Tumor and Liquid Biopsy-based Biomarkers for Immunotherapy
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: Modulating the immune system in patients via immunotherapy to attack one’s cancer is one of the most important breakthroughs in cancer treatment in the past decade. While initial clinical trials have revealed exciting results in cancers such as lung and melanoma, its promise has not been fully realized in patients with metastatic breast cancer. Recent findings from clinical studies in early breast cancer, including from our own I-SPY 2 TRIAL, have shown more encouraging results. These studies demonstrated that aggressive cancer subtypes, e.g., triple-negative and HER2-positive breast cancer, appear to derive benefit from immunotherapy drugs, like pembrolizumab (an anti-PD-1 checkpoint inhibitor). Despite this initial success, immunotherapy has not been proven effective in a majority of breast cancer patients. 
 The goal of this proposed study is to try to identify features (biomarkers) of a woman’s tumor and her immune system that will tell doctors if immunotherapy will be the right treatment for her breast cancer. Knowing who will respond to these therapies will help in the selection of treatment that will be most effective for each woman. 
 The question(s) or central hypotheses of the research: How can we realize the potential benefit from immunotherapy in breast cancer? Which biomarkers can differentiate good responders from poor responders, and thus spare non-responding patients from therapy-related toxicities and enable them to proceed to other treatment modalities? 
 We hypothesize that a comprehensive approach to profiling of patients’ tumors and blood over the duration of therapy will yield molecular and cellular signatures associated with response and resistance to immunotherapy. 
 The general methodology: To address our hypothesis, we will comprehensively characterize immune landscapes in the tumor and blood of patients, and we will couple this information with available tumor- and blood-based molecular data. 
 We will examine the population of immune cells present in the tumor and in blood during the course of treatment. We will then compare immune landscapes between the two compartments (tumor vs. blood), and between patients who respond to therapy vs. those who did not. Next, we will perform an integrative analysis by combining immune cell profiling data with available tumor gene expression (RNA) and mutation data (DNA), as well as circulating tumor DNA (ctDNA) levels in the blood. These analyses will provide “high-resolution” cellular and molecular portraits of tumors, thereby generating a detailed analysis of candidate biomarkers of response. 
 Innovative elements of the project and potential impact: We will be utilizing state-of-the-art technologies that provide new ways of assessing the state of the immune system. For example, examination of immune cells in tumors will be performed using multiplex immunofluorescence microscopy, an innovative approach that enables simultaneous identification of more than a dozen immune cell types. This approach also allows for the examination of spatial relationship (the distance) between immune and tumor cells. We will also utilize cytometry time-of-flight (CyTOF) analysis, a recently developed method for robust classification of blood cells into different immune cell types. Another novel method is personalized ctDNA analysis, which involves the creation of a panel of tests based on patient-specific mutations to detect the presence or absence of tumor DNA fragments in the blood. 
 All these analyses will be performed on samples from I-SPY 2 patients who will receive both pembrolizumab and SD-101. SD-101 is a promising novel drug that has been shown to activate immune response when introduced locally in the tumor, thereby potentiating the anti-tumor effect of immuno-targeted drugs like pembrolizumab. 
 I-SPY 2 is a ground-breaking clinical trial that tests investigational drugs in the pre-operative setting. It uses an “adaptive” design to know whether a drug is effective or not, and therefore involves less time and fewer patients than a conventional trial. The end goal is to expedite the approval of promising drugs in breast cancer. 
 We anticipate that the synergy of immune and molecular profiles will provide a robust dataset to elucidate signatures associated with immunotherapy response. In addition, the development of blood-based biomarkers (immune cell and ctDNA profiles) will enable minimally-invasive and real-time disease monitoring that may capture on-going immune and molecular changes associated with cancer progression and treatment resistance.