EAU 2018: Systemic Immunotherapy in Urological Cancers: Basics and Beyond - What We Need to Know
Dr. Bedke starts his lecture by providing a quick summary of the mechanism behind checkpoint blockade inhibitors. He describes the cancer immunity cell cycle which involves T-cell activation, T-cell extravasation into cancer tissues, the interaction of T-cell with the tumor, tumor killing by the TcCell and lastly further activation of more T-cells. Immune cancer therapy can have an effect in any of these steps, and some of them have been used in the past with some success such as IL-2 for RCC and Provenge for PCa. Checkpoint blockade works during the T-cell-tumor interaction step by allowing the T-Cell to recognize the cell as pathologic, creating a cascade of tumor killing, neoantigen release, and further T-Cell activation.
The PD-1/L1 pathway is one of many checkpoint mechanism and to date remains the most studied and targeted. However, there are several other checkpoint mechanisms that are currently being targeted such as the IDO, ICOS and RGMb pathways. Several inhibitors are currently available for targeting some of these pathways (Ipilimumab: CTLA-4) and are currently being a used as adjuncts for PD-1/L1 blockade therapy. These immune therapy combinations have the potential to dramatically improve responses since the phenotype of tumor-infiltrating lymphocytes (TILs) can be quite varied with only a small subset of TILs expressing PD-1. A study by the author (Eur Urol 2017), showed that in RCC only 8.5% of the TILs expressed PD-1, with a smaller but significant percentage showing CTLA-4 expression. This finding is leading the way into combination trials such as the CheckMate 214 which used Nivolumab (PD-1 Inhibitor) and Ipilimumab (CTLA-4 inhibitor) for the treatment of patients with metastatic RCC in the 1st line setting, with unprecedented complete response rates in patients with intermediate and poor risk factors.
Mutational load has been found to be highly correlated with response to checkpoint blockade. The theory behind this phenomenon is that mutational load is highly associated with higher neoantigen release which allows for easier recognition of the immune system of tumor as foreign. While urothelial carcinoma has been found to have high mutational load the same cannot be said for RCC. In RCC the mutational load is quite low, and this might explain the smaller subset of patients that achieve a durable complete or partial responses. Study of this subset of patients in RCC that achieve complete and durable responses have shown a link to mutations in the PBRM1 gene complex. The Van Allen group at Harvard (Science 2018), recently published their work that showed that clinical benefit (n=35 patients) was associated with loss-of-function mutations in the PBRM1 gene (P = 0.012), which encodes a subunit of the PBAF switch-sucrose nonfermentable (SWI/SNF) chromatin remodeling complex. The finding was confirmed in an independent validation cohort of 63 ccRCC patients treated with PD-1 or PD-L1 (PD-1 ligand) blockade therapy alone or in combination with anti-CTLA-4 (therapies (P = 0.0071). Gene-expression analysis of PBAF-deficient ccRCC cell lines and PBRM1-deficient tumors revealed altered transcriptional output in JAK-STAT, hypoxia, and immune signaling pathways.
Lastly, combination therapy with anti-VEGF inhibitors have shown promise in the lab and recently in the clinical setting. VEGF-inhibitors have been found to inhibit maturation of dendritic cells, promote immune suppressive cell infiltration and enhance immune checkpoint molecules expression. Moreover, a recent study by Nadal et al (ESMO 2017), reviewed the TIL phenotype of patients treated with cabozantinib, which showed a significant decrease in the percentage of T-Regulatory cell (Tregs) present in the tumor infiltrate, which had been previously associated with decreased response to PD-1 therapy. Several phase I/II trials are now ongoing in RCC assessing the added value of anti-VEGF inhibitors to checkpoint therapy.
In summary, immune evasion of one of the hallmarks of cancer progression and is now being challenged with the use of checkpoint blockade therapies. The introduction of checkpoint inhibitors has revolutionized the treatment of several malignancies over the last 10 years, and novel combinations are currently being studied to further maximize their anti-neoplastic properties.
Speaker: J. Bedke, Department of Urology, University of Tübingen (Germany)
Written by: Andres F. Correa, MD, Urologic Oncology Fellow, Fox Chase Cancer Center, Philadelphia, PA, at the 2018 European Association of Urology Meeting EAU18, 16-20 March, 2018 Copenhagen, Denmark