Circulating T Follicular Helper Cells as a Predictive Marker for Immunotherapy Response in Renal Cell Carcinoma
Abstract
Scientific Objective and Rationale: Kidney cancer is the 8th most common malignancy in the United States. Multiple immuno-oncology (IO)-based combination treatments have been approved by the Food and Drug Administration for first-line treatment of metastatic kidney cancer. However, there are no guidelines to direct which of these combinations should be assigned to individual patients. Between 29%-44% of patients do not respond to their assigned first-line IO-based therapy, and among these, about half are unable to go on to receive a second-line treatment due to clinical decompensation. There is critical need for a mechanism-based rationale for assigning patients the first-line systemic therapy with optimal efficacy for their individual cancers; however, there is little understanding of how IO combinations differ in their mechanisms of action. T follicular helper (Tfh) cells are immune cells that provide essential support for antibody production in lymph nodes; they play a critical role in allowing a long-term response to any immune provocation, including cancer. Importantly, Tfh cells have been found to infiltrate tumors and peripheral blood. Both intratumoral and peripheral blood Tfh cells have been linked with survival in multiple cancer types. Furthermore, it is likely that IO combination therapies differ in their stimulation of Tfh cells, suggesting that monitoring Tfh cell activity may offer a method for differentiating IO treatments. Despite this, the utility of Tfh cells for predicting treatment outcomes has not yet been explored. We propose a study of Tfh cell activity in patients with metastatic kidney cancer receiving IO therapy. The aims of our study will be twofold: First, to determine whether circulating Tfh (cTfh) cell activity can act as a peripherally accessible marker for intra-tumoral Tfh cell activity, thus validating cTfh cells as an indicator of intratumoral immune stimulation. Second, we will explore whether cTfh cell activity before or during treatment can predict response to different IO combination therapies. This work will play a critical role in advancing understanding of the cellular mechanisms underlying the function of IO combinations, and will contribute to the development of a paradigm by which individual patients can be stratified to their optimal systemic therapy. Applicability of this Research: This work is aimed at establishing cTfh cells as a marker to gauge patients immune response to IO treatment, and as a tool to predict responses to different IO combination regimens used for kidney cancer. The ultimate goal of this work is to lay the groundwork for the development of a method for stratifying patients with metastatic kidney cancer to their optimal therapeutic option. The projected timeframe for the experiments described herein is 12 months; at the conclusion of this study, we will have established the utility of baseline cTfh cell activity as a predictor for response to different IO combinations. The immediate next step would be the design of a clinical trial to validate a method for stratifying patients to their optimal first-line treatment based on baseline Tfh cell activity. The results of such a trial would have a direct impact on the treatment of all patients with metastatic kidney cancer and would be expected to improve outcomes by reducing each patient s risk of being assigned to an ineffective treatment regimen. Principal Investigator s Career Goals: I am a medical oncology fellow at Memorial Sloan Kettering Cancer Center, with special interests in kidney cancer, cancer immuno-metabolism, and overcoming mechanisms of resistance to immunotherapy. During my fellowship at MSKCC, I will be investigating novel immunotherapeutic approaches to renal cell carcinoma, under the direct co-mentorship of Drs. Robert Motzer, Chung-Han Lee, and David Knorr. This model will allow me to receive direct support in clinical, translational, and laboratory-based c
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210984
Entities
People
- Kelly Fitzgerald
Organizations
- Sloan-Kettering Institute
- United States Army