Using Single-Cell Transcriptomics to Understand Tumor and Immune Heterogeneity Driving Resistance to Immune Therapy in Advanced RCC
Abstract
Kidney cancer (also known as renal cell cancer, or "RCC") is one of the 10 most common cancers in the United States, and one of the 5 most commonly diagnosed cancers in the VA system. Each year, over 60,000 people are newly diagnosed with RCC and 14,000 patients die from the disease. One-third of patients either have at the time of diagnosis, or ultimately develop, disease spread to distant areas of the body (called "advanced" kidney cancer). While there have been many new therapies developed for patients with advanced kidney cancer over the past decade, still only 8% to 12% of patients with advanced kidney cancer live for 5 years or longer. Recently, a new type of therapy, called immune checkpoint blockade (or "CPB"), has shown considerable success in the treatment of patients with advanced RCC. These therapies work by "removing the brakes" on the immune system, allowing a patient s immune cells to recognize and, in some cases, eliminate kidney cancer cells throughout the body. One such therapy, called nivolumab (or "nivo"), is already approved as a second-line treatment (after a patient s cancer has grown on another therapy), and the combination of nivo with another immune checkpoint blocking drug called ipilimumab (or "ipi"), is poised to become the dominant first-line treatment option for patients with advanced kidney cancer. This clinical progress raises several fundamental questions with direct impact on patient clinical care: (1) Can we identify in advance which patients will benefit from nivo therapy? (2) Can the combination of nivo + ipi work in patients who fail to respond to single agent nivo therapy and, if so, in which patients? To address these important questions we have launched a clinical trial of first-line nivo therapy, and if no response, then combination nivo + ipi, in patients with advanced RCC (the HCRN GU16-260 trial). This trial will also allow us to study each patient s tumor in the laboratory, where we hope to identify features of the tumor (biomarkers) that will allow us to predict in advance which patients will benefit from single agent nivo therapy, which patients need the combination of nivo + ipi, and which patients will not benefit from either treatment. However, despite the ability of CPB therapies to lengthen the lives of patients with kidney cancer, over half the patients have disease that is resistant to these treatments. Thus, in addition to identifying which patients will benefit from single agent and combinations of CPB drugs (like nivo and ipi), a fundamental challenge is to understand why certain patients tumors are resistant to treatment and then to design combinations of therapies to overcome this resistance so that more patients with RCC can benefit from CPB therapies. Patients can be resistant to CPB therapies for many reasons, including the presence of individual resistant tumor cells, or dysfunction in the patient s immune response to the tumor. Traditional laboratory methods for analyzing tumors average the effects of all cells (tumor and immune) together -- meaning the effects of individual resistant tumor cells or dysfunctional immune cells are obscured in the analysis. This problem is particularly relevant to kidney cancer, which is characterized by remarkable variability in both its tumor cell and immune cell components. A new technology called single-cell RNA-sequencing (or "scRNA-seq") can overcome this obstacle. ScRNA-seq provides a unique ability to define the composition and function of tumor and immune subpopulations within the tumor mass and understand the role individual cells play in response and resistance to CPB therapy. In this grant proposal, we aim to use scRNA-seq to dissect and analyze individual tumor and immune cells using tumor samples collected from the HCRN GU16-260 clinical trial. We will integrate our analysis of individual cells with information about each patient s response (or resistance) to nivo therapy. Through this analysis, we aim t
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810367
Entities
People
- Catherine Wu
Organizations
- Dana–Farber Cancer Institute
- United States Army