Follicular Helper T Cells Predict Clinical Efficacy of PD-1 Inhibition in MIBC - Expert Commentary
However, efficacy and toxicity rates are highly variable across patients, therefore highlighting the need for biomarkers that can aid in predicting clinical benefit with this treatment modality. For instance, tertiary lymphoid structures (TLS) and mutations in certain genes were found to be associated with response to PD-1 inhibition. Follicular helper T cells (TFH) are known to play a role in TLS formation and tumor suppression. Goubet et al. carried out a single-arm, phase II trial (PANDORE) on MIBC patients treated with pembrolizumab to determine whether TFH status and other parameters may be used as biomarkers of patient response.
The final analysis included a total of 39 with localized MIBC, of whom 64% were cisplatin-ineligible and 36% declined chemotherapy. Patients underwent transurethral resection of bladder tumor (TURBT) followed by three cycles of pembrolizumab treatment before radical cystectomy. The median age in the cohort was 72 years and 74.4% were men. Most patients had a clinical stage of cT2 (82.1%) and cN0 (89.7%). Only two patients did not receive the planned three cycles of treatment due to adverse effects. Most adverse effects were classified as grade 1 and were experienced by 62% of patients. There were no patient deaths due to treatment. The median time between the third cycle of pembrolizumab and radical cystectomy was 16 days, with 34 out of 39 patients subsequently undergoing radical cystectomy. The overall pathologic complete response rate was 29.4% and the major pathologic response rate (downstaging) was 41.2%. The median follow-up time was 28.7 months at data cutoff. A total of 16 patients experienced relapse (6) or death (10). The median progression-free survival (PFS) time was 38.2 months. Overall survival was 94.1% in the first year and 78.9% in the second year, while median overall survival was not reached. DNA sequencing revealed that the presence of causal variants in both genes RB1 and TP53 was associated with pathologic complete response or major pathologic response. High tumor mutational burden was associated with longer PFS.
Goubet et al. subsequently performed an exploratory biomarker analysis. PD-L1 expression and tumor-infiltrating lymphocytes (TILs) data were obtained from TURBT (pre-treatment) and cystectomy (post-treatment). The density of CD8+ cells at both time points was associated with PFS while PD-L1 expression was not. After treatment, the proximity between CD8+ T cells and PD-L1+ cells was associated with longer PFS. The density of CD4+PD-1+ cells was correlated with the density of CD8+ cells at baseline.
Pembrolizumab led to coordinated association between density of TLS-like structures and CD8+ cells. TLS-like structures were similarly associated with PFS. Density of CD8+ cells was negatively correlated with major pathologic response. Analysis of expression of various markers in blood cells before, during, and after cystectomy revealed specific populations of T helper cells were associated with PFS at baseline and after treatment. The data also highlighted that pembrolizumab may preferentially activate TFH cells. Further analysis showed that central memory TFH cells were the most significant predictors of PFS at baseline while specific antibody-secreting cells were associated with PFS after treatment. Spatial analysis revealed that the accumulation of TFH cells in the vicinity of TLS-like structures at baseline was strongly associated with PFS at 24 months. Release of the chemokine CXCL13 was most strongly induced by pembrolizumab and its expression was associated with absence of progression at 24 months. Ex vivo experiments on patient samples confirmed that tumor TFH cells potentiate the response to pembrolizumab by coordinating anti-tumor activity with B cells and CD8+ cells. Since intra-tumoral microbiota can affect tumor progression, researchers then evaluated the presence of bacterial species in tumor samples. The presence of E. coli, which is known to invade urothelial tissue, was detected in 70% of samples. Bacterial-specific T helper and TFH memory T cell responses were impacted by pembrolizumab and CXCL13-producing TFH responses against E. coli (but not other bacterial species) were associated with absence of progression at 24 months. Finally, E. coli IgG titers were associated with long-term response to pembrolizumab.
These findings reveal that TFH cells are crucial targets of pembrolizumab as they help coordinate various cell types to activate anti-tumor responses. The activity of these cells is dependent on CXCL13 release and is strongly associated with E. coli immunogenicity. The responses of TFH cells against tumor or bacterial antigens can therefore represent biomarkers for immune checkpoint blockade therapies. These results can be validated in a larger cohort and in relation to a control group.
Written by: Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine
References:
Read the Abstract