Eur Urol: In patients with non-muscle-invasive bladder cancer, T cell depletion and elevated levels of tumor DNA in the urine are associated with BCG treatment failure

In patients with high-risk non-muscle-invasive bladder cancer, the functional status and tumor characteristics of immune cells in the tumor microenvironment may explain the failure
of BCG (NMIBC) therapy.

Researchers from Denmark recently published an article in Eur Urol, in which the researchers identified the factors associated with the recurrence of high-grade (HG) after BCG treatment through multi-omics analysis.

BCG-treated patients with NMIBC (n = 156)
were included in the study.
The researchers analyzed heterochronous tumor samples
using RNA sequencing (n=170) and whole exome sequencing (n=195).
Urine samples were used to analyze immuno-oncology-related proteins (n=190) and tumor-derived DNA (tdDNA; n=187）
。 The primary endpoint of the study was HG recurrence
after BCG.
The analysis was performed
using Cox regression and Wilcoxon's rank sum, t, and Fisher exact tests.

The results of the study found that BCG induces the activation of the immune system regardless of the clinical response; However, after BCG treatment, immunosuppressive proteins (CD70, PD1, CD5)
were observed in the urine of patients with recurrent HG.
HG recurrence after BCG treatment was associated with T cell failure after BCG treatment (P=0.
002).

In patients with T cell failure after BCG treatment, they had high expression
of genes related to cell division and immune function in their tumors before BCG treatment.
In addition, a higher BCG failure score before BCG treatment was associated with a poorer recurrence-free survival rate for HG after BCG (HGRFS; p=0.
002), and verified in a separate queue
.
Before BCG treatment, grade 2a and 2b tumors (URMOL2021 regimen) were associated with worsening of HGRFS after BCG treatment (p=0.
015).

Post-BCG failure
was also observed in patients with high BCG neoantigen load (p=0.
017) and MUC4 mutation (p=0.
002) before BCG treatment.
Finally, if tdDNA is not cleared after BCG treatment, it can be identified as a high-risk patient for recurrence (p=0.
018).

Study limitations were retrospective design and partially overlapping analyses
.

T cell exhaustion analysis

In summary, HG recurrence after BCG treatment may be caused by
T cell failure.
Tumor subtypes and tumor characteristics prior to BCG treatment identify patients
at high risk of HG recurrence after BCG treatment.
Urinalyscopy has the potential to provide real-time assessment of treatment response.

Original source:

Trine Strandgaard， Sia Viborg Lindskrog， Iver Nordentoft et al.
Elevated T-cell Exhaustion and Urinary Tumor DNA Levels Are Associated with Bacillus Calmette-Guérin Failure in Patients with Non-muscle-invasive Bladder Cancer.
Eur Urol.
Oct 2022