Improving Anti-PD-1/PD-L1 Therapy for Localized Bladder Cancer

Abstract

In high-risk non-muscle invasive bladder cancer (HR-NMIBC), patient outcome is negatively affected by lack of response to Bacillus-Calmette Guérin (BCG) treatment. Lack of response to cisplatin-based neoadjuvant chemotherapy and cisplatin ineligibility reduces successful treatment outcomes in muscle-invasive bladder cancer (MIBC) patients. The effectiveness of PD-1/PD-L1 immune checkpoint inhibitors (ICI) in metastatic disease has stimulated its evaluation as a treatment option in HR-NMIBC and MIBC patients. However, the observed responses, immune-related adverse events and high costs associated with ICI have provided impetus for the development of methods to improve patient stratification, enhance anti-tumorigenic effects and reduce toxicity. Here, we review the challenges and opportunities offered by PD-1/PD-L1 inhibition in HR-NMIBC and MIBC. We highlight the gaps in the field that need to be addressed to improve patient outcome including biomarkers for response stratification and potentially synergistic combination therapy regimens with PD-1/PD-L1 blockade.

Keywords: BCG-unresponsive; PD-1; PD-L1; bladder cancer; immune checkpoint inhibition; neoadjuvant chemotherapy.

Figure 1

PRISMA flow diagram of evidence acquisition.

Figure 2

Hypothesized mechanisms of combination treatments to improve clinical response to anti-PD-1/PD-L1 treatments in localized bladder cancer patients. (A) Platinum-Based Chemotherapy (PBC) and/or radiation prompts tumor cell death. This process attracts Antigen Presenting Cells (APC), which upregulate presentation of tumor-specific neoantigens to cytotoxic T cells. Activation via IFN-γ released in the tumor microenvironment stimulates anti-tumor immunity. Direct effects of DNA damage by PBC and radiation cause upregulated expression of PD-L1 and MHC in tumor cells. (B) CTLA-4 checkpoint inhibitors block CTLA-4 on CD8+ T cells and T regulatory (T reg), thereby further stimulating CD28–CD80/CD86 T cell co-stimulatory responses and anti-tumor immunity. (C) Genomic instability is observed in tumor cells, especially in patients with BRCA alterations. The inability to restore DNA damage with blockade of PARP, normally used for DNA repair, leads to more somatic mutations, a higher Tumor Mutational Burden (TMB) and more tumor-specific neoantigens. Neoantigens are presented by Antigen Presenting Cells (APC) to provoke additional cytotoxic T cell responses. (D) Blockade of VEGF and TGF-β excreted by the tumor prevents activation of T regulatory cells (T reg) and Myeloid Derived Suppressor Cells (MDSC) that caused an immunosuppressive microenvironment. Inhibition of DDR2 prevents development of Cancer Associated Fibroblasts (CAFs), which stimulated metastases and yielded additional immune suppressive effects and increased CD8+ T cell infiltration.