Genomic and Commensal Variants Associated with Immunotherapy in Cancer Patients
Abstract
The recent development of broadly effective immunotherapies is revolutionizing cancer treatment however currently only approximately 25% of patients benefit. Our group has proposed a model known as the “T cell-inflamed tumor microenvironment” that can be defined by a technique known as gene expression profiling and this model has been closely associated with optimal clinical response to immunotherapy. As immunotherapy treatment is predicated on the immune system, we hypothesize that factors influencing the immune system could function on at least three levels, including (1) differences (mutations) in cancer cells compared with normal cells, (2) variation (polymorphisms) in the way normal genes are turned on and off in individual cancer patients, and (3) environmental differences between individual cancer patients (microbiota). Our group has developed preliminary data around each of these in melanoma, notably including the first cancer specific molecular change (WNT/beta-catenin) that leads to exclusion of immune cells from the tumor as well as the first bacteria (Bifidobacterium) that is closely associated with the T cell-inflamed tumor microenvironment. The objectives of this research will be to extend this model to patients with cancer of all types who are receiving immunotherapy. We will first apply large-scale bioinformatic research techniques to an existing database (The Cancer Genome Atlas or TCGA) to identify molecular pathways in other cancer types followed by biological confirmation in archived cancer specimens at our institution. We will additionally complete the development of a large multi-institutional biorepository (including tumor, blood, and fecal materials) and apply large-scale genomic analyses of these samples looking for associations with the T cell-inflamed tumor microenvironment. The career goals of the Principal Investigator, Jason Luke, M.D., include translational investigation of factors influencing immunotherapy response and new immunotherapy drug development to improve the outcomes of patients with cancer. Dr. Luke has developed a robust developmental immunotherapy clinical trials program at the University of Chicago. To expand the translational impact of his work, he has begun to develop expertise in bioinformatics and create scientific collaborations to support large-scale analysis of patients with cancer receiving immunotherapy. This award will allow Dr. Luke to robustly pursue these translational endeavors. Upon completion of this research, Dr. Luke will be positioned to propose the higher level questions to drive immunotherapy research forward and will be positioned as a leader in the field. The translational research proposed here has broad applicability being relevant to any patient with cancer and perhaps other diseases in which regulation of the immune system is important (rheumatology and others). Results of this research will be immediately relevant for cancers in which immunotherapy is known to help some but not all patients (lung, head and neck, kidney and bladder cancers, as well as melanoma). Our research will suggest mechanisms mediating lack of effectiveness in some patients and promote combination approaches for immediate investigation in clinical trials. This includes both drugs as well as environmental and lifestyle interventions. Our approach minimizes patient risk as we will initially use bioinformatics on data already obtained from patients (i.e., TCGA) followed by analysis of biospecimens that would be obtained either in a noninvasive manner or as part of standard of care patient treatment. The projected timeframe for our research is 3 years, including approximately 2 years for bioinformatics and the development of the biorepository, followed by a year of analysis on the obtained specimens. As we have already launched clinical trials based on our findings in melanoma, we expect to generate clinically relevant data throughout the grant period. We believe
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710265
Entities
People
- Jason J Luke
Organizations
- United States Army
- University of Chicago