Mechanism-Based Approach for Combination Therapies with Immune Modulation for Management of Patients with Urothelial Cancers of the Upper Urinary Tract
Abstract
Upper tract urothelial carcinoma (UTUC) is a highly lethal cancer that affects the lining of the ureters and renal pelvis. Though similar histologically to urothelial carcinoma of the bladder, key genetic differences found in upper tract tumors suggest a distinct mutational landscape that leads to a unique disease course. UTUC is an aggressive cancer, typically presenting with a higher rate of invasive disease than urothelial carcinoma of the bladder, leading to significant challenges for urologists and medical oncologists who manage this disease. The “gold standard” for UTUC treatment remains a procedure called radical nephron-ureterectomy, in which the kidney, ureter, and a cuff of bladder tissue are removed. However, this frequently debilitating operation leads to Stage 3 chronic kidney disease or end-stage renal disease in four-fifths of patients. Radical nephron-ureterectomy can be avoided in select cases by using the less invasive procedure of endoscopic tumor destruction. However, there is a higher rate of disease recurrence after this endoscopic procedure compared to the radical surgery (60% vs 30%, respectively). There is an urgent need for additional research to better characterize UTUC tumors in order to develop effective and less debilitating treatment modalities. There have been numerous studies evaluating UTUC that have focused on genomic sequencing of tumor tissue specimens from nephron-ureterectomy, but this approach fails to take into account the tumor microenvironment: highly complex interactions between different tumor cells and associated immune cells that can predict the aggressiveness of the tumor and its response to therapies. Preliminary data from our group has indicated that the immune system plays a significant role in response to both systemic therapies and ablative techniques. The principal objective of this proposed research is to characterize the tumor and immune landscape of UTUC in order to develop more effective immune-based therapies. We will leverage the high volume of this disease at our institution in order to perform comprehensive sequencing of genetic material (from tumor tissue, blood, and urine specimens) using techniques that allow us to evaluate both the genes and their expression products. Single-cell RNA sequencing, a relatively new technology that allows us to define the intratumoral heterogeneity by studying subpopulations of tumor and immune cells, will be used in combination with bulk DNA and RNA sequencing. This will be complemented with immunohistochemical staining in order to better characterize the role that the immune system plays in the tumor microenvironment. We will also correlate our findings from the tissue sequencing with detection of clinically relevant tumor characteristics from urine samples. Development of improved noninvasive testing will substantially lessen the burden of the invasive diagnostics that are involved in UTUC evaluation. We will then evaluate the effect of our endoscopic ablative treatments, using vascular-targeted photodynamic therapy, on the local immune response. In the near future, we are planning a Phase 2 UTUC clinical trial that will combine two less invasive treatments: immunotherapy and ablation with vascular-targeted photodynamic therapy. In order to choose the optimal immunotherapy for this trial, we need to understand more about the immune landscape of UTUC, including how it is affected by vascular-targeted photodynamic therapy. The proposed research will provide us with information that is urgently needed to develop more effective treatment for UTUC.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010722
Entities
People
- Jonathan Coleman
Organizations
- Sloan-Kettering Institute
- United States Army