following pLBs. When MRI scans proved tumor recurrence, treatment with pembrolizumab was started again leading to a rapid decrease of MM/mL in the pLB to again zero. Treatment response was then also confirmed by MRI.This case shows that use of immunotherapy and PNMV might be a promising treatment option for patients with high-risk metastatic UTUC. Furthermore, measurement of individually known tumor mutations in plasma ctDNA by the use of pLB could be a very sensitive biomarker to longitudinally monitor disease.

The mutational pattern of homologous recombination repair genes in urothelial carcinoma and its correlation with immunotherapeutic response

“…Therefore, neoantigen‐based combination therapy may be a promising approach for UC patients with HRR alterations. A previous study reported a personalized neoepitope‐derived multipeptide vaccine complementary with immunotherapy (pembrolizumab), which induced very strong CD4+ as well as CD8+ T cell responses in patients with metastatic UC 53 . A phase Ib trial in patients with high TMB metastatic tumors demonstrated that personalized neoantigen vaccine plus anti‐PD‐1 induced neoantigen‐specific CD4+ and CD8+ T cell responses, with antitumor capability 54 …”

Consultation on UTUC II Stockholm 2022: diagnostic and prognostic methods—what’s around the corner?

“…Analysis of the gene mutational profile of tumour tissue and liquid biopsies is a growing field, and much work have been done on both UCB and UTUC. Genetic markers have been identified and analyzed in different sample types (RNU specimens, URS biopsies, liquid biopsies) [ 25 , 26 , 29 , 31 , 37 ] and have been studied both in a pre-treatment diagnostic/prognostic setting and a monitoring setting [ 27 , 38 , 39 ]. For UTUC no single genetic marker has yet been identified, but studying patterns of gene mutations or gene expression seems to be the way forward.…”

“…cfDNA in urine can be used for the diagnosis of UTUC [ 37 ]. ctDNA in plasma was used for disease monitoring in a case report by Blumendeller et al [ 38 ]. A recent study on UTUC by Nakano et al [ 39 ] showed that a high fraction of preoperative ctDNA and sustained ctDNA postoperatively were associated with a worse prognosis.…”

Application of Data Science in Circulating Tumor DNA Detection: A Promising Avenue Towards Liquid Biopsy

“…The increased concentration of ctDNA could identify patients with cancer from healthy cohorts and stratify patients in the early and advanced stages ( 16 ). Besides, the changes in ctDNA levels before and after drug treatment are related to the therapeutic effect for patients ( 17 ). Furthermore, for tumor-free patients after treatment, the concentration level of ctDNA indicates the risk of cancer recurrence ( 18 ).…”